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Weng B, Braaten M, Lehn J, Morrissey R, Asghar MS, Silberstein P, Abdul Jabbar AB, Mathews A, Tauseef A, Mirza M. Survival and treatment of stage IV renal cell carcinoma in academic vs non-academic medical centers. World J Nephrol 2025; 14:103923. [DOI: 10.5527/wjn.v14.i2.103923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/22/2025] [Accepted: 02/08/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Renal cell carcinoma (RCC) is treated with surgical resection as the gold standard, as it is notoriously resistant to systemic therapy. Advancements with targeted therapies contribute to declining mortality, but metastatic RCC (mRCC) survival remains poor. One possible factor is treatment at academic centers, which employ advanced providers and novel therapies. This study compared outcomes of mRCC in patients treated at academic/research facilities compared to those treated at non-academic centers.
AIM To compare survival outcomes of mRCC and their various etiologies between academic and non-academic centers.
METHODS The National Cancer Database was used to identify mRCC patients including all histology subtypes and stage IV disease. Descriptive statistics and Kaplan-Meier curves measured survival outcomes for user file facility types sorted into a binary academic/research and non-academic research variable. Multivariate logistic regression and Cox proportional hazard testing generated odds ratio and hazard ratio. Data was analyzed using Statistical Package for the Social Sciences version 29.0 using a significance level of P < 0.05.
RESULTS Overall, academic facility patients experienced greater 5-year and 10-year overall survival than non-academic facility patients. Treatment at non-academic facilities was associated with increased odds of death that persisted even after controlling for age, tumor size, sex, and distance traveled to treatment center. In comparison, non-academic facility patients also experienced greater risk of hazard.
CONCLUSION Patients with mRCC treated at academic/research facilities experienced increased survival compared to patients treated at non-academic facilities, were more likely to be younger, carry private insurance, and come from a large metropolitan area. They also were significantly more likely to receive surgery and adjuvant immunotherapy.
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Affiliation(s)
- Bob Weng
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Marco Braaten
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Jenna Lehn
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Reid Morrissey
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Muhammad Sohaib Asghar
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, United States
| | - Peter Silberstein
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Ali Bin Abdul Jabbar
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Abraham Mathews
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Abubakar Tauseef
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Mohsin Mirza
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
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2
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Agrawal M, Chowhan AK. Paediatric renal tumors: An insight into molecular characteristics, histomorphology and syndromic association. World J Nephrol 2025; 14:99380. [DOI: 10.5527/wjn.v14.i2.99380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 04/09/2025] Open
Abstract
Paediatric renal tumors are rare and accounts for about 7% of all paediatric malignant tumors. The spectrum of paediatric renal tumors ranges from benign to malignant. Benign tumors include cystic nephroma, metanephric tumors and ossifying renal tumor of infancy. Tumor with low grade malignancy includes mesoblastic nephroma. Malignant tumors are nephroblastoma, clear cell sarcoma, malignant rhabdoid tumor, anaplastic sarcoma and Ewing sarcoma. Additionally, there are molecularly defined renal tumors, which includes renal cell carcinoma (RCC) with MiT translocations, ALK-rearranged RCC, eosinophilic solid and cystic RCC and SMARCB1- deficient renal medullary carcinoma. These tumors apart from having characteristic clinical presentation and histomorphology, also carry typical molecular mutations and translocations. Certain renal tumors have association with various genetic syndromes such as Beckwith-Weidmann syndrome, Wilm’s tumor, aniridia, genitourinary anomalies and mental retardation syndrome, Denys-Drash syndrome, rhabdoid tumor predisposition syndrome and DICER syndrome. This review article focusses on molecular characteristics, histomorphology and syndromic association of pediatric renal tumors, their immunohistochemical approach to diagnosis with recent updates in molecularly defined renal tumors.
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Affiliation(s)
- Mousmi Agrawal
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences (AIIMS), Raipur 492099, Chhattisgarh, India
| | - Amit K Chowhan
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences (AIIMS), Raipur 492099, Chhattisgarh, India
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3
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Marletta S, Caliò A, Pierconti F, Harada S, Netto GJ, Antonini P, Segala D, Pedron S, Marcolini L, Stefanizzi L, Martignoni G. SFPQ::TFE3-rearranged PEComa: Differences and analogies with renal cell carcinoma carrying the same translocation. Pathol Res Pract 2025; 270:155963. [PMID: 40239600 DOI: 10.1016/j.prp.2025.155963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/23/2025] [Accepted: 04/08/2025] [Indexed: 04/18/2025]
Abstract
Among perivascular epithelioid cell neoplasms (PEComas), some tumors have been found to carry rearrangements of the TFE3 gene. Such tumors can rarely occur in the kidney, closely resembling TFE3-rearranged renal cell carcinoma. This study describes one additional case of TFE3-rearranged PEComa, two TFE3-rearranged renal cell carcinomas, and a detailed literature review. All three tumors were composed of nested clear to eosinophilic cells with peculiar morphological findings in each case. By immunohistochemistry, PEComa expressed cathepsin K, HMB45, and CD68 (PG-M1), while labeling negative for PAX8, Melan-A, S100, smooth muscle actin, desmin, CD10, CD13, and keratins 7 and AE1/AE3. Conversely, both TFE3-rearranged renal cell carcinomas were positive for PAX8, HMB45, and CD10, alongside staining negative for CD68 (PG-M1), Melan-A, CD13, and keratins. One of them expressed cathepsin K. TFE3 gene rearrangement was identified in all three cases by FISH, along with SFPQ::TFE3 fusion by molecular analysis. Our cases, combined with a comprehensive literature review, highlight several key differences and similarities: SFPQ::TFE3-rearranged PEComas lack the pseudorosettes frequently observed in SFPQ::TFE3-rearranged renal cell carcinoma, although both may exhibit nested epithelioid morphology. Both tumor types can be positive for cathepsin K and melanogenesis markers and negative for smooth muscle markers. However, PAX8, keratins, and CD10 were expressed in TFE3-rearranged renal cell carcinoma while CD68(PG-M1) was positive in PEComa. Notably, the SFPQ gene is the most common fusion partner in TFE3-rearranged PEComas, while it is the third most frequent one in TFE3-rearranged renal cell carcinoma. Nevertheless, the exon breakpoints are analogous in both tumor types.
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Affiliation(s)
- Stefano Marletta
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Italy; Division of Pathology, Humanitas Istituto Clinico Catanese, Catania, Italy
| | - Anna Caliò
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Italy
| | - Francesco Pierconti
- Division of Anatomic Pathology and Histology, Foundation "A. Gemelli" University Hospital, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Shuko Harada
- Division of Genomic Diagnostics & Bioinformatics, Department of Pathology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - George J Netto
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Pietro Antonini
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Italy
| | - Diego Segala
- Department of Molecular and Translational Medicine, Section of Pathology, University-Spedali Civili of Brescia, Brescia, Italy
| | - Serena Pedron
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Italy
| | - Lisa Marcolini
- Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy
| | | | - Guido Martignoni
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Italy; Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy.
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4
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Shin D, Lim B, Song C, You D, Jeong IG, Hong JH, Ahn H, Hong B, Jeong CW, Han JH, Suh J. Comparative analysis of oncologic outcomes in surgically treated patients with renal cell carcinoma and renal vein thrombosis by pathologic subtypes. Sci Rep 2025; 15:15946. [PMID: 40335555 PMCID: PMC12059190 DOI: 10.1038/s41598-025-00452-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 04/28/2025] [Indexed: 05/09/2025] Open
Abstract
This study compares recurrence-free survival (RFS) and overall survival (OS) in patients with non-clear cell (nccRCC) and clear cell renal cell carcinoma (ccRCC) undergoing surgical nephrectomy with thrombectomy (SNTx) for RCC with venous thrombus. Data from patients who underwent SNTx at two tertiary centers (June 1990-December 2022) were retrospectively reviewed. Patients were grouped as ccRCC or nccRCC and stratified by metastasis status at surgery. Primary endpoints were RFS and OS for metastasis-naive RCC and OS for the entire cohort, including both metastasis-naive and metastatic RCC. Kaplan-Meier analysis with log-rank tests and adjusted multivariable Cox proportional hazards models were performed, with TN adjustments for the metastasis-naive group and TNM adjustments for the entire population. Among 604 patients, 504 (83.5%) were ccRCC. In nccRCC, 44 (44.0%) were papillary, 17 (17.0%) were chromophobe, and 39 (39.0%) were rare subtypes, most commonly TFE3 rearranged RCC, followed by the RCC not otherwise specified subtype (according to the 2022 World Health Organization Classification of RCC). Median OS was 85.8 months for ccRCC, 37.7 for papillary, 90.2 for chromophobe, and 16.9 for rare subtypes. Rare RCC histology was significantly associated with worse RFS (HR 1.63, p = 0.038) and OS (HR 1.82, p = 0.039) in metastasis-naive RCC. For the entire cohort including metastatic diseases, rare subtypes had worse OS (HR 2.20, p < 0.001), while other nccRCC subtypes did not differ significantly from ccRCC in OS. In patients with RCC with venous thrombosis, rare nccRCC subtypes exhibited poorer survival outcomes, even after adjustment for TN(M) stage.
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Affiliation(s)
- Dongrul Shin
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Bumjin Lim
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Cheryn Song
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Dalsan You
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - In Gab Jeong
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Jun Hyuk Hong
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Hanjong Ahn
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Bumsik Hong
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Chang Wook Jeong
- Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jang Hee Han
- Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Jungyo Suh
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea.
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5
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Helleux A, Davidson G, Lallement A, Hourani FA, Haller A, Michel I, Fadloun A, Thibault-Carpentier C, Su X, Lindner V, Tricard T, Lang H, Tannir NM, Davidson I, Malouf GG. TFE3 fusions drive oxidative metabolism and ferroptosis resistance in translocation renal cell carcinoma. EMBO Mol Med 2025; 17:1041-1070. [PMID: 40148585 DOI: 10.1038/s44321-025-00221-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025] Open
Abstract
The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterized. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos). Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumor aggressiveness is related to their EMT and their associated enrichment in myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We define tRCC as a novel metabolic subtype of renal cancer and provide unique insights into how broad genomic binding of TFE3 fusion proteins regulates OxPhos and ferroptosis resistance.
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Affiliation(s)
- Alexandra Helleux
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Guillaume Davidson
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Antonin Lallement
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Fatima Al Hourani
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Alexandre Haller
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Isabelle Michel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Anas Fadloun
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Christelle Thibault-Carpentier
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France
- Université de Strasbourg, 67404, Illkirch, France
| | - Xiaoping Su
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Véronique Lindner
- Department of Pathology, Strasbourg University Hospital, Strasbourg, France
| | - Thibault Tricard
- Department of Urology, Strasbourg University Hospital, Strasbourg, France
| | - Hervé Lang
- Department of Urology, Strasbourg University Hospital, Strasbourg, France
| | - Nizar M Tannir
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center Houston, Houston, TX, USA
| | - Irwin Davidson
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France.
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France.
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France.
- Université de Strasbourg, 67404, Illkirch, France.
| | - Gabriel G Malouf
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France.
- Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France.
- Institut National de la Santé et de la Recherche Médicale, U1258, 67404, Illkirch, France.
- Université de Strasbourg, 67404, Illkirch, France.
- Department of Medical Oncology, Institut de Cancérologie de Strasbourg-Europe, Strasbourg, France.
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He C, Yuan E, Yao J, Chen Y, Song B. Imaging characteristics of rare renal cell carcinoma subtypes: diagnostic challenges and clinical implications. CHINESE JOURNAL OF ACADEMIC RADIOLOGY 2025. [DOI: 10.1007/s42058-025-00192-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/15/2025] [Accepted: 04/06/2025] [Indexed: 05/03/2025]
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Sun X, Wang H, Man X, Chen C, Cong X, Zhang J, Yang L. Metastatic MiT family/TFE translocation renal cell carcinoma in adults: case series reports and literature reviews. Front Oncol 2025; 15:1501820. [PMID: 40177240 PMCID: PMC11961414 DOI: 10.3389/fonc.2025.1501820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 03/03/2025] [Indexed: 04/05/2025] Open
Abstract
This article presents a case study of three patients diagnosed with MiT/TFE tRCC at our hospital. The tumors were located in the left kidney of all three patients, with two of them being under 30 years old. Within a short timeframe, two of all patients developed liver metastases. Genetic testing was conducted in one case, FISH testing in another, and all cases underwent a combination of targeted therapy and immunotherapy. By analyzing the clinical, pathological, and genomic characteristics of these patients, this article aims to enhance the understanding of MiT family translocation renal cell carcinoma, as well as improve the diagnosis, treatment, and prognosis of this rare form of renal cell carcinoma. Further evidence is provided to support these findings.
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Affiliation(s)
| | | | | | | | | | | | - Lei Yang
- Department of Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China
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8
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Zeng J, Indajang J, Pitt D, Lo CH. Lysosomal acidification impairment in astrocyte-mediated neuroinflammation. J Neuroinflammation 2025; 22:72. [PMID: 40065324 PMCID: PMC11892208 DOI: 10.1186/s12974-025-03410-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 03/05/2025] [Indexed: 03/14/2025] Open
Abstract
Astrocytes are a major cell type in the central nervous system (CNS) that play a key role in regulating homeostatic functions, responding to injuries, and maintaining the blood-brain barrier. Astrocytes also regulate neuronal functions and survival by modulating myelination and degradation of pathological toxic protein aggregates. Astrocytes have recently been proposed to possess both autophagic activity and active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete degradation of cellular cargos. Defective lysosomal acidification in astrocytes impairs their autophagic and phagocytic functions, resulting in the accumulation of cellular debris, excessive myelin and lipids, and toxic protein aggregates, which ultimately contributes to the propagation of neuroinflammation and neurodegenerative pathology. Restoration of lysosomal acidification in impaired astrocytes represent new neuroprotective strategy and therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, myelin and lipid mediated toxicity, and toxic protein aggregates, that contribute to lysosomal acidification impairment and associated autophagic and phagocytic dysfunction in astrocytes. We discuss the role of lysosomal acidification dysfunction in astrocyte-mediated neuroinflammation primarily in the context of neurodegenerative diseases along with other brain injuries. We then highlight re-acidification of impaired lysosomes as a therapeutic strategy to restore autophagic and phagocytic functions as well as lysosomal degradative capacity in astrocytes. We conclude by providing future perspectives on the role of astrocytes as phagocytes and their crosstalk with other CNS cells to impart neurodegenerative or neuroprotective effects.
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Affiliation(s)
- Jialiu Zeng
- Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, NY, 13244, USA.
- Interdisciplinary Neuroscience Program, Syracuse University, Syracuse, NY, 13244, USA.
| | - Jonathan Indajang
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA
| | - David Pitt
- Department of Neurology, Yale School of Medicine, New Haven, CT, 06511, USA
| | - Chih Hung Lo
- Interdisciplinary Neuroscience Program, Syracuse University, Syracuse, NY, 13244, USA.
- Department of Biology, Syracuse University, Syracuse, NY, 13244, USA.
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9
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Li J, Huang K, Thakur M, McBride F, Sadagopan A, Gallant DS, Khanna P, Laimon YN, Li B, Mohanna R, Ge M, Weiss CN, Achom M, Xu Q, Matar S, Lee GSM, Huang K, Gui M, Wu CL, Cornejo KM, Choueiri TK, Ryback BA, Signoretti S, Bar-Peled L, Viswanathan SR. Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma. Nat Metab 2025; 7:478-492. [PMID: 39915638 DOI: 10.1038/s42255-025-01218-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 01/09/2025] [Indexed: 02/12/2025]
Abstract
Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1α and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability for OXPHOS-dependent tRCC cells. Our study defines tRCC as being dependent on a mitochondria-centred metabolic programme driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy in this cancer.
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Affiliation(s)
- Jiao Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Kaimeng Huang
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Meha Thakur
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Fiona McBride
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ananthan Sadagopan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Daniel S Gallant
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Prateek Khanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Bingchen Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Razan Mohanna
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Maolin Ge
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
| | - Cary N Weiss
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Mingkee Achom
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Qingru Xu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sayed Matar
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Gwo-Shu Mary Lee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Kun Huang
- Molecular Imaging Core and Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Miao Gui
- Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Chin-Lee Wu
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Kristine M Cornejo
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Toni K Choueiri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Birgitta A Ryback
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sabina Signoretti
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Liron Bar-Peled
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
| | - Srinivas R Viswanathan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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10
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Chaudhry S, Kravtsov O. Fumarate Hydratase-Deficient Renal Cell Carcinoma with Nucleolar Pattern of GATA3 Immunoexpression: Report of 2 Cases. Int J Surg Pathol 2025; 33:199-203. [PMID: 38766863 DOI: 10.1177/10668969241253210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare aggressive type of renal cell carcinoma. The significant morphologic overlap with other types of renal neoplasia and the limited availability of FH and 2-succinylcholine immunostains for diagnostic use outside large referral centers have created numerous diagnostic pitfalls. As FH-deficient RCC can be associated with hereditary leiomyomatosis and renal cell cancer syndrome, the importance of an accurate diagnosis goes beyond the prognosis and treatment of an individual patient. We present 2 patients with FH-deficient RCC showing a peculiar pattern of GATA3 immunoexpression restricted to tumor nucleoli. If confirmed in further larger studies, this could provide an additional diagnostic clue for considering the FH-deficient RCC diagnosis, and given the frequent papillary morphology and possible hilar location can lead to the misdiagnosis as high-grade urothelial carcinoma, and is an important diagnostic pitfall to be aware of.
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Affiliation(s)
- Sidhartha Chaudhry
- Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Oleksandr Kravtsov
- Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA
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11
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Dorobantu-Lungu LR, Dinca V, Gegiu A, Spataru D, Toma A, Welt L, Badea MF, Caruntu C, Scheau C, Savulescu-Fiedler I. The Relevance of the Virchow Node and Virchow Triad in Renal Cancer Diagnosis. Clin Pract 2025; 15:18. [PMID: 39851801 PMCID: PMC11763355 DOI: 10.3390/clinpract15010018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/30/2024] [Accepted: 01/10/2025] [Indexed: 01/26/2025] Open
Abstract
Background: The purpose of this article is to overview the clinical significance of left supraclavicular adenopathy and review the etiology of inferior vena cava (IVC) thrombosis, starting from a presentation of a rare case of renal cell carcinoma (RCCs) with Xp11.2 translocation involving TFE3 gene fusion. This article also aims to review the literature to understand the characteristics of this rare type of renal tumor. Renal cell carcinoma (RCC) associated with Xp11.2 translocation/gene fusion TFE3 is a rare subtype of kidney cancer that was classified in 2016 as belonging to the family of renal carcinomas with MiT gene translocation (microphthalmia-associated transcription factor). The prognosis for these kidney cancers is poorer compared to other types. Methods: We present a case of a 66-year-old man with Virchow-Troisier adenopathy during physical examination, which raises the suspicion of infra-diaphragmatic tumor. The echocardiography highlighted a heterogeneous mass in the right cardiac cavities, and the abdominal ultrasound exam revealed a solid mass at the upper pole of the left kidney. Results: Following computed tomography, magnetic resonance imaging, PET-CT, and histopathological and immunohistochemical examinations, the patient was diagnosed with renal carcinoma with Xp11.2 translocation and TFE3 gene fusion. Conclusions: IVC thrombosis is often associated with neoplastic disease due to the procoagulant state of these patients, the most common malignancies related to IVC thrombosis being represented by RCCs (38%), genitourinary cancers (25%), bronchus and lung cancers, retroperitoneal leiomyosarcoma, and adrenal cortical carcinoma. Imaging methods play a crucial role in differential diagnosis, allowing for the localization of the primary tumor and assessment of its characteristics.
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Affiliation(s)
- Luiza-Roxana Dorobantu-Lungu
- Department of Cardiology, Emergency Institute for Cardiovascular Diseases “C.C. Iliescu”, 022328 Bucharest, Romania;
| | - Viviana Dinca
- Department of Cardiology and Internal Medicine, Colțea Clinical Hospital, 030167 Bucharest, Romania; (V.D.); (A.G.); (D.S.); (I.S.-F.)
| | - Andrei Gegiu
- Department of Cardiology and Internal Medicine, Colțea Clinical Hospital, 030167 Bucharest, Romania; (V.D.); (A.G.); (D.S.); (I.S.-F.)
| | - Dan Spataru
- Department of Cardiology and Internal Medicine, Colțea Clinical Hospital, 030167 Bucharest, Romania; (V.D.); (A.G.); (D.S.); (I.S.-F.)
| | - Andreea Toma
- Department of Otorhinolaryngology (ORL), Colțea Clinical Hospital, 030167 Bucharest, Romania;
- Department of Otorhinolaryngology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Luminita Welt
- Department of Pathological Anatomy, Colțea Clinical Hospital, 030167 Bucharest, Romania;
| | - Mihaela Florentina Badea
- Department of Radiology and Medical Imaging, Colțea Clinical Hospital, 030167 Bucharest, Romania;
| | - Constantin Caruntu
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Cristian Scheau
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Radiology and Medical Imaging, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 030167 Bucharest, Romania
| | - Ilinca Savulescu-Fiedler
- Department of Cardiology and Internal Medicine, Colțea Clinical Hospital, 030167 Bucharest, Romania; (V.D.); (A.G.); (D.S.); (I.S.-F.)
- Department of Internal Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
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12
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Mansour H, Tran-Dang MA, Walkden M, Boleti E, Barod R, Patki P, Mumtaz F, Tran MGB, Bex A, El Sheikh S. Renal mass biopsy - a practical and clinicopathologically relevant approach to diagnosis. Nat Rev Urol 2025; 22:8-25. [PMID: 38907039 DOI: 10.1038/s41585-024-00897-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2024] [Indexed: 06/23/2024]
Abstract
Advancements in imaging modalities have increased the frequency of renal mass discovery. Imaging has typically been considered sufficient to guide management for a large proportion of these tumours, but renal mass biopsies (RMBs) have an increasing role in determining malignancy and can be a valuable tool for preventing unnecessary surgery in patients with benign tumours. A structured approach should be used to help to navigate the expanding repertoire of renal tumours, many of which are molecularly defined. In terms of tumour subtyping, the pathologist's strategy should focus on stratifying patients into clinically different prognostic groups according to our current knowledge of tumour behaviour, including benign, low-grade or indolent, intermediate malignant or highly aggressive. Crucial pathological features and morphological mimicry of tumours can alter the tumour's prognostic group. Thus, pathologists and urologists can use RMB to select patients with tumours at a reduced risk of progression, which can be safely managed with active surveillance within a tailored imaging schedule, versus tumours for which ablation or surgical intervention is indicated. RMB is also crucial in the oncological setting to distinguish between different high-grade tumours and guide tailored management strategies.
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Affiliation(s)
- Hussein Mansour
- Research Department of Pathology, UCL Cancer Institute, London, UK
| | - My-Anh Tran-Dang
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK
| | - Miles Walkden
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK
- UCL Division of Surgery and Interventional Science, Rowland Street, London, UK
| | - Ekaterini Boleti
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK
| | - Ravi Barod
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK
- UCL Division of Surgery and Interventional Science, Rowland Street, London, UK
| | - Prasad Patki
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK
- UCL Division of Surgery and Interventional Science, Rowland Street, London, UK
| | - Faiz Mumtaz
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK
- UCL Division of Surgery and Interventional Science, Rowland Street, London, UK
| | - Maxine G B Tran
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK
- UCL Division of Surgery and Interventional Science, Rowland Street, London, UK
| | - Axel Bex
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK
- UCL Division of Surgery and Interventional Science, Rowland Street, London, UK
| | - Soha El Sheikh
- Research Department of Pathology, UCL Cancer Institute, London, UK.
- Specialist centre for kidney cancer, Royal Free London Hospital, London, UK.
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13
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Yan M, Wang R, Guan W, Jiang R, Wang K, Liu Y, Wang L. A clinicopathological and molecular series of five TFEB-altered renal cell carcinoma (RCC) cases: highlighting an aggressive subset of TFEB-rearranged RCC concomitant with TFEB amplification/gene copy number gains. Virchows Arch 2024; 485:1041-1051. [PMID: 39523245 DOI: 10.1007/s00428-024-03968-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/14/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
The classification of TFEB-altered renal cell carcinoma (RCC) has been revised to include TFEB-rearranged RCC and TFEB-amplified RCC in the 2022 World Health Organization (WHO) Classification of Tumors of the Urinary System. Given the wide spectrum of TFEB-altered RCC in terms of morphology and clinical behavior, an accurate diagnosis is challenging yet crucial, particularly in aggressive cases. Moreover, the concurrence of TFEB gene rearrangement and amplification/gene copy number (GCN) gains was also observed, but there was limited knowledge of these cases. We presented three TFEB-rearranged RCC cases, one TFEB-amplified RCC case, and one case of concomitant TFEB-rearranged and -amplified RCC, comparing the similarities and differences among these three subgroups. Furthermore, we summarized the clinicopathological and molecular features of TFEB-rearranged RCC concomitant with TFEB amplification/GCN gains from the literature and the present study. TFEB-altered RCCs exhibit significant heterogeneity in morphology and clinical behavior while displaying similar immunohistochemical profiles, including positive staining for Melan-A, PAX8, and CD117, and negative staining for CK7. A typical biphasic "rosette-like" morphology has been observed in a proportion of TFEB-rearranged RCC concomitant with TFEB amplification/GCN gains, which has been noted in TFEB-rearranged RCC, but not in cases with only TFEB amplification. Notably, TFEB-rearranged RCCs concomitant with TFEB amplification/GCN gains tend to be aggressive, in contrast to the often indolent nature of TFEB-rearranged cases, irrespective of the extent of TFEB gene copy increase. Therefore, a TFEB FISH assay is essential for unclassified RCC cases that exhibit melanocytic marker expression, and fluorescent signals should be counted and interpreted acurrately.
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Affiliation(s)
- Minhua Yan
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Ruifen Wang
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Wenbin Guan
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Ruiqi Jiang
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Kezhou Wang
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yi Liu
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Lifeng Wang
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
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14
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Pezzicoli G, Musci V, Ciciriello F, Salonne F, Cafforio P, Lionetti N, Ragno A, Rizzo M. Genomic profiling and molecular characterization of non-clear cell renal cell carcinoma: a narrative review from a clinical perspective. Ther Adv Med Oncol 2024; 16:17588359241298500. [PMID: 39563719 PMCID: PMC11574901 DOI: 10.1177/17588359241298500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 10/23/2024] [Indexed: 11/21/2024] Open
Abstract
While the clear-cell renal cell carcinoma (ccRCC) treatment has undergone several paradigm shifts in recent years, the non-clear cell renal cell carcinoma (nccRCC) therapeutic approach has yet to be extensively investigated and improved. The WHO 2022 classification of renal neoplasms redefined the most common nccRCC subtypes (papillary and chromophobe RCC) and introduced the molecularly defined RCC class, which is a first step in the direction of better molecular profiling of nccRCC. We reviewed the literature data on known genomic alterations of clinical interest in nccRCC and discussed their potential role in guiding therapeutic choices in each nccRCC entity. Among the alterations discussed, we focused on the ones that could be treated with already available drugs, such as MET-driven papillary RCC, mechanistic target of rapamycin altered chromophobe RCC, anaplastic lymphoma kinase-rearranged RCC, and fumarate-hydratase deficient RCC. Furthermore, we focused on the currently ongoing clinical trials and further evidence for all the other entities, such as SMARCB1-deficient RCC, TFE3 and transcription factorEB (TFEB)-altered RCC, and Elongin C (ELOC)-mutated RCC. The vast heterogeneity of nccRCC does not allow a one-size-fits-all solution; therefore, molecular characterization is the path toward effective therapies and fully personalized medicine for these entities.
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Affiliation(s)
- Gaetano Pezzicoli
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Vittoria Musci
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Federica Ciciriello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Francesco Salonne
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Paola Cafforio
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Nicoletta Lionetti
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Anna Ragno
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Consorziale, Policlinico di Bari, Bari, Italy
| | - Mimma Rizzo
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Consorziale, Policlinico di Bari, piazza G. Cesare 11, Bari 70124, Italy
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15
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Bai YM, Yang L, Yang Y, Wang XX, Zheng MD, Chai X, Dou QY, Zhang HM. The Clinicopathological Characteristics and Prognosis of 55 Patients With TFE3-Rearranged Renal Cell Carcinomas. Clin Genitourin Cancer 2024; 22:102165. [PMID: 39111254 DOI: 10.1016/j.clgc.2024.102165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/09/2024] [Accepted: 07/13/2024] [Indexed: 09/17/2024]
Abstract
OBJECTIVE To explore the clinicopathological features and prognosis of TFE3-rearranged renal cell carcinomas (TFE3-rRCC). METHODS In this retrospective observational study, the data of patients with TFE3-rRCC admitted to Xijing Hospital from January 2010 to October 2023 were collected, encompassing the general information, pathological diagnosis, immunohistochemistry, and the results of FISH detection. The treatment information and survival data of the patients were recorded during the follow-up. RESULTS A total of 55 patients with TFE3-rRCC were enrolled, among whom 25 were males and 30 were females. TFE3 FISH assay suggested the disruption of the TFE3 gene. Fifty-four patients underwent surgical resection of kidney lesions, while 1 patient did not. By the end of follow-up in December 2023, 3 patients were lost to follow-up, 28 patients remained alive, and 24 patients had died. Among the 52 patients followed up, 31 developed metastases, involving lymph nodes, liver, bone, lung, peritoneum, pleura, adrenal gland, and brain. The 1-year and 5-year survival rates of the patients were 84.6% and 50.6%, respectively. In this study, there were 31 patients with TFE3-rRCC recurrence or metastasis. Median PFS was 7 and 13 months in the VEGFR-TKI and VEGFR-TKI+ ICI groups, respectively. The median OS was 12 months in the VEGFR-TKI treatment group. The median OS data of VEGFR-TKI+ ICI group has not been reached. The ORR and DCR was 25%, 66.7% in the VEGFR-TKI group. The ORR and DCR was 33.3%, 77.8% in the VEGFR-TKI+ ICI group. CONCLUSION TFE3-rRCC is a rare subtype of malignant renal tumor. The diagnosis mainly relies on pathological morphology, immunohistochemistry, and the detection of TFE3 gene disruption by FISH. In terms of treatment, surgery is the primary approach, and lymph nodes, liver, and bone are the main metastatic sites. VEGFR-TKI+ICI treatment might be an option of recurrent or metastatic TFE3-rRCC.
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Affiliation(s)
- Yin-Miao Bai
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Li Yang
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yue Yang
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiang-Xu Wang
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Meng-Di Zheng
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiao Chai
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Qiong-Yi Dou
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Hong-Mei Zhang
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
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16
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Caliò A, Marletta S, Stefanizzi L, Marcolini L, Rotellini M, Serio G, Bariani E, Vicentini C, Pedron S, Martelli FM, Antonini P, Brunelli M, Martignoni G. Comparison of Primary and Metastatic Fumarate Hydratase-Deficient Renal Cell Carcinomas Documents Morphologic Divergence and Potential Diagnostic Pitfall With Peritoneal Mesothelioma. Mod Pathol 2024; 37:100561. [PMID: 38996839 DOI: 10.1016/j.modpat.2024.100561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 06/05/2024] [Accepted: 07/01/2024] [Indexed: 07/14/2024]
Abstract
Fumarate hydratase (FH)-deficient renal cell carcinomas are rare neoplasms characterized by wide morphologic heterogeneity and pathogenetic mutations in the FH gene. They often show aggressive behavior with rapid diffusion to distant organs, so novel therapeutic scenarios have been explored, including EGFR inhibitors and PD-L1 expression for targeted immunotherapy. Herein, we investigated a series of 11 primary FH-deficient renal cell carcinomas and 7 distant metastases to evaluate tumor heterogeneity even in metastatic sites and estimate the specific spread rates to various organs. Furthermore, the tumors were tested for immunohistochemical PD-L1 expression and EGFR mutations. Most metastatic cases involved the abdominal lymph nodes (4/7; 57%), followed by the peritoneum (3/7; 42%), the liver (2/7; 29%), and the lungs (1/7; 14%). Six metastatic localizations were histologically documented, revealing a morphologic heterogeneous architecture often differing from that of the corresponding primary renal tumor. Peritoneal involvement morphologically resembled a benign reactive mesothelial process or primary peritoneal mesothelioma, thus advocating to perform an accurate immunohistochemical panel, including PAX8 and FH, to reach a proper diagnosis. A pure low-grade succinate dehydrogenase-looking primary FH-deficient renal cell carcinoma was also recorded. As for therapy, significant PD-L1 labeling was found in 60% of primary renal tumors, whereas none of them carried pathogenetic EGFR mutations. Our data show that FH-deficient renal cell carcinoma may be morphologically heterogeneous in metastases as well, which involve the lymph nodes, the liver, and the peritoneum more frequently than other renal tumors. Due to the high frequency of this latter (42%), pathologists should always be concerned about ruling out mesothelial-derived mimickers, and the occurrence of rarer, primary, low-grade-looking types. Finally, contrary to EGFR mutations, PD-L1 expression could be a possible predictive biomarker for the therapy of these tumors.
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Affiliation(s)
- Anna Caliò
- Section of Pathology, Department of Diagnostic and Public Health, University of Verona, Verona, Italy
| | - Stefano Marletta
- Section of Pathology, Department of Diagnostic and Public Health, University of Verona, Verona, Italy; Division of Pathology, Humanitas Istituto Clinico Catanese, Catania, Italy
| | - Lavinia Stefanizzi
- Department of Pathology and Laboratory Medicine, Pederzoli Hospital, Peschiera, Verona, Italy
| | - Lisa Marcolini
- Department of Pathology and Laboratory Medicine, Pederzoli Hospital, Peschiera, Verona, Italy
| | - Matteo Rotellini
- Anatomia Patologica Massa Carrara Azienda Toscana Nord Ovest, Italy
| | - Gabriella Serio
- Pathology Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Italy
| | - Elena Bariani
- Unit of Anatomic Pathology, Department of Oncology, Bellaria Hospital, Bologna, Italy
| | - Caterina Vicentini
- Department of Pathology and Laboratory Medicine, Pederzoli Hospital, Peschiera, Verona, Italy
| | - Serena Pedron
- Section of Pathology, Department of Diagnostic and Public Health, University of Verona, Verona, Italy
| | - Filippo M Martelli
- Department of Pathology and Laboratory Medicine, Pederzoli Hospital, Peschiera, Verona, Italy
| | - Pietro Antonini
- Section of Pathology, Department of Diagnostic and Public Health, University of Verona, Verona, Italy
| | - Matteo Brunelli
- Section of Pathology, Department of Diagnostic and Public Health, University of Verona, Verona, Italy
| | - Guido Martignoni
- Section of Pathology, Department of Diagnostic and Public Health, University of Verona, Verona, Italy; Department of Pathology and Laboratory Medicine, Pederzoli Hospital, Peschiera, Verona, Italy.
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17
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Li J, Huang K, McBride F, Sadagopan A, Gallant DS, Thakur M, Khanna P, Li B, Ge M, Weiss CN, Achom M, Xu Q, Huang K, Ryback BA, Gui M, Bar-Peled L, Viswanathan SR. TFE3 fusions direct an oncogenic transcriptional program that drives OXPHOS and unveils vulnerabilities in translocation renal cell carcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.09.607311. [PMID: 39149323 PMCID: PMC11326252 DOI: 10.1101/2024.08.09.607311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other renal cancers. This TFE3 fusion-driven OXPHOS program, together with heightened glutathione levels found in renal cancers, renders tRCCs sensitive to reductive stress - a metabolic stress state induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1a and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability to OXPHOS-dependent tRCC cells. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring.
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Affiliation(s)
- Jiao Li
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
- Department of Medicine, Harvard Medical School; Boston, MA, USA
| | - Kaimeng Huang
- Department of Medicine, Harvard Medical School; Boston, MA, USA
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Fiona McBride
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
| | - Ananthan Sadagopan
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
| | - Daniel. S Gallant
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
| | - Meha Thakur
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
| | - Prateek Khanna
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
| | - Bingchen Li
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
- Department of Medicine, Harvard Medical School; Boston, MA, USA
| | - Maolin Ge
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
| | - Cary N. Weiss
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Mingkee Achom
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
- Department of Medicine, Harvard Medical School; Boston, MA, USA
| | - Qingru Xu
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
| | - Kun Huang
- Molecular Imaging Core and Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Birgitta A. Ryback
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Miao Gui
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, Zhejiang, China; Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China
| | - Liron Bar-Peled
- Department of Medicine, Harvard Medical School; Boston, MA, USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
| | - Srinivas R. Viswanathan
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA, USA
- Department of Medicine, Harvard Medical School; Boston, MA, USA
- Cancer Program, Broad Institute of MIT and Harvard; Cambridge, MA, USA
- Department of Medicine, Brigham and Women’s Hospital; Boston, MA, USA
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18
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Kanakaraj J, Chang J, Hampton LJ, Smith SC. The New WHO Category of "Molecularly Defined Renal Carcinomas": Clinical and Diagnostic Features and Management Implications. Urol Oncol 2024; 42:211-219. [PMID: 38519377 DOI: 10.1016/j.urolonc.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 01/27/2024] [Accepted: 02/12/2024] [Indexed: 03/24/2024]
Abstract
The evolution of classification of renal tumors has been impacted since the turn of the millennium by rapid progress in histopathology, immunohistochemistry, and molecular genetics. Together, these features have enabled firm recognition of specific, classic types of renal cell carcinomas, such as clear cell renal cell carcinoma, that in current practice trigger histologic-type specific management and treatment protocols. Now, the fifth Edition World Health Classification's new category of "Molecularly defined renal carcinomas" changes the paradigm, defining a total of seven entities based specifically on their fundamental molecular underpinnings. These tumors, which include TFE3-rearranged, TFEB-altered, ELOC-mutated, fumarate hydratase-deficient, succinate dehydrogenase-deficient, ALK-rearranged, and SMARCB1-deficient renal medullary carcinoma, encompass a wide clinical and histopathologic phenotypic spectrum of tumors. Already, important management aspects are apparent for several of these entities, while emerging therapeutic angles are coming into view. A brief, clinically-oriented introduction of the entities in this new category, focusing on relevant diagnostic, molecular, and management aspects, is the subject of this review.
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Affiliation(s)
- Jonathan Kanakaraj
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Justin Chang
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Lance J Hampton
- Division of Urology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA; Department of Pathology, Richmond Veterans Affairs Medical Center, Richmond, VA; VCU Massey Comprehensive Cancer Center, Richmond, VA
| | - Steven Christopher Smith
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA; Division of Urology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA; Department of Pathology, Richmond Veterans Affairs Medical Center, Richmond, VA; VCU Massey Comprehensive Cancer Center, Richmond, VA.
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Xue Z, Tang S, Ou J, Fang Y, Qiu M, Hong K, Tian X, Zhang H, Liu C, Ma L, Zhang S. Clear cell and non-clear cell renal cell carcinoma in young adults: clinicopathological features, survival outcomes and prognostic factors. World J Urol 2024; 42:364. [PMID: 38819448 DOI: 10.1007/s00345-024-05028-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 02/13/2024] [Indexed: 06/01/2024] Open
Abstract
OBJECTIVES Renal cell carcinoma (RCC) is infrequent among young adults. Few studies reported the outcome of RCC in young adults by pathological subtypes. The purpose of this study was to explore the clinicopathological features, survival outcomes and prognostic factors of young adult patients with clear cell (CCRCC) and non-clear cell renal cell carcinoma (NCCRCC). METHODS This study included young adult patients aged 18-40 years who were diagnosed as renal cell carcinoma (RCC) between 2012 and 2022 at Peking University Third Hospital. All patients underwent either partial nephrectomy or radical nephrectomy, and some received adjuvant therapy. A comparative analysis was performed to investigate the differences in clinicopathological characteristics between the cohort of CCRCC and NCCRCC. Kaplan-Meier survival analysis was utilized to plot survival curves for young adults with RCC. The univariate and multifactorial prognostic analyses were conducted using the log-rank test and COX proportional hazards model. RESULTS A total of 300 RCC patients aged 18-40 years were performed, of which 201 were diagnosed with CCRCC (67%) and 99 were diagnosed with NCCRCC(33%). The NCCRCC included 29 cases (9.7%) of chromophobe RCC, 28 cases (9.3%) of MiT family translocation RCC, 22 cases (7.3%) of papillary RCC, 11 cases (3.7%) of low malignant potential multifocal cystic RCC, and 6 cases of unclassified RCC (2.0%), 2 cases of mucinous tubule and spindle cell carcinoma (0.7%), and 1 case of FH-deficient RCC (0.3%).The mean age was 33.4 ± 6.1 years old. The overall and progression free 5-year survival rate was 99.1 and 95.3%, respectively. The NCCRCC cohort demonstrated a statistically significant decrease in progression-free survival (PFS) rate when compared to the CCRCC cohort (p < 0.001). There was no statistically significant difference observed in overall survival (OS) (p = 0.069). Pathological stage was a significant independent predictor for OS (p = 0.045). Pathological stage and nuclear grade were both independent predictors for PFS (p = 0.020; p = 0.005). CONCLUSIONS The clinical and pathological features of young adults diagnosed with CCRCC exhibit notable distinctions from those of NCCRCC patients. The survival outcome was significantly influenced by the pathological stage, while both the nuclear grade and pathological stage had a significant impact on tumor progression. This study offered significant contributions to the understanding of the clinicopathological characteristics and prognostic determinants of renal cell carcinoma (RCC) in young adults.
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Affiliation(s)
- Zixuan Xue
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China
| | - Shiying Tang
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China
| | - Junyong Ou
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China
| | - Yangyi Fang
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China
| | - Min Qiu
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China.
| | - Kai Hong
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China.
| | - Xiaojun Tian
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China
| | - Hongxian Zhang
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China
| | - Cheng Liu
- Department of Urology, Shanghai First Peoples Hospital, Shanghai, China
| | - Lulin Ma
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China
| | - Shudong Zhang
- Department of Urology, Peking University Third Hospital, Beijing, 100083, China
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Damayanti NP, Cordova RA, Rupert C, Delle Fontane I, Shen L, Orsi S, Klunk AJ, Linehan WM, Staschke KA, Hollenhorst PC, Heppner DE, Pili R. TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma. Cancer Res 2024; 84:1286-1302. [PMID: 38266162 DOI: 10.1158/0008-5472.can-23-1789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 12/05/2023] [Accepted: 01/22/2024] [Indexed: 01/26/2024]
Abstract
TFE3 is a member of the basic helix-loop-helix leucine zipper MiT transcription factor family, and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of gene fusions, most TFE3 fusion partner genes are related to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer. Here, by using a combination of in silico structure prediction, transcriptome profiling, molecular characterization, and high-throughput high-content screening (HTHCS), we interrogated a number of oncogenic mechanisms of TFE3-SF fusions. TFE3-SF fusions drove the transformation of kidney cells and promoted distinct oncogenic phenotypes in a fusion partner-dependent manner, differentially altering the transcriptome and RNA splicing landscape and activating different oncogenic pathways. Inhibiting TFE3-SF dimerization reversed its oncogenic activity and represented a potential target for therapeutic intervention. Screening the FDA-approved drugs library LOPAC and a small-molecule library (Microsource) using HTHCS combined with FRET technology identified compounds that inhibit TFE3-SF dimerization. Hit compounds were validated in 2D and 3D patient-derived xenograft models expressing TFE3-SF. The antihistamine terfenadine decreased cell proliferation and reduced in vivo tumor growth of tRCC. Overall, these results unmask therapeutic strategies to target TFE3-SF dimerization for treating patients with tRCC. SIGNIFICANCE TFE3-splicing factor fusions possess both transcription and splicing factor functions that remodel the transcriptome and spliceosome and can be targeted with dimerization inhibitors to suppress the growth of translocation renal cell carcinoma.
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Affiliation(s)
- Nur P Damayanti
- Genitourinary Program, Division of Hematology & Oncology, Indiana University, Indianapolis, Indiana
- Department of Neurosurgery, Division of Neuro-Oncology, Indiana University, Indianapolis, Indiana
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
| | - Ricardo A Cordova
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
- Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, Indiana
| | - Christopher Rupert
- Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Ilaria Delle Fontane
- Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Li Shen
- Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Sabrina Orsi
- Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Angela J Klunk
- Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, Indiana
| | - W Marston Linehan
- Urological Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | - Kirk A Staschke
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
- Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, Indiana
| | - Peter C Hollenhorst
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
- Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana
| | - David E Heppner
- Department of Chemistry, University at Buffalo, Buffalo, New York
| | - Roberto Pili
- Genitourinary Program, Division of Hematology & Oncology, Indiana University, Indianapolis, Indiana
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
- Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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21
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Soares A, Monteiro FSM, da Trindade KM, Silva AGE, Cardoso APG, Sasse AD, Fay AP, Carneiro APCD, Alencar Junior AM, de Andrade Mota AC, Santucci B, da Motta Girardi D, Herchenhorn D, Araújo DV, Jardim DL, Bastos DA, Rosa DR, Schutz FA, Kater FR, da Silva Marinho F, Maluf FC, de Oliveira FNG, Vidigal F, Morbeck IAP, Rinck Júnior JA, Costa LAGA, Maia MCDF, Zereu M, Freitas MRP, Dias MSF, Tariki MS, Muniz P, Beato PMM, Lages PSM, Velho PI, de Carvalho RS, Mariano RC, de Araújo Cavallero SR, Oliveira TM, Souza VC, Smaletz O, de Cássio Zequi S. Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update. J Cancer Res Clin Oncol 2024; 150:183. [PMID: 38594593 PMCID: PMC11003910 DOI: 10.1007/s00432-024-05663-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 02/22/2024] [Indexed: 04/11/2024]
Abstract
PURPOSE Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.
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Affiliation(s)
- Andrey Soares
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil.
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
- Centro Paulista de Oncologia/Oncoclínicas, São Paulo, SP, Brazil.
| | - Fernando Sabino Marques Monteiro
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Sírio-Libanês, Brasília, DF, Brazil
| | - Karine Martins da Trindade
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Oncologia D'Or, Fortaleza, CE, Brazil
| | - Adriano Gonçalves E Silva
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Instituto do Câncer e Transplante de Curitiba/PR (ICTr Curitiba), Curitiba, PR, Brazil
| | - Ana Paula Garcia Cardoso
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - André Deeke Sasse
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo SONHE de Campinas, Campinas, SP, Brazil
| | - André P Fay
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Escola de Medicina da Pontifícia, Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - André Paternò Castello Dias Carneiro
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Hospital Municipal Vila Santa Catarina, São Paulo, SP, Brazil
| | - Antonio Machado Alencar Junior
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital São Domingos, São Luís, MA, Brazil
- Dasa Oncologia, Brasília, DF, Brazil
- Hospital Universitário da Universidade Federal do Maranhão (UFMA), São Luís, MA, Brazil
| | - Augusto César de Andrade Mota
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Clínica AMO-DASA, Feira de Santana, BA, Brazil
| | - Bruno Santucci
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Instituto Paulista de Cancerologia, São Paulo, SP, Brazil
| | - Daniel da Motta Girardi
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Sírio-Libanês, Brasília, DF, Brazil
| | - Daniel Herchenhorn
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Oncologia D'Or, Rio de Janeiro, RJ, Brazil
| | - Daniel Vilarim Araújo
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital de Base de São José do Rio Preto/SP, São José do Rio Preto, São Paulo, SP, Brazil
| | - Denis Leonardo Jardim
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, São Paulo, São Paulo, SP, Brazil
| | - Diogo Assed Bastos
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Sirio-Libanês de São Paulo, São Paulo, SP, Brazil
| | - Diogo Rodrigues Rosa
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Rio de Janeiro, RJ, Brazil
| | - Fabio A Schutz
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Fábio Roberto Kater
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Felipe da Silva Marinho
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Recife, PE, Brazil
| | - Fernando Cotait Maluf
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Fernando Nunes Galvão de Oliveira
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Salvador, BA, Brazil
| | - Fernando Vidigal
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Dasa Oncologia, Brasília, DF, Brazil
| | - Igor Alexandre Protzner Morbeck
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Brasília, DF, Brazil
| | - Jose Augusto Rinck Júnior
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Leonardo Atem G A Costa
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Oncologia D'Or, Fortaleza, CE, Brazil
| | - Manuel Caitano Dias Ferreira Maia
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital do Câncer Porto Dias, Belém, PA, Brazil
| | - Manuela Zereu
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
| | - Marcelo Roberto Pereira Freitas
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Centro Especializado de Oncologia de Florianópolis, Florianópolis, SC, Brazil
| | - Mariane Sousa Fontes Dias
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Rio de Janeiro, RJ, Brazil
| | - Milena Shizue Tariki
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Pamela Muniz
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, São Paulo, São Paulo, SP, Brazil
- Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Patrícia Medeiros Milhomem Beato
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Amaral Carvalho, Jaú, SP, Brazil
| | - Paulo Sérgio Moraes Lages
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Brasília, DF, Brazil
| | - Pedro Isaacsson Velho
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Moinhos de Vento, Porto Alegre, RS, Brazil
- Johns Hopkins University, Baltimore, MD, USA
| | - Ricardo Saraiva de Carvalho
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Rodrigo Coutinho Mariano
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Sandro Roberto de Araújo Cavallero
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Adventista de Belém, Belém, PA, Brazil
| | - Thiago Martins Oliveira
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital São Rafael, Salvador, BA, Brazil
| | - Vinicius Carrera Souza
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Instituto D'Or de Ensino e Pesquisa, Salvador, BA, Brazil
| | - Oren Smaletz
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Stênio de Cássio Zequi
- AC Camargo Cancer Center, São Paulo, SP, Brazil
- National Institute for Science and Technology in Oncogenomics and Therapeutic Innovation, AC Camargo Cancer Center, São Paulo, SP, Brazil
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Wu J, Cao CZ, Cui HL, Du G, Shi HZ, Liang J, Guo L, Wang YC, Zhang J, Zhou AP, Li CL, Zheng S, Shou JZ. Prognosis and Clinicopathological Characters of Adult TFEB-Altered Renal Cell Carcinoma: A Single Center Experience of 18 Cases. Clin Genitourin Cancer 2024; 22:261-268.e3. [PMID: 38104031 DOI: 10.1016/j.clgc.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/13/2023] [Accepted: 11/13/2023] [Indexed: 12/19/2023]
Abstract
INTRODUCTION TFEB-altered renal cell carcinoma (RCC) is a rare entity characterized by the rearrangement of the TFEB gene or TFEB amplified. The therapeutic implications and long-term survival of TFEB-altered RCC remain unclear, especially for metastatic cases. MATERIALS AND METHODS The current study initially enrolled 7604 consecutive RCC patients at our center and a total of 248 patients were selected for FISH and immunohistochemistry (IHC) analysis. Eventually, eighteen TFEB-altered RCC patients were identified. We then reported the clinical, morphological, IHC, and radiological features of these cases. RESULTS The median age at initial diagnosis was 45 years, ranging from 18 years to 66 years. The majority of the TFEB-altered RCC patients were male (61.1%), with localized disease (T1-2N0M0, 77.8%). The median split TFEB fluorescent signal was 24%, ranging from 15%-80%. The morphological characteristics of TFEB-altered RCC were variable, with acinar, papillary, solid, or nest patterns. IHC and magnetic resonance imaging features of TFEB-altered RCC were nonspecific. Nine patients with localized disease received partial nephrectomy and five patients with localized disease received radical nephrectomy. During the median follow-up of 67 months, no signs of recurrence or metastasis were found in these patients. Two patients had distant metastasis and received axitinib plus PD-1 immunotherapy. One of them died at 40-month follow-up and another still alive at 88-month follow-up. CONCLUSION TFEB-altered RCC is an extremely rare variant, exhibited mixed morphological characteristics. The radiological feature lack specificity, resembling clear cell RCC or papillary RCC. Genetic analyses including FISH analysis is crucial in the diagnosis of TFEB-altered RCC. For localized TFEB-altered RCC, both radical nephrectomy and partial nephrectomy conferred satisfactory prognosis. For metastatic TFEB-altered RCC, immunotherapy-based drug combinations could be a promising treatment strategy.
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Affiliation(s)
- Jie Wu
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chuan-Zhen Cao
- Department of Urology, China-Japan Friendship Hospital, Beijing, China
| | - Hong-Lei Cui
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Gan Du
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong-Zhe Shi
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Liang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Guo
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi-Cheng Wang
- Department of Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin Zhang
- Department of Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ai-Ping Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chang-Ling Li
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shan Zheng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jian-Zhong Shou
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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23
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Zhang Y, Li C, Deng X, Urabe F, Burotto M, Buti S, Giudice GC, Zhao Z, Yang C, Sun J, Du Y, Wang S. Treatment of metastatic TFE3 microphthalmia transcription factor translocation renal cell carcinoma: a case report. Transl Pediatr 2024; 13:499-507. [PMID: 38590368 PMCID: PMC10998990 DOI: 10.21037/tp-24-35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 03/12/2024] [Indexed: 04/10/2024] Open
Abstract
Background Microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) translocation renal cell carcinoma (RCC) is a rare type of non-clear cell RCC (nccRCC), which is more common in females. Currently, there is no standardized treatment for advanced metastatic microphthalmia translocation RCC (MiT-RCC). The main treatment modalities include surgery, chemotherapy, immunotherapy, anti-vascular endothelial growth factor or vascular endothelial growth factor receptor (VEGFR) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and targeted therapy against the mesenchymal-epithelial transition (MET) factor signaling pathway. Case Description We present the case of an 8-year-old male patient with hematuria and paroxysmal urinary pain. Based on tumor genetic testing results and targeted drug matching analysis, the patient underwent tumor biopsy, tumor radical surgery with vascular osteotomy, and cervicothoracic lymph node dissection. The patient was then treated with a combination of immunotherapy [sintilimab, a drug directed against programmed cell death receptor-1 (PD-1)] and VEGFR tyrosine kinase inhibitor (TKI) (from pazopanib to sunitinib). Throughout the 10 cycles of conventional chemotherapy (seven courses of sintilimab since the start of the third chemotherapy treatment), the patient's condition remained stable, with no tumor recurrence at the primary site. However, in the later stages, the patient developed a large amount of ascites, and the family requested discontinuation of treatment, ultimately leading to the patient's death. Conclusions In this case report, we summarize the therapeutic strategy of a young patient with metastatic transcription factor E3 (TFE3) MiT-RCC. For this disease, early immunotherapy and the use of precision-targeted drugs may have a favorable impact on the survival prognosis of the patient but may still be of less benefit in children with advanced multiple metastases. Therefore, further research on tumor driver genes, among other treatment components, is urgently needed to improve precision therapy.
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Affiliation(s)
- Yunlong Zhang
- Department of Pediatric Surgical Oncology, Children’s Hospital of Chongqing Medical University, The National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Changchun Li
- Department of Pediatric Surgical Oncology, Children’s Hospital of Chongqing Medical University, The National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xiaobin Deng
- Department of Pediatric Surgical Oncology, Children’s Hospital of Chongqing Medical University, The National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Fumihiko Urabe
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | | | - Sebastiano Buti
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Giulia Claire Giudice
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Zhenzhen Zhao
- Department of Pediatric Surgical Oncology, Children’s Hospital of Chongqing Medical University, The National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Chao Yang
- Department of Pediatric Surgical Oncology, Children’s Hospital of Chongqing Medical University, The National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jian Sun
- Department of Pediatric Surgical Oncology, Children’s Hospital of Chongqing Medical University, The National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yifei Du
- Department of Pediatric Surgical Oncology, Children’s Hospital of Chongqing Medical University, The National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Shan Wang
- Department of Pediatric Surgical Oncology, Children’s Hospital of Chongqing Medical University, The National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
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24
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Li P, Xu Q, Chen M, Zhu J, Wang Y, Mumin MA, Huang K, Jiang Z, Liang H, Deng Q, Wang Z, Liao B, Chen W, Cao Y, Cao J, Luo J. A nomogram based on TFE3 IHC results and clinical factors as a preliminary screening scheme for TFE3-rearranged renal cell carcinoma. Cancer Med 2024; 13:e6813. [PMID: 38477529 PMCID: PMC10935875 DOI: 10.1002/cam4.6813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 10/30/2023] [Accepted: 11/29/2023] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND TFE3 immunohistochemistry (TFE3-IHC) is controversial in the diagnosis of TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC). This study is to investigate the accuracy and sensitivity of IHC and establish a predictive model to diagnose TFE3-rearranged RCC. METHODS Retrospective analysis was performed by collecting IHC and fluorescence in situ hybridization (FISH) results from 228 patients. IHC results were evaluated using three scoring systems. Scoring system 1 is graded based on nuclear staining intensity, scoring system 2 is graded based on the percentage of stained tumor cell nuclei, and scoring system 3 is graded based on both the nuclear staining intensity and the percentage. We collected patients' IHC results and clinical information. Important variables were screened based on univariate logistic regression analysis. Then, independent risk factors were established through multivariate logistic regression, and a nomogram model was constructed. The model was validated in internal test set and external validation set. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) were generated to assess discriminative ability of the model. RESULTS The accuracy of IHC based on three scoring systems were 0.829, 0.772, and 0.807, respectively. The model included four factors including age, gender, lymph node metastasis and IHC results. Area under the curve (AUC) values were 0.935 for the training set, 0.934 for the internal test set, 0.933 for all 228 patients, and 0.916 for the external validation set. CONCLUSIONS TFE3 IHC has high accuracy in the diagnosis of TFE3-rearranged RCC. Clinical information such as age and lymph node metastasis are independent risk factors, which can be used as a supplement to the results of TFE3 IHC. This study confirms the value of IHC in the diagnosis of TFE3-rearranged RCC. The accuracy of the diagnosis can be improved by incorporating IHC with other clinical risk factors.
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Affiliation(s)
- Pengju Li
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Quanhui Xu
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Minyu Chen
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jiangquan Zhu
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yinghan Wang
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Mukhtar A. Mumin
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Kangbo Huang
- Department of UrologyThe Cancer Center of Sun Yat‐sen UniversityGuangzhouChina
| | - Zeying Jiang
- Department of PathologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Hui Liang
- Department of UrologyAffiliated Longhua People's Hospital, Southern Medical UniversityShenzhenChina
| | - Qiong Deng
- Department of UrologyAffiliated Longhua People's Hospital, Southern Medical UniversityShenzhenChina
| | - Zhu Wang
- Department of UrologyAffiliated Longhua People's Hospital, Southern Medical UniversityShenzhenChina
| | - Bing Liao
- Department of PathologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Wenfang Chen
- Department of PathologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yun Cao
- Department of PathologyThe Cancer Center of Sun Yat‐sen UniversityGuangzhouChina
| | - Jiazheng Cao
- Department of UrologyJiangmen Central HospitalJiangmenChina
| | - Junhang Luo
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
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25
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Prakasam G, Mishra A, Christie A, Miyata J, Carrillo D, Tcheuyap VT, Ye H, Do QN, Wang Y, Reig Torras O, Butti R, Zhong H, Gagan J, Jones KB, Carroll TJ, Modrusan Z, Durinck S, Requena-Komuro MC, Williams NS, Pedrosa I, Wang T, Rakheja D, Kapur P, Brugarolas J. Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis. J Clin Invest 2024; 134:e170559. [PMID: 38386415 PMCID: PMC10977987 DOI: 10.1172/jci170559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 02/06/2024] [Indexed: 02/24/2024] Open
Abstract
Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research.
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Affiliation(s)
- Gopinath Prakasam
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
| | - Akhilesh Mishra
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
| | - Alana Christie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Peter O’ Donnell Jr. School of Public Health
| | - Jeffrey Miyata
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
| | - Deyssy Carrillo
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
| | - Vanina T. Tcheuyap
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
| | - Hui Ye
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
| | | | - Yunguan Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Oscar Reig Torras
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Department of Medical Oncology and Translational Genomics and Targeted Therapies in Solid Tumors, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Barcelona, Spain
| | - Ramesh Butti
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
| | - Hua Zhong
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jeffrey Gagan
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Kevin B. Jones
- Department of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Thomas J. Carroll
- Department of Molecular Biology and Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Zora Modrusan
- Department of Microchemistry, Proteomics, Lipidomics and Next Generation Sequencing and
| | - Steffen Durinck
- Department of Oncology Bioinformatics, Genentech Inc., South San Francisco, California, USA
| | - Mai-Carmen Requena-Komuro
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
| | | | - Ivan Pedrosa
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Department of Radiology, and
- Advanced Imaging Research Center, and
- Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Tao Wang
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Peter O’ Donnell Jr. School of Public Health
- Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Dinesh Rakheja
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Payal Kapur
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - James Brugarolas
- Kidney Cancer Program, Simmons Comprehensive Cancer Center
- Hematology-Oncology Division, Department of Internal Medicine
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26
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Chen H, Gong S, Zhang H, Chen Y, Liu Y, Hao J, Liu H, Li X. From the regulatory mechanism of TFEB to its therapeutic implications. Cell Death Discov 2024; 10:84. [PMID: 38365838 PMCID: PMC10873368 DOI: 10.1038/s41420-024-01850-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/01/2024] [Accepted: 02/05/2024] [Indexed: 02/18/2024] Open
Abstract
Transcription factor EB (TFEB), known as a major transcriptional regulator of the autophagy-lysosomal pathway, regulates target gene expression by binding to coordinated lysosomal expression and regulation (CLEAR) elements. TFEB are regulated by multiple links, such as transcriptional regulation, post-transcriptional regulation, translational-level regulation, post-translational modification (PTM), and nuclear competitive regulation. Targeted regulation of TFEB has been victoriously used as a treatment strategy in several disease models such as ischemic injury, lysosomal storage disorders (LSDs), cancer, metabolic disorders, neurodegenerative diseases, and inflammation. In this review, we aimed to elucidate the regulatory mechanism of TFEB and its applications in several disease models by targeting the regulation of TFEB as a treatment strategy.
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Affiliation(s)
- Huixia Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Siqiao Gong
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Hongyong Zhang
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhan-jiang Central Hospital, Zhanjiang, 524001, China
| | - Yongming Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yonghan Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Junfeng Hao
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Huafeng Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Xiaoyu Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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27
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Liu Z, Hua X. Primary retroperitoneal renal cell carcinoma associated with transcription EB gene fusion. Minerva Med 2024; 115:32-36. [PMID: 32239878 DOI: 10.23736/s0026-4806.20.06527-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Renal cell carcinoma (RCC) with the distinct type of t(6;11) (p21;q12) translocation (transcription factor EB, TFEB) is a rare neoplasm. It is even less when talks about primary retroperitoneal TFEB RCCs. To our knowledge, no previous literature has been reported about this kind of RCCs. In this article, we report a case of primary retroperitoneal renal cell carcinoma associated with transcription EB gene fusion. METHODS A 73-year-old male patient presented with a retroperitoneal mass for more than one month. RESULTS Pathologically, the mass was soft and colorful, tumor cells showed a biphasic morphology characterized by nests of larger epithelioid cells surrounding intraluminal collections of smaller cells clustered around basement membrane materia. These tumor cells were positive for Pax-8, EMA, TFEB, CK, P504S, Vimentin and CD10 on immunohistochemical stain, and positive for TFEB on fluorescence in situ hybridization assay. CONCLUSIONS We reported the first case of primary retroperitoneal renal cell carcinoma associated with transcription EB gene fusion. The pathological feature of the case we reported was very typical. The best treatment at presentation is the total resection. Long-term follow-up study is needed in order to acquire better diagonitic quality and fulfill diagnostic requirements.
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Affiliation(s)
- Zhen Liu
- Department of Pathology, School of Clinical Medicine, Guizhou Medical University, Yunyan District, Guiyang, China
| | - Xing Hua
- Department of Pathology, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, China -
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28
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Yang Y, Zhao C, Wang Z, Liu F, Zhao M, Yang H, Chen J, Chen X, Shi M, Jiang D, Luo X, Duan Y, Bai Y. Therapeutic strategies and predictive models for Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma in adults based on data of two Chinese medical centers. Aging (Albany NY) 2024; 16:1696-1711. [PMID: 38261736 PMCID: PMC10866448 DOI: 10.18632/aging.205452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 12/14/2023] [Indexed: 01/25/2024]
Abstract
OBJECTIVE This study aims to establish an effective predictive model for predicting Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma (TFE3-RCC) and develop optimal therapeutic strategies. METHODS Data from 4961 patients diagnosed with renal cell carcinoma at two medical centers in China were retrospectively analyzed. A cohort of 1571 patients from Zhejiang Provincial People's Hospital (Ra cohort) was selected to construct the model. Another cohort of 1124 patients from the Second Affiliated Hospital of Zhejiang Chinese Medical University was used for external validation (the Ha cohort). All patients with TFE3-RCC in both cohorts were included in the Ta cohort for the prognostic analysis. Univariate and multivariate binary logistic regression analyses were performed to identify independent predictors of the predictive nomogram. The apparent performance of the model was validated. Decision curve analysis was also performed to assess the clinical utility of the developed model. Factors associated with progression and prognosis in the Ta cohort were analyzed using the log-rank method, and Cox regression analysis and Kaplan-Meier survival curves were used to describe the effects of factors on prognosis and progression. RESULTS Univariate and multivariate logistic regression analyses demonstrated that age, sex, BMI, smoking, eosinophils, and LDL were independent predictors of TFE3-RCC. Therefore, a predictive nomogram for TFE3-RCC, which had good discriminatory power (AUC = 0.796), was constructed. External validation (AUC = 0.806) also revealed good predictive ability. The calibration curves displayed good consistency between the predicted and observed incidences of TFE3-RCC. Invasion of regional lymph nodes, tyrosine kinase inhibitors, and surgical methods were independent factors associated with progression. Tyrosine kinase inhibitors are independent prognostic factors. CONCLUSION This study not only proposed a high-precision clinical prediction model composed of various variables for the early diagnosis of Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma but also optimized therapeutic strategies through prognostic analysis.
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Affiliation(s)
- Yunkai Yang
- Department of Urology, Urology and Nephrology Center, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310011, China
| | - Changfeng Zhao
- Department of Urology, Urology and Nephrology Center, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310011, China
- Graduate School of Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Zhida Wang
- Department of Urology, Urology and Nephrology Center, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310011, China
| | - Feng Liu
- Department of Urology, Urology and Nephrology Center, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310011, China
| | - Ming Zhao
- Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang 310011, China
| | - Huiwen Yang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, China
| | - Jun Chen
- Department of Urology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, China
| | - Xuejing Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, China
| | - Min Shi
- Department of Medical Psychology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, China
| | - Dixing Jiang
- Department of Urology, Zhejiang Medical and Health Group Hangzhou Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310022, China
| | - Xiaoting Luo
- Department of Urology, Urology and Nephrology Center, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310011, China
| | - Yue Duan
- Department of Urology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, China
| | - Yuchen Bai
- Department of Urology, Urology and Nephrology Center, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310011, China
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29
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Caliò A, Marletta S, Settanni G, Rizzo M, Gobbo S, Pedron S, Stefanizzi L, Munari E, Brunelli M, Marcolini L, Pesci A, Fratoni S, Pierconti F, Raspollini MR, Marchetti A, Doglioni C, Amin MB, Porta C, Martignoni G. mTOR eosinophilic renal cell carcinoma: a distinctive tumor characterized by mTOR mutation, loss of chromosome 1, cathepsin-K expression, and response to target therapy. Virchows Arch 2023; 483:821-833. [PMID: 37938323 PMCID: PMC10700445 DOI: 10.1007/s00428-023-03688-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/17/2023] [Accepted: 10/24/2023] [Indexed: 11/09/2023]
Abstract
In the spectrum of oncocytic renal neoplasms, a subset of tumors with high-grade-appearing histologic features harboring pathogenic mutations in mammalian target of rapamycin (mTOR) and hitherto clinical indolent behavior has been described. Three cases (2F,1 M) with histologically documented metastases (lymph node, skull, and liver) were retrieved and extensively investigated by immunohistochemistry, FISH, and next-generation sequencing. Tumors were composed of eosinophilic cells with prominent nucleoli (G3 by ISUP/WHO) arranged in solid to nested architecture. Additionally, there were larger cells with perinuclear cytoplasmic shrinkage and sparse basophilic Nissl-like granules, superficially resembling the so-called spider cells of cardiac rhabdomyomas. The renal tumors, including the skull and liver metastases, showed immunoexpression PAX8, CK8-18, and cathepsin-K, and negativity for vimentin. NGS identified mTOR genetic alterations in the three cases, including the skull and liver metastases. One patient was then treated with Everolimus (mTOR inhibitors) with clinical response (metastatic tumor shrinkage). We present a distinct renal tumor characterized by high-grade eosinophilic cells, cathepsin-K immunohistochemical expression, and harboring mTOR gene mutations demonstrating a malignant potential and showing responsiveness to mTOR inhibitors.
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Affiliation(s)
- Anna Caliò
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Largo L. Scuro 10, 37134, Verona, Italy
| | - Stefano Marletta
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Largo L. Scuro 10, 37134, Verona, Italy
- Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy
| | - Giulio Settanni
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy
| | - Mimma Rizzo
- Division of Medical Oncology, A.O.U. Consorziale Policlinico Di Bari, Bari, Italy
| | - Stefano Gobbo
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Serena Pedron
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Largo L. Scuro 10, 37134, Verona, Italy
| | | | - Enrico Munari
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Matteo Brunelli
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Largo L. Scuro 10, 37134, Verona, Italy
| | - Lisa Marcolini
- Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy
| | - Anna Pesci
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy
| | - Stefano Fratoni
- Division of Anatomic Pathology, S. Eugenio Hospital, Rome, Italy
| | - Francesco Pierconti
- Division of Anatomic Pathology and Histology, Foundation "A. Gemelli" University Hospital, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maria Rosaria Raspollini
- Histopathology and Molecular Diagnostics, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Antonio Marchetti
- Division of Anatomic Pathology and Histology, Ospedale Clinicizzato "SS. Annunziata" Università Di Chieti, Chieti, Italy
| | | | - Mahul B Amin
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science, Memphis, TN, USA
- Department of Urology, USC Keck School of Medicine, Los Angeles, CA, USA
| | - Camillo Porta
- Interdisciplinary Department of Medicine, University of Bari "A. Moro, Bari, Italy
| | - Guido Martignoni
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Largo L. Scuro 10, 37134, Verona, Italy.
- Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy.
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Murakami S, Nagawa K, Inui T, Yamamoto A, Suzuki M, Koga F, Motoi T, Takaki Y. Case Reports of TFE3-Rearranged Renal Cell Carcinoma: FDG-PET Uptake Might Help Diagnosis. J Kidney Cancer VHL 2023; 10:61-68. [PMID: 37789903 PMCID: PMC10542702 DOI: 10.15586/jkcvhl.v10i3.266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 09/10/2023] [Indexed: 10/05/2023] Open
Abstract
Translocation and transcription factor E3 (TFE3)-rearranged renal cell carcinoma (RCC) is a rare subtype of RCCs characterised by the fusion of the TFE3 transcription factor genes on chromosome Xp11.2 with one of the multiple genes. TFE3-rearranged RCC occurs mainly in children and adolescents, although middle-aged cases are also observed. As computed tomography (CT)/magnetic resonance imaging (MRI) findings of TFE3-rearranged RCC overlap with those of other RCCs, differential diagnosis is often challenging. In the present case reports, we highlighted the features of the fluorine-18-labelled fluorodeoxyglucose positron emission tomography with CT (FDG PET-CT) in TFE3-rearranged RCCs. Due to the rarity of the disease, FDG PET-CT features of TFE3-rearranged RCC have not yet been reported. In our cases, FDG PET-CT showed high standardised uptake values (SUVmax) of 7.14 and 6.25 for primary tumours. This might imply that TFE3-rearranged RCC has high malignant potential. This is conceivable when the molecular background of the disease is considered in terms of glucose metabolism. Our cases suggest that a high SUVmax of the primary tumour is a clinical characteristic of TFE3-rearranged RCCs.
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Affiliation(s)
- Sho Murakami
- Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Keita Nagawa
- Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Takanori Inui
- Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Aya Yamamoto
- Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Mizuka Suzuki
- Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Fumitaka Koga
- Department of Urology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Toru Motoi
- Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Yasunobu Takaki
- Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
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Hu X, Tan C, Zhu G. Clinical Characteristics of Molecularly Defined Renal Cell Carcinomas. Curr Issues Mol Biol 2023; 45:4763-4777. [PMID: 37367052 DOI: 10.3390/cimb45060303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/28/2023] Open
Abstract
Kidney tumors comprise a broad spectrum of different histopathological entities, with more than 0.4 million newly diagnosed cases each year, mostly in middle-aged and older men. Based on the description of the 2022 World Health Organization (WHO) classification of renal cell carcinoma (RCC), some new categories of tumor types have been added according to their specific molecular typing. However, studies on these types of RCC are still superficial, many types of these RCC currently lack accurate diagnostic standards in the clinic, and treatment protocols are largely consistent with the treatment guidelines for clear cell RCC (ccRCC), which might result in worse treatment outcomes for patients with these types of molecularly defined RCC. In this article, we conduct a narrative review of the literature published in the last 15 years on molecularly defined RCC. The purpose of this review is to summarize the clinical features and the current status of research on the detection and treatment of molecularly defined RCC.
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Affiliation(s)
- Xinfeng Hu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Congzhu Tan
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Guodong Zhu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
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Lin J, Tang Z, Zhang C, Dong W, Liu Y, Huang H, Liu H, Huang J, Lin T, Chen X. TFE3 gene rearrangement and protein expression contribute to a poor prognosis of renal cell carcinoma. Heliyon 2023; 9:e16076. [PMID: 37215783 PMCID: PMC10196445 DOI: 10.1016/j.heliyon.2023.e16076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 04/30/2023] [Accepted: 05/04/2023] [Indexed: 05/24/2023] Open
Abstract
Background TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC) is a type of kidney cancer with a low incidence, with no consensus about whether it has a worse prognosis than clear cell renal cell carcinoma (ccRCC). This study attempted to elucidate the impact of TFE3-rearranged RCC by analyzing its clinical features and prognosis. Methods Patients treated in Sun Yat-sen Memorial Hospital (SYSMH) who were suspected to be diagnosed with TFE3-rearranged RCC were divided into two groups, TFE3-rearranged RCC and ccRCC with positive TFE3 protein expression on immunohistochemistry [TFE3(+) ccRCC], by dual-color, break-apart fluorescence in situ hybridization (FISH). After balancing the baseline characteristics with TFE3(+) ccRCC using the propensity score matching (PSM) method in a ratio of 2, we selected patients diagnosed with ccRCC with negative TFE3 protein expression on immunohistochemistry [TFE3(-) ccRCC]. The impact of TFE3 gene rearrangement and protein expression on renal cell carcinoma was determined by feature comparison with a nonparametric test and survival analysis with the Kaplan‒Meier method. Results Among 37 patients suspected of having TFE3-rearranged RCC, 13 patients were diagnosed with TFE3-rearranged RCC, and 24 patients had TFE3(+) ccRCC. The recurrence and new metastasis of TFE3-rearranged RCC was relatively common, even if the tumor stage was early at the first diagnosis. Through feature comparison and survival analysis, we found that TFE3-rearranged RCC was quite similar to TFE3(+) ccRCC. Compared with TFE3(-) ccRCC, TFE3(+) ccRCC tended to have a larger tumor diameter (P = 0.011), higher neutrophil/lymphocyte ratio (NLR) (P = 0.017) and metastatic potential (P = 0.022), and worse overall survival (OS) (P = 0.043) and PFS (P = 0.016). The survival analysis showed that TFE3-rearranged RCC had a worse PFS than ccRCC (P = 0.002), and TFE3(+) RCC had a worse PFS than TFE3(-) RCC (P = 0.001). According to the stratification system based on the combination of TFE3 and lymphovascular invasion (LVI), we further found that the prognosis from good to poor was TFE3(-) LVI(-), TFE3(+) LVI(-), TFE3(+) LVI(+) and TFE3(-) LVI(+), with statistically significant differences in both OS (P = 0.001) and PFS (P < 0.001). In addition, we also reported two cases with poor prognosis, of which one was TFE3-rearranged RCC and the other was TFE3(+) ccRCC. Conclusions This is a novel finding that both FISH confirmed TFE3 gene rearrangement-mediated TFE3-rearranged RCC and IHC confirmed positive TFE3 protein expression [TFE3(+)] contribute to a poor prognosis in RCC, suggesting more active treatment and careful follow-up for TFE3(+) RCC patients. The combination of TFE3 and LVI may be a new risk stratification system for RCC.
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Affiliation(s)
- Junyi Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Department of Urology, Minimally Invasive Surgery Center, Guangdong Key Laboratory of Urology, Guangzhou Urology Research Institute, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhuang Tang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Chengjunyu Zhang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Wen Dong
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China
| | - Yeqing Liu
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Hao Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Hao Liu
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
| | - Jian Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China
| | - Tianxin Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China
| | - Xu Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China
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Mimma R, Anna C, Matteo B, Gaetano P, Carlo G, Guido M, Camillo P. Clinico-pathological implications of the 2022 WHO Renal Cell Carcinoma classification. Cancer Treat Rev 2023; 116:102558. [PMID: 37060647 DOI: 10.1016/j.ctrv.2023.102558] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/03/2023] [Accepted: 04/07/2023] [Indexed: 04/17/2023]
Abstract
The new WHO classification of urogenital tumours published in 2022, contains significant revisions upon the previous 2016 version regarding Renal Cell Carcinoma (RCC). While the most common histotype remains almost untouched, some of the main novelties concerns papillary RCC and oncocytic neoplasms. The main change is the introduction of a new category of molecularly-defined RCC, which includes TFE3-rearranged RCC, TFEB-rearranged, and TFEB-amplified RCC, FH-deficient RCC, SDH-deficient RCC, ALK-rearranged RCC, ELOC (formerly TCEB1)-mutated RCC, SMARCB1 (INI1)-deficient RCC. In this paper we analyze the current knowledge on emerging entities and molecularly-defined RCC to assess whether the current pathological classification offers the oncologist the possibility of selecting more specific and personalized treatments, from both those currently available, as well as those that will soon be available.
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Affiliation(s)
- Rizzo Mimma
- Division of Medical Oncology, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, Bari, Italy.
| | - Caliò Anna
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy
| | - Brunelli Matteo
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy
| | - Pezzicoli Gaetano
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari "A. Moro", Bari, Italy
| | - Ganini Carlo
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari "A. Moro", Bari, Italy
| | - Martignoni Guido
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy; Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Verona, Italy
| | - Porta Camillo
- Division of Medical Oncology, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, Bari, Italy; Chair of Oncology, Interdisciplinary Department of Medicine, University of Bari "A. Moro", Bari, Italy
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Song T, Lv S, Ma X, Zhao X, Fan L, Zou Q, Li N, Yan Y, Zhang W, Sun L. TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy. J Biol Chem 2023; 299:104621. [PMID: 36935008 PMCID: PMC10141522 DOI: 10.1016/j.jbc.2023.104621] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Autophagy plays a pivotal role in physiology and pathophysiology, including cancer. Mechanisms of autophagy dysregulation in cancer remain elusive. Loss-of-function of TRIM28, a multi-function protein, is seen in familial kidney malignancy, but the mechanism by which TRIM28 contributes to the etiology of kidney malignancy is unclear. In this study, we show TRIM28 retards kidney cancer cell proliferation through inhibiting autophagy. Mechanistically, we find TRIM28 promotes ubiquitination and proteasome-mediated degradation of transcription factor TFE3, which is critical for autophagic gene expression. Genetic activation of TFE3 due to gene fusion is known to cause human kidney malignancy, but whether and how transcription activation by TFE3 involves chromatin changes is unclear. Here, we find another mode of TFE3 activation in human renal carcinoma. We find that TFE3 is constitutively localized to the cell nucleus in human and mouse kidney cancer, where it increases autophagic gene expression and promotes cell autophagy as well as proliferation. We further uncover that TFE3 interacts with and recruits histone H3K27 demethylase KDM6A for autophagic gene upregulation. We reveal that KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27. Collectively, in this study, we identify a functional TRIM28-TFE3-KDM6A signal axis which plays a critical role in kidney cancer cell autophagy and proliferation.
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Affiliation(s)
- Tanjing Song
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Suli Lv
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Xianyun Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Xuefeng Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Li Fan
- Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,China
| | - Qingli Zou
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Neng Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Yingying Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030
| | - Wen Zhang
- Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,China
| | - Lidong Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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Li X, Chen Y, Gong S, Chen H, Liu H, Li X, Hao J. Emerging roles of TFE3 in metabolic regulation. Cell Death Discov 2023; 9:93. [PMID: 36906611 PMCID: PMC10008649 DOI: 10.1038/s41420-023-01395-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/13/2023] Open
Abstract
TFE3 is a member of the MiT family of the bHLH-leucine zipper transcription factor. We previously focused on the role of TFE3 in autophagy and cancer. Recently, an increasing number of studies have revealed that TFE3 plays an important role in metabolic regulation. TFE3 participates in the metabolism of energy in the body by regulating pathways such as glucose and lipid metabolism, mitochondrial metabolism, and autophagy. This review summarizes and discusses the specific regulatory mechanisms of TFE3 in metabolism. We determined both the direct regulation of TFE3 on metabolically active cells, such as hepatocytes and skeletal muscle cells, and the indirect regulation of TFE3 through mitochondrial quality control and the autophagy-lysosome pathway. The role of TFE3 in tumor cell metabolism is also summarized in this review. Understanding the diverse roles of TFE3 in metabolic processes can provide new avenues for the treatment of some metabolism-related disorders.
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Affiliation(s)
- Xingyu Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yongming Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Siqiao Gong
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Huixia Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Huafeng Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Xiaoyu Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Junfeng Hao
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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Takamori H, Maeshima AM, Kato I, Baba M, Nakamura E, Matsui Y.
TFEB
‐translocated and ‐amplified renal cell carcinoma with
VEGFA
co‐amplification: A case of long‐term control by multimodal therapy including a vascular endothelial growth factor‐receptor inhibitor. IJU Case Rep 2023; 6:161-164. [PMID: 37144078 PMCID: PMC10151203 DOI: 10.1002/iju5.12575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/05/2023] [Indexed: 03/06/2023] Open
Abstract
Introduction Renal cell carcinoma with TFEB amplification is rare and reportedly aggressive. We herein report a case of renal cell carcinoma with TFEB translocation and amplification in which long-term control was achieved by multimodal therapy including a vascular endothelial growth factor -receptor inhibitor. Case presentation A 70-year-old man was referred to our institution for the treatment of renal cell carcinoma with multinodal metastases. Open nephrectomy and lymph node dissection were performed. Immunohistochemistry for transcription factor EB was positive, and fluorescent in situ hybridization revealed TFEB rearrangement and amplification. The diagnosis was TFEB-translocated and -amplified renal cell carcinoma. VEGFA amplification was also demonstrated by fluorescent in situ hybridization. The residual and recurrent tumors were treated and controlled for 52 months by vascular endothelial growth factor-receptor target therapy, radiation therapy, and additional surgery. Conclusion A good long-term response to anti-vascular endothelial growth factor drug therapy may be due to VEGFA amplification and subsequent vascular endothelial growth factor overexpression.
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Affiliation(s)
- Hajime Takamori
- Department of Urology National Cancer Center Hospital Tokyo Japan
| | | | - Ikuma Kato
- Department of Molecular Pathology Yokohama City University Graduate School of Medicine Yokohama Japan
| | - Masaya Baba
- International Research Center for Medical Sciences Kumamoto University Kumamoto Japan
| | - Eijiro Nakamura
- Department of Urology National Cancer Center Hospital Tokyo Japan
| | - Yoshiyuki Matsui
- Department of Urology National Cancer Center Hospital Tokyo Japan
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Guo W, Zhu Y, Pu X, Guo H, Gan W. Clinical and pathological heterogeneity of four common fusion subtypes in Xp11.2 translocation renal cell carcinoma. Front Oncol 2023; 13:1116648. [PMID: 36816933 PMCID: PMC9935599 DOI: 10.3389/fonc.2023.1116648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Background Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a group of rare and highly heterogeneous renal cell carcinoma (RCC). The translocation involving TFE3 and different fusion partners lead to overexpression of the chimeric protein. The purpose of this study is to explore the clinicopathological features of Xp11.2 tRCC with four common fusion subtypes. Methods We screened out 40 Xp11.2 tRCC patients from January 2007 to August 2021 in our institution. The diagnosis was initially confirmed by TFE3 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assay and their fusion partners were verified by RNA sequencing. Then the 40 cases were divided into two groups (DBHS family and non-DBHS family group) and a clinical comparison among the four common fusion subtypes was performed. Results Among the 40 cases, 11 cases with SFPQ-TFE3 gene fusion and 7 cases with NONO-TFE3 gene fusion were classified in DBHS group, the remaining cases with ASPL-TFE3 (11 cases) or PRCC-TFE3 (11 cases) gene fusion were classified in non-DBHS group. Lymph node (LN) metastasis (P=0.027) and distant metastasis (P=0.009) were more common seen in non-DBHS family group than DBHS family group and cases in DBHS family group have better progressive-free survival (PFS) (P=0.02). In addition, ASPL-TFE3 fusion was associated with worse outcome (P=0.03) while NONO-TFE3 fusion (P=0.04) predicted a better prognosis. Conclusions Different fusion partner genes may play a functional role in various morphology, molecular and biological features of Xp11.2 tRCCs. The impact of fusion partners on clinical characteristics of Xp11.2 tRCCs deserves further exploration.
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Affiliation(s)
- Wei Guo
- Department of Urology, Drum Tower Clinical Medical School of Nanjing Medical University, Nanjing, Jiangsu, China,Department of Urology, Taizhou People’s Hospital Affiliated to Nanjing Medical University, Taizhou, Jiangsu, China
| | - Yiqi Zhu
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiaohong Pu
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Hongqian Guo
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weidong Gan
- Department of Urology, Drum Tower Clinical Medical School of Nanjing Medical University, Nanjing, Jiangsu, China,Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China,*Correspondence: Weidong Gan,
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Zhao J, Peng J, Liu J, Deng Q, Pang X. Primary Alveolar Soft-Part Sarcoma of the Lung: A Case Report. Int J Surg Pathol 2023; 31:98-103. [PMID: 35521911 DOI: 10.1177/10668969221096869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Alveolar soft-part sarcoma is a rare type of soft tissue malignant tumor. Although the tumor can occur in many parts of the body, primary alveolar soft-part sarcoma of the lung is extremely rare. According to previous literature, only 3 cases of primary alveolar soft-part sarcoma of the lung were reported, and no comprehensive analysis was conducted on these cases. Here, we describe another case of alveolar soft-part sarcoma in the lung, where the negative results of immunohistochemical staining cause extreme difficulty in distinguishing this lesion from other tumors. A 30-year-old Chinese male presented with chest pain and dyspnea. Computed tomography revealed a pulmonary mass, and biopsy results showed vacuolar tumor cells with abundant eosinophilic cytoplasm. A number of immunohistochemical markers were negative, but the tumor cells were positive for TFE3 and ASPSCR1::TFE3 fusion gene. No other tumor masses were found in the patient after whole-body scanning. The final diagnosis was primary alveolar soft-part sarcoma of the lung. Pathologists should consider the possibility of alveolar soft-part sarcoma in lung tumors with typical "organ like" or "acinar like" cell nests, where the tumor cells are large, vacuolated, and the nucleolus is obvious. After excluding metastasis from other sites, TFE3 immunohistochemical staining and ASPSCR1::TFE3 fusion gene detection are recommended for the diagnosis of primary alveolar soft-part sarcoma.
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Affiliation(s)
- Jiangying Zhao
- Department of Pathology, 118385Mianyang Hospital of T.C.M, Mianyang, Sichuan 621000, P.R. China
| | - Jiao Peng
- Department of Pathology, 118385Mianyang Hospital of T.C.M, Mianyang, Sichuan 621000, P.R. China
| | - Jingtao Liu
- Department of Thoracic Surgery, 118385Mianyang Hospital of T.C.M, Mianyang, Sichuan 621000, P.R. China
| | - Qiang Deng
- Department of Thoracic Surgery, 118385Mianyang Hospital of T.C.M, Mianyang, Sichuan 621000, P.R. China
| | - Xiaojun Pang
- Department of Pathology, 118385Mianyang Hospital of T.C.M, Mianyang, Sichuan 621000, P.R. China
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A Novel Predictive Model of Pathological Lymph Node Metastasis Constructed with Preoperative Independent Predictors in Patients with Renal Cell Carcinoma. J Clin Med 2023; 12:jcm12020441. [PMID: 36675368 PMCID: PMC9866659 DOI: 10.3390/jcm12020441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/21/2022] [Accepted: 12/25/2022] [Indexed: 01/06/2023] Open
Abstract
Introduction: Renal cell carcinoma (RCC) is one of the most common urinary tumors. The risk of metastasis for patients with RCC is about 1/3, among which 30−40% have lymph node metastasis, and the existence of lymph node metastasis will greatly reduce the survival rate of patients. However, the necessity of lymph node dissection is still controversial at present. Therefore, a new predictive model is urgently needed to judge the risk of lymph node metastasis and guide clinical decision making before operation. Method: We retrospectively collected the data of 189 patients who underwent retroperitoneal lymph node dissection or enlarged lymph node resection due to suspected lymph node metastasis or enlarged lymph nodes found during an operation in Tongji Hospital from January 2016 to October 2021. Univariate and multivariate logistic regression and least absolute shrinkage and selection operator (lasso) regression analyses were used to identify preoperative predictors of pathological lymph node positivity. A nomogram was established to predict the probability of lymph node metastasis in patients with RCC before surgery according to the above independent predictors, and its efficacy was evaluated with a calibration curve and a DCA analysis. Result: Among the 189 patients, 54 (28.60%) were pN1 patients, and 135 (71.40%) were pN0 patients. Three independent impact factors were, finally, identified, which were the following: age (OR = 0.3769, 95% CI = 0.1864−0.7622, p < 0.01), lymph node size according to pre-operative imaging (10−20 mm: OR = 15.0040, 95% CI = 1.5666−143.7000, p < 0.05; >20 mm: OR = 4.4013, 95% CI = 1.4892−7.3134, p < 0.01) and clinical T stage (cT1−2 vs. cT3−4) (OR = 3.1641, 95% CI = 1.0336−9.6860, p < 0.05). The calibration curve and DCA (Decision Curve Analysis) showed the nomogram of this predictive model had good fitting. Conclusions: Low age, large lymph node size in pre-operative imaging and high clinical T stage can be used as independent predictive factors of pathological lymph node metastasis in patients with RCC. Our predictive nomogram using these factors exhibited excellent discrimination and calibration.
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Zhu Y, Xia C, Ou Y, Zhang C, Li L, Yang D. TFEB-associated renal cell carcinoma: A case report and literature review. Medicine (Baltimore) 2022; 101:e31870. [PMID: 36550835 PMCID: PMC9771232 DOI: 10.1097/md.0000000000031870] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
RATIONALE TFEB-associated renal cell carcinoma is very rare and belongs to the microphthalmia - associated transcription family translocation renal cell carcinoma. PATIENT CONCERNS Hospitalized for fever, a 29-year-old male patient had a left kidney lesion without any additional discomfort. DIAGNOSES Histopathological and immunohistochemical results were corresponding with TFEB renall cell carcinoma features. INTERVENTIONS Surgical resection of the tumor was performed. OUTCOMES After 8 months of follow-up, no tumor recurrence was observed. LESSONS TFEB-associated renal cell carcinoma is rare. The diagnosis is explicit. However, the optimal treatment needs to be further explored.
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Affiliation(s)
- Yong Zhu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Chengxing Xia
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yitian Ou
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Chao Zhang
- Department of Oncology, Qujing First People’s Hospital, Qujing, Yunnan, China
| | - Lin Li
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Delin Yang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- * Correspondence: Delin Yang, Department of Urology, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Kunming, Yunnan 650101, China (e-mail: )
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Qu Y, Wu X, Anwaier A, Feng J, Xu W, Pei X, Zhu Y, Liu Y, Bai L, Yang G, Tian X, Su J, Shi GH, Cao DL, Xu F, Wang Y, Gan HL, Ni S, Sun MH, Zhao JY, Zhang H, Ye D, Ding C. Proteogenomic characterization of MiT family translocation renal cell carcinoma. Nat Commun 2022; 13:7494. [PMID: 36470859 PMCID: PMC9722939 DOI: 10.1038/s41467-022-34460-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 10/26/2022] [Indexed: 12/12/2022] Open
Abstract
Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare type of kidney cancer, which is not well characterized. Here we show the comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues to elucidate the molecular landscape of this disease. Our study reveals that defective DNA repair plays an important role in tRCC carcinogenesis and progression. Metabolic processes are markedly dysregulated at both the mRNA and protein levels. Proteomic and phosphoproteome data identify mTOR signaling pathway as a potential therapeutic target. Moreover, molecular subtyping and immune infiltration analysis characterize the inter-tumoral heterogeneity of tRCC. Multi-omic integration reveals the dysregulation of cellular processes affected by genomic alterations, including oxidative phosphorylation, autophagy, transcription factor activity, and proteasome function. This study represents a comprehensive proteogenomic analysis of tRCC, providing valuable insights into its biological mechanisms, disease diagnosis, and prognostication.
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Affiliation(s)
- Yuanyuan Qu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Xiaohui Wu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Aihetaimujiang Anwaier
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Jinwen Feng
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Wenhao Xu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Xiaoru Pei
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Yu Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Yang Liu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Lin Bai
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Guojian Yang
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Xi Tian
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Jiaqi Su
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Guo-Hai Shi
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Da-Long Cao
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Fujiang Xu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yue Wang
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Hua-Lei Gan
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
- Tissue Bank & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Shujuan Ni
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
- Tissue Bank & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Meng-Hong Sun
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
- Tissue Bank & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Jian-Yuan Zhao
- Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Hailiang Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China.
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China.
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China.
- Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China.
| | - Chen Ding
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China.
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Contemporary Clinical Definitions, Differential Diagnosis, and Novel Predictive Tools for Renal Cell Carcinoma. Biomedicines 2022; 10:biomedicines10112926. [PMID: 36428491 PMCID: PMC9687297 DOI: 10.3390/biomedicines10112926] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/26/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Despite significant progress regarding clinical detection/imaging evaluation modalities and genetic/molecular characterization of pathogenesis, advanced renal cell carcinoma (RCC) remains an incurable disease and overall RCC mortality has been steadily rising for decades. Concomitantly, clinical definitions have been greatly nuanced and refined. RCCs are currently viewed as a heterogeneous series of cancers, with the same anatomical origin, but fundamentally different metabolisms and clinical behaviors. Thus, RCC pathological diagnosis/subtyping guidelines have become increasingly intricate and cumbersome, routinely requiring ancillary studies, mainly immunohistochemistry. Meanwhile, RCC-associated-antigen targeted systemic therapy has been greatly diversified and emerging, novel clinical applications for RCC immunotherapy have already reported significant survival benefits, at least in the adjuvant setting. Even so, systemically disseminated RCCs still associate very poor clinical outcomes, with currently available therapeutic modalities only being able to prolong survival. In lack of a definitive cure for advanced RCCs, integration of the amounting scientific knowledge regarding RCC pathogenesis into RCC clinical management has been paramount for improving patient outcomes. The current review aims to offer an integrative perspective regarding contemporary RCC clinical definitions, proper RCC clinical work-up at initial diagnosis (semiology and multimodal imaging), RCC pathological evaluation, differential diagnosis/subtyping protocols, and novel clinical tools for RCC screening, risk stratification and therapeutic response prediction.
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Bukavina L, Bensalah K, Bray F, Carlo M, Challacombe B, Karam JA, Kassouf W, Mitchell T, Montironi R, O'Brien T, Panebianco V, Scelo G, Shuch B, van Poppel H, Blosser CD, Psutka SP. Epidemiology of Renal Cell Carcinoma: 2022 Update. Eur Urol 2022; 82:529-542. [PMID: 36100483 DOI: 10.1016/j.eururo.2022.08.019] [Citation(s) in RCA: 319] [Impact Index Per Article: 106.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 07/27/2022] [Accepted: 08/16/2022] [Indexed: 11/18/2022]
Abstract
CONTEXT International variations in the rates of kidney cancer (KC) are considerable. An understanding of the risk factors for KC development is necessary to generate opportunities to reduce its incidence through prevention and surveillance. OBJECTIVE To retrieve and summarize global incidence and mortality rates of KC and risk factors associated with its development, and to describe known familial syndromes and genetic alterations that represent biologic risk factors. EVIDENCE ACQUISITION A systematic review was conducted via Medline (PubMed) and Scopus to include meta-analyses, reviews, and original studies regarding renal cell carcinoma, epidemiology, and risk factors. EVIDENCE SYNTHESIS Our narrative review provides a detailed analysis of KC incidence and mortality, with significant variations across time, geography, and sex. In particular, while KC incidence has continued to increase, mortality models have leveled off. Among the many risk factors, hypertension, obesity, and smoking are the most well established. The emergence of new genetic data coupled with observational data allows for integrated management and surveillance strategies for KC care. CONCLUSIONS KC incidence and mortality rates vary significantly by geography, sex, and age. Associations of the development of KC with modifiable and fixed risk factors such as obesity, hypertension, smoking, and chronic kidney disease (CKD)/end-stage kidney disease (ESKD) are well described. Recent advances in the genetic characterization of these cancers have led to a better understanding of the germline and somatic mutations that predispose patients to KC development, with potential for identification of therapeutic targets that may improve outcomes for these at-risk patients. PATIENT SUMMARY We reviewed evidence on the occurrence of kidney cancer (KC) around the world. Currently, the main avoidable causes are smoking, obesity, and high blood pressure. Although other risk factors also contribute, prevention and treatment of these three factors provide the best opportunities to reduce the risk of developing KC at present.
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Affiliation(s)
- Laura Bukavina
- Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA; University Hospitals Cleveland Medical Center, Case Western Reserve School of Medicine, Cleveland, OH, USA
| | - Karim Bensalah
- Department of Urology, University of Rennes, Rennes, France
| | - Freddie Bray
- Cancer Surveillance Section, International Agency for Research on Cancer, Lyon, France
| | - Maria Carlo
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ben Challacombe
- Department of Urology, Guy's and St. Thomas Hospitals, London, UK
| | - Jose A Karam
- Departments of Urology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wassim Kassouf
- Division of Adult Urology, McGill University, Montreal, Canada
| | - Thomas Mitchell
- Department of Urology, Wellcome Sanger Institute, Cambridge, UK
| | - Rodolfo Montironi
- Molecular Medicine and Cell Therapy Foundation, Polytechnic University of the Marche Region, Ancona, Italy
| | - Tim O'Brien
- Department of Urology, Guy's and St. Thomas Hospitals, London, UK
| | | | | | - Brian Shuch
- Department of Urology, University of California-Los Angeles, Los Angeles, CA, USA
| | - Hein van Poppel
- Department of Urology, Catholic University of Leuven, Leuven, Belgium
| | - Christopher D Blosser
- Department of Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA, USA
| | - Sarah P Psutka
- Department of Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.
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MiT translocation renal cell carcinoma: A review of the literature from molecular characterization to clinical management. Biochim Biophys Acta Rev Cancer 2022; 1877:188823. [DOI: 10.1016/j.bbcan.2022.188823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/17/2022] [Accepted: 10/04/2022] [Indexed: 11/23/2022]
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Dong X, Chen Y, Pan J, Ma W, Zhou P, Chen M, Guo H, Gan W. Clinicopathological features and prognosis of TFE3-positive renal cell carcinoma. Front Oncol 2022; 12:1017425. [PMID: 36276115 PMCID: PMC9582134 DOI: 10.3389/fonc.2022.1017425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/22/2022] [Indexed: 11/26/2022] Open
Abstract
Background This study aimed to investigate the expression profile of TFE3 in renal cell carcinoma (RCC) and the clinicopathological features as well as prognosis of TFE3-positive RCC. Methods Tissue sections from 796 patients with RCC were collected for immunohistochemical staining of TFE3. Molecular TFE3 rearrangement tests were also carried out on the TFE3-positive RCCs using fluorescence in situ hybridization and RNA-sequencing assays. Both clinicopathological features and follow-up information were collected for further analysis. Results The present study showed that 91 patients with RCC (91/796, 11.4%) were TFE3 positive expression but only 31 (31/91, 34.1%) of the patients were diagnosed with Xp11.2 translocation RCC. Further, it was found that the patients with TFE3-positive RCCs were more likely to develop lymph node and distant metastasis at diagnosis as well as presented a significantly higher WHO/ISUP nuclear grade and AJCC stage as compared with patients with TFE3-negative RCCs (p<0.01). Results of univariate and multivariate analyses showed that TFE3 positive expression was an independent prognostic factor associated with poor progression-free survival. Further, the findings of survival analysis showed that patients with positive TFE3 expression showed a shorter progression-free survival as compared with the patients with negative expression of TFE3 (p<0.001). In addition, results of the survival analysis found that there was no significant difference in progression-free survival between the Xp11.2 translocation RCC and TFE3-positive non-Xp11.2 translocation RCC groups (p=0.9607). Conclusion This study found that nuclear TFE3 expression is not specific to the Xp11.2 translocation RCC. Moreover, the positive TFE3 expression is associated with tumor progression and poor prognosis in patients with RCC irrespective of the presence of TFE3 translocation.
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Affiliation(s)
- Xiang Dong
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yuxin Chen
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jun Pan
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wenliang Ma
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Peng Zhou
- Department of Urology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Ming Chen
- Department of Pathology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Hongqian Guo
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Weidong Gan
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
- *Correspondence: Weidong Gan,
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Zhao J, Dai K, Xie J, Fang C, Chen N, Dai J, Xu D. Case Report: Clinical complete response of advanced renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion by treated by camrelizumab and axitinib: A rare case report. Front Pharmacol 2022; 13:927299. [PMID: 36034832 PMCID: PMC9403306 DOI: 10.3389/fphar.2022.927299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusions is a rare subtype of renal tumor. This entity predominantly occurs in juveniles, but rarely in adults. Xp11.2 translocation RCC (tRCC) patients with lymph node or organ metastasis are associated with poor prognosis, and the strategy remains controversial. Herein, we presented our experience with the diagnosis and treatment of an adult case of Xp11.2 tRCC. In our clinical practice, a 32-year-old male manifested fever and right flank paroxysmal blunt pain, and computed tomography showed an inhomogeneous mass, 6 cm in diameter, in the right kidney. Then right partial nephrectomy (PN) and renal hilar lymph node dissection by laparoscopic surgery were performed. Pathology revealed that the tumor cells were positive for TFE3 immunohistologically and positive for TFE3 break-apart fluorescence in situ hybridization assay. A splice site mutation c.1544-1G>T of protein tyrosine phosphatase receptor delta (PTPRD) was detected by next-generation sequencing and weak PTPRD expression was confirmed in tumor tissues compared to tumor periphery. This patient was diagnosed with stage III RCC and received immune checkpoint inhibitor (camrelizumab) in combination with tyrosine kinase inhibitor (axitinib) treatment for 1 year. He achieved a clinical complete response with no sign of recurrence or metastasis. PTPRD mutation might be a favorable indicator for Xp11.2 tRCC patients managed by PN and followed by the adjuvant therapy of immune checkpoint inhibitor and tyrosine kinase inhibitor.
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Affiliation(s)
- Juping Zhao
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Juping Zhao, ; Jun Dai, ; Danfeng Xu,
| | - Kun Dai
- Hangzhou Jichenjunchuang Medical Laboratory Co.Ltd, Hangzhou, China
| | - Jialing Xie
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Fang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Na Chen
- Hangzhou Jichenjunchuang Medical Laboratory Co.Ltd, Hangzhou, China
| | - Jun Dai
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Juping Zhao, ; Jun Dai, ; Danfeng Xu,
| | - Danfeng Xu
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Juping Zhao, ; Jun Dai, ; Danfeng Xu,
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Wang Y, Xu G, Yang H, Zhou X, Wen H. Renal Cell Carcinoma Associated with t (6;11) Translocation/TFEB Gene Fusion: A Case Report and Review of Literature. Clin Genitourin Cancer 2022; 21:309-313. [PMID: 36153295 DOI: 10.1016/j.clgc.2022.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/16/2022] [Accepted: 08/20/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Yiming Wang
- Department of Urology, Zhejiang University Mingzhou Hospital, Ningbo, Zhejiang, China
| | - Guangjun Xu
- Department of Urology, Zhejiang University Mingzhou Hospital, Ningbo, Zhejiang, China
| | - Haitao Yang
- Department of Pathology, Zhejiang University Mingzhou Hospital, Ningbo, Zhejiang, China
| | - Xiaolong Zhou
- Department of Pathology, Zhejiang University Mingzhou Hospital, Ningbo, Zhejiang, China
| | - Haitao Wen
- Department of Urology, Zhejiang University Mingzhou Hospital, Ningbo, Zhejiang, China.
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Simonaggio A, Ambrosetti D, Verkarre V, Auvray M, Oudard S, Vano YA. MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights. Int J Mol Sci 2022; 23:ijms23147649. [PMID: 35886994 PMCID: PMC9324307 DOI: 10.3390/ijms23147649] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 12/30/2022] Open
Abstract
MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC.
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Affiliation(s)
- Audrey Simonaggio
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France; (A.S.); (M.A.); (S.O.)
| | - Damien Ambrosetti
- Department of Pathology, CHU Nice, Université Côte d’Azur, F-06107 Nice, France;
- Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’Azur, F-06107 Nice, France
| | - Virginie Verkarre
- Department of Pathology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France;
- INSERM UMR-970, PARCC, Université Paris-Cité, F-75015 Paris, France
| | - Marie Auvray
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France; (A.S.); (M.A.); (S.O.)
| | - Stéphane Oudard
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France; (A.S.); (M.A.); (S.O.)
- INSERM UMR-970, PARCC, Université Paris-Cité, F-75015 Paris, France
| | - Yann-Alexandre Vano
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France; (A.S.); (M.A.); (S.O.)
- INSERM UMR-970, PARCC, Université Paris-Cité, F-75015 Paris, France
- Centre de Recherche des Cordeliers, INSERM, Université Paris-Cité, Sorbonne Université, F-75006 Paris, France
- Correspondence: ; Tel.: +33-624281311
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Kammerer-Jacquet SF, Gandon C, Dugay F, Laguerre B, Peyronnet B, Mathieu R, Verhoest G, Bensalah K, Leroy X, Aubert S, Vermaut C, Escande F, Verkarre V, Compérat E, Ambrosetti D, Pedeutour F, Belaud-Rotureau MA, Rioux-Leclercq N. Comprehensive study of 9 novel cases of TFEB-amplified renal cell carcinoma: an aggressive tumor with frequent PDL1 expression. Histopathology 2022; 81:228-238. [PMID: 35562857 DOI: 10.1111/his.14683] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 05/02/2022] [Accepted: 05/12/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND & OBJECTIVES First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain unclear. METHODS We report here the clinical, histological, immunohistochemical and genetic features of 9 novel cases. The pathological and immunohistochemical features were centrally reviewed by expert uropathologists. Fluorescence in situ hybridization (FISH) confirmed the diagnosis and comparative genomic hybridization (CGH) was performed to determine quantitative genomic alterations. We also performed an exhaustive review of the literature and compiled our data. RESULTS TFEB-amplified RCC were locally advanced with initial lymph node involvement in one case and liver metastasis in another case. They were high-grade eosinophilic tumors with papillary/pseudopapillary architecture, frequent positivity for melanocytic markers and frequent PDL1 expression. FISH demonstrated high-level TFEB amplification in 6 cases. One case showed concomitant TFEB translocation. CGH analysis identified complex alterations with frequent losses of 1p, 2q, 3p, 6p, and frequent 6p and 8q gains. VEGFA co-amplification was identified in all cases with a lower level than TFEB. The prognosis was poor with five patients having lymph node or distant metastases. CONCLUSION TFEB-amplified RCC is a rare molecular subgroup with variable morphology whose diagnosis is confirmed by FISH analysis. The complex alterations identified by CGH are consistent with an aggressive clinical behavior. The co-amplification of VEGFA and the expression of PDL1 could suggest a potential benefit from antiangiogenics and targeted immunotherapy in combination for these aggressive tumors.
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Affiliation(s)
| | - Camille Gandon
- Department of Pathology, University Hospital, Rennes, France
| | - Frederic Dugay
- UMR 6290-IGDR, Rennes, France.,Department of Cytogenetics, University Hospital, Rennes, France
| | | | | | - Romain Mathieu
- Department of Urology, University Hospital, Rennes, France
| | | | - Karim Bensalah
- Department of Urology, University Hospital, Rennes, France
| | - Xavier Leroy
- Univ.Lille, CHU Lille, Department of Pathology, F-59000, Lille, France
| | - Sebastien Aubert
- Univ.Lille, CHU Lille, Department of Pathology, F-59000, Lille, France
| | - Catherine Vermaut
- Department of Biochemistry and Molecular Biology, University Hospital, Lille, France
| | - Fabienne Escande
- Department of Biochemistry and Molecular Biology, University Hospital, Lille, France
| | - Virginie Verkarre
- Department of Pathology, HEGP, AP-HP-centre, Paris University, Paris, France
| | - Eva Compérat
- Department of Pathology, Tenon, AP-HP, Paris, France
| | | | - Florence Pedeutour
- Laboratory of Solid Tumor Genetics, University Hospital of Nice-Côte d'Azur University, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, Nice, France
| | - Marc-Antoine Belaud-Rotureau
- UMR 6290-IGDR, Rennes, France.,Department of Cytogenetics, University Hospital, Rennes, France.,Department of Oncology, Eugène Marquis Centre, Rennes, France
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50
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Liu N, Chen Y, Yang L, Shi Q, Lu Y, Ma W, Han X, Guo H, Li D, Gan W. Both SUMOylation and ubiquitination of TFE3 fusion protein regulated by androgen receptor are the potential target in the therapy of Xp11.2 translocation renal cell carcinoma. Clin Transl Med 2022; 12:e797. [PMID: 35452181 PMCID: PMC9029019 DOI: 10.1002/ctm2.797] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 03/14/2022] [Accepted: 03/18/2022] [Indexed: 01/06/2023] Open
Abstract
Background The aggressiveness of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 translocation RCC [Xp11.2 tRCC]) is age‐dependent, which is similar to the overall trend of reproductive endocrine hormones. Therefore, this study focused on the effect and potential mechanism of androgen and androgen receptor (AR) on the progression of Xp11.2 tRCC. Methods The effects of androgen and AR on the proliferation and migration of Xp11.2 tRCC cells were first evaluated utilising Xp11.2 tRCC cell lines and tissues. Because Transcription factor enhancer 3 (TFE3) fusion proteins play a key role in Xp11.2 tRCC, we focused on the regulatory role of AR and TFE3 expression and transcriptional activity. Results When Xp11.2 tRCC cells were treated with dihydrotestosterone, increased cell proliferation, invasion and migration were observed. Compared with clear cell RCC, the positive rate of AR in Xp11.2 tRCC tissues was higher, and its expression was negatively associated with the progression‐free survival of Xp11.2 tRCC. Further studies revealed that AR could positively regulate the transcriptional activity of TFE3 fusion proteins by small ubiquitin‐related modifier (SUMO)‐specific protease 1, inducing the deSUMOylation of TFE3 fusion. On the other hand, UCHL1 negatively regulated by AR plays a role in the deubiquitination degradation of the PRCC‐TFE3 fusion protein. Therefore, the combination of the AR inhibitor MDV3100 and the UCHL1 inhibitor 6RK73 was effective in delaying the progression of Xp11.2 tRCC, especially PRCC‐TFE3 tRCC. Conclusions Androgen and AR function as facilitators in Xp11.2 tRCC progression and may be a novel therapeutic target for Xp11.2 tRCC. The combined use of AR antagonist MDV3100 and UCHL1 inhibitor 6RK73 increased both the SUMOylation and ubiquitination of the PRCC‐TFE3 fusion protein
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Affiliation(s)
- Ning Liu
- Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Yi Chen
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Lei Yang
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Qiancheng Shi
- Department of Urology, Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yanwen Lu
- Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Wenliang Ma
- Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Hongqian Guo
- Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Dongmei Li
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Weidong Gan
- Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China
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