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1
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Burghout KST, Breimer GE, Koppes S, Hazelbag HM, Ooft ML, Raicu GM, Cleton-Jansen AM, van Wezel T, van Eijk R, Terlouw D, van Egmond SL, Smit VTHBM, Rupp NJ, Cohen D. Recurrent MDM2 Amplification in the Spectrum of HMGA2-Altered Pleomorphic Adenoma, Atypical Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma. Head Neck Pathol 2025; 19:56. [PMID: 40338436 PMCID: PMC12061814 DOI: 10.1007/s12105-025-01794-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 04/11/2025] [Indexed: 05/09/2025]
Abstract
INTRODUCTION Pleomorphic adenoma is the most common neoplasm of the salivary glands. While the overall risk of malignancy is relatively low, a distinct molecular sub-group harboring HMGA2 alterations seems to show an increased risk of malignant progression to carcinoma ex pleomorphic adenoma. PURPOSE This study investigates MDM2 amplification in HMGA2-altered pleomorphic adenoma, atypical pleomorphic adenoma, and carcinoma ex pleomorphic adenoma. METHODS In this multicenter, retrospective case series analysis, we examined 37 cases of HMGA2-altered pleomorphic adenoma, carcinoma ex pleomorphic adenoma, and pleomorphic adenoma with atypical features. A total of 18 cases were included from our institutional archives, with 19 additional cases derived from published literature. The cases from our institutes were analyzed for MDM2 amplification using a stepped approach by immunohistochemistry and FISH. RESULTS Collectively, an MDM2 amplification was present in 27% of pleomorphic adenoma (4 of 15), compared to 78% of carcinoma ex pleomorphic adenoma (14 of 18) (p-value = 0.003). In the group of pleomorphic adenomas with atypical features, an MDM2 amplification was present in 50% of cases (2 of 4). These findings indicate an association between MDM2 amplification and malignancy. Strikingly, a mixed control group of 12 benign and malignant PLAG1-altered neoplasms showed no immunohistochemical staining for MDM2. CONCLUSION Immunohistochemical MDM2 expression, including MDM2 amplification, is enriched in the group of HMGA2-altered pleomorphic adenoma, and potentially plays role in malignant progression. This study highlights the importance of recognizing the molecular sub-group of HMGA2-altered pleomorphic adenomas and integrate MDM2 analysis into routine diagnostics to corroborate the cytonuclear atypia in these challenging cases.
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Affiliation(s)
- Kimberly S T Burghout
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, ZA 2333, The Netherlands.
| | - G E Breimer
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - S Koppes
- Department of Pathology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - H M Hazelbag
- Department of Pathology, Haaglanden Medical Center, The Hague, The Netherlands
| | - M L Ooft
- Department of Pathology, Pathology-DNA, location Rijnstate Hospital, Arnhem, The Netherlands
| | - G M Raicu
- Department of Pathology, St. Antonius Hospital, Utrecht, 3543 AZ, The Netherlands
| | - A M Cleton-Jansen
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, ZA 2333, The Netherlands
| | - T van Wezel
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, ZA 2333, The Netherlands
- Department of Pathology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands
| | - R van Eijk
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, ZA 2333, The Netherlands
| | - D Terlouw
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, ZA 2333, The Netherlands
| | - S L van Egmond
- Department of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - V T H B M Smit
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, ZA 2333, The Netherlands
| | - N J Rupp
- Department of Pathology and Molecular Pathology, University Hospital, Zürich, Switzerland
- University of Zürich, Zürich, 8006, Switzerland
| | - D Cohen
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, ZA 2333, The Netherlands
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2
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Wang Y, Huang Y, Wang L, Chen Z, Zhou L, Xiang F, Li G, Yang J, Chen R, Xu Q, Shen Y. TP53INP2 promotes mitophagic degradation of YAP to impede dedifferentiated liposarcoma development. Oncogene 2025:10.1038/s41388-025-03358-4. [PMID: 40185868 DOI: 10.1038/s41388-025-03358-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 02/21/2025] [Accepted: 03/17/2025] [Indexed: 04/07/2025]
Abstract
Dedifferentiated liposarcoma (DDLPS) accounts for 15-20% of liposarcoma (LPS) and has high rates of local recurrence and distant metastasis. Hyperactivation of yes-associated protein (YAP) has been implicated in DDLPS development. However, the mechanisms that drive aberrant YAP signaling remain largely unknown. Here, we show that tumor protein p53 inducible nuclear protein 2 (TP53INP2) is a potential negative modulator of the malignant progression of DDLPS. The TP53INP2 protein expression level in tumor tissues from 79 patients with DDLPS decreased progressively. Compared with primary tumors, recurrent tumors also exhibited reduced TP53INP2 expression. More importantly, low TP53INP2 expression is correlated with poor prognosis. TP53INP2 gain- or loss-of-function experiments in DDLPS cell lines showed profound inhibitory effects on processes and properties linked with cancer malignancy, such as proliferation, migration, stemness and dedifferentiation. Mechanistically, TP53INP2 is located mainly in mitochondria and promotes mitophagic degradation of YAP in a VDAC1-dependent manner. The WW domain in YAP and the PPTY motif in VDAC1 are required for their interaction. Taken together, these data demonstrate that TP53INP2 represses the malignant progression of DDLPS by inactivating YAP via a mitophagy-dependent mechanism and that TP53INP2 may constitute a novel prognostic biomarker for advanced DDLPS.
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Affiliation(s)
- Yixuan Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Ying Huang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Liwei Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Zhixiu Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Lin Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Feng Xiang
- Department of Urology, Shanghai Changhai Hospital, Naval Medical University (Second Military University), Shanghai, 200433, China
| | - Guoyu Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Jiawen Yang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China
| | - Rui Chen
- Department of Urology, Shanghai Changhai Hospital, Naval Medical University (Second Military University), Shanghai, 200433, China.
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
| | - Yan Shen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
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3
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Zalfa F, Manca P, Carotti S, Vallese S, Righi D, Taffon C, Nibid L, Sbaraglia M, Rabitti C, Pantano F, Tonini G, Dei Tos AP, Vincenzi B, Perrone G. A Nanostring gene expression approach identifies aggressive clinical behavior related genes in dedifferentiated liposarcoma. Sci Rep 2025; 15:9204. [PMID: 40097500 PMCID: PMC11914264 DOI: 10.1038/s41598-025-91791-6] [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: 09/22/2024] [Accepted: 02/24/2025] [Indexed: 03/19/2025] Open
Abstract
Dedifferentiated liposarcoma (DDLPS) is one of the most common subtypes of soft tissue sarcoma with a highly variable clinical behavior. Despite advanced molecular approaches are exploring the genetic panorama of DDLPS progression, to date the driver genes of the aggressive clinical behavior in DDLPS have not been identified yet. Here, we used a Nanostring nCounter approach to study the gene expression profile of 60 selected genes involved in DDLPS progression, in a cohort of DDLPS with aggressive clinical behavior, in comparison to a cohort of DDLPS with indolent clinical behavior. We identified five genes whose expression is significantly and consistently altered in aggressive compared to indolent DDLPS. Moreover, by a clinical outcome analyses we found MAP3K12 gene expression linked with both a higher risk of metastases and death. We envisage that the identified genes could represent the first genes of a genetic signature able to predict the clinical evolution of a DDLPS.
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Affiliation(s)
- Francesca Zalfa
- Operative Research Unit of Predictive Molecular Diagnostic, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
- Research Unit of Microscopic and Ultrastructural Anatomy, Department of Medicine and Surgery, Università Campus Bio-Medico, Rome, Italy.
| | - Paolo Manca
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Simone Carotti
- Operative Research Unit of Predictive Molecular Diagnostic, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Microscopic and Ultrastructural Anatomy, Department of Medicine and Surgery, Università Campus Bio-Medico, Rome, Italy
| | - Silvia Vallese
- Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, 00165, Rome, Italy
| | - Daniela Righi
- Operative Research Unit of Predictive Molecular Diagnostic, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Chiara Taffon
- Operative Research Unit of Anatomical Pathology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Anatomical Pathology, Department of Medicine, Università Campus Bio-Medico, Rome, Italy
| | - Lorenzo Nibid
- Operative Research Unit of Anatomical Pathology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Anatomical Pathology, Department of Medicine, Università Campus Bio-Medico, Rome, Italy
| | - Marta Sbaraglia
- Department of Medicine DIMED, University of Padua, Padua, Italy
- Pathology Unit, University-Hospital of Padua, Padua, Italy
| | - Carla Rabitti
- Operative Research Unit of Anatomical Pathology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Francesco Pantano
- Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico, Rome, Italy
| | - Giuseppe Tonini
- Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico, Rome, Italy
| | - Angelo Paolo Dei Tos
- Department of Medicine DIMED, University of Padua, Padua, Italy
- Pathology Unit, University-Hospital of Padua, Padua, Italy
| | - Bruno Vincenzi
- Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico, Rome, Italy
| | - Giuseppe Perrone
- Operative Research Unit of Anatomical Pathology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of Anatomical Pathology, Department of Medicine, Università Campus Bio-Medico, Rome, Italy
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Shafer AM, Kenna E, Golden LAF, Elhossiny AM, Perry KD, Wilkowski J, Yan W, Kaczkofsky B, McGue J, Bresler SC, Courtney AH, Dalman JM, Galban CJ, Jiang W, Espinoza CE, Chugh R, Iyer MK, Frankel TL, Pasca di Magliano M, Dlugosz AA, Angeles CV. An immunocompetent mouse model of liposarcoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.31.634916. [PMID: 40297505 PMCID: PMC12036434 DOI: 10.1101/2025.01.31.634916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Liposarcoma (LPS) is the most prevalent soft tissue sarcoma. The most common biological subtypes are well-differentiated (WDLPS), a low-grade disease that can evolve to high-grade dedifferentiated LPS (DDLPS), with increased rates of recurrence and metastasis and low response rates to chemotherapy and targeted therapies. Preclinical testing of immunotherapeutics for LPS has been held back by the lack of an immunocompetent mouse model. Here, we present a spontaneous immunocompetent LPS mouse model, ACPP, with targeted deletion of Trp53 and Pten in adipocytes to mimic signaling alterations observed in human LPS. Similar to human LPS, tumors arising in ACPP mice produce WDLPS and DDLPS, along with tumors that exhibit both WD and DD components. Murine and human DDLPS tumors possess transcriptional similarities, including increased expression of oncogenes Cdk4 and Hmga2 and reduced expression of the tumor suppressor Cebpa; further, both mouse and human DDLPS exhibit either high or low T cell infiltration. Syngeneic cell lines derived from spontaneous ACPP DDLPS reliably produce tumors following orthotopic injection, each with distinct growth patterns, aggressiveness and tumor infiltrating lymphocyte profiles. These models provide much needed tools to understand the complex immunobiology of LPS and greatly accelerate the pace of preclinical studies to uncover new therapies for patients with this aggressive malignancy.
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Sekita T, Asano N, Kubo T, Totsuka H, Mitani S, Hattori N, Yoshida A, Kobayashi E, Komiyama M, Ushijima T, Nakayama R, Nakamura M, Kawai A, Ichikawa H. Early separation and parallel clonal selection of dedifferentiated and well-differentiated components in dedifferentiated liposarcoma. Neoplasia 2025; 59:101074. [PMID: 39591761 PMCID: PMC11626829 DOI: 10.1016/j.neo.2024.101074] [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: 08/29/2024] [Revised: 10/12/2024] [Accepted: 10/15/2024] [Indexed: 11/28/2024]
Abstract
Dedifferentiated liposarcoma (DDLPS) comprises a high-grade dedifferentiated (DD) component and a juxtaposed well-differentiated (WD) component. The DD component is believed to originate from the WD component by acquiring additional genomic alterations. In this study, we performed multiregion genome, epigenome, and transcriptome analyses of three patients with DDLPS. In two patients, there were few common genomic alterations across all samples, but many common alterations within DD or WD component samples. Phylogenetic trees predicted from the genomic alterations were consistent with those predicted from DNA methylation patterns. The expression patterns of adipogenesis-related genes differed between DD and WD components and also among patients in connection with their CpG island methylation status. These results indicate that in some patients, WD and DD components are evolutionarily separated at very early stages of tumorigenesis, and are formed through relatively long clonal selection with acquisition of different driver genomic alterations and DNA methylation changes.
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Affiliation(s)
- Tetsuya Sekita
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan; Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Naofumi Asano
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan; Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
| | - Takashi Kubo
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan; Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan
| | | | - Sachiyo Mitani
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Naoko Hattori
- Division of Epigenome, National Cancer Center Research Institute, Tokyo, Japan; Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Akihiko Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Eisuke Kobayashi
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Motokiyo Komiyama
- Department of Urology, National Cancer Center Hospital, Tokyo, Japan
| | - Toshikazu Ushijima
- Division of Epigenome, National Cancer Center Research Institute, Tokyo, Japan; Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Robert Nakayama
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Akira Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hitoshi Ichikawa
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.
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6
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Mavroeidis L, Napolitano A, Huang P, Jones RL. Novel Therapeutics in Soft Tissue Sarcoma. Cancers (Basel) 2024; 17:10. [PMID: 39796641 PMCID: PMC11718850 DOI: 10.3390/cancers17010010] [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: 11/17/2024] [Revised: 12/20/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma. The FDA has also recently granted accelerated approval for autologous T-cell therapy with afami-cel in patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. There are other promising treatments that are still investigational, such as MDM2 and CDK4/6 inhibitors in well-/dedifferentiated liposarcoma, immune checkpoint inhibitors in the head and neck angiosarcoma and a subset of patients with undifferentiated pleomorphic sarcoma, and PARP inhibitors in leiomyosarcoma. The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult targets such as proteolysis targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale.
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Affiliation(s)
- Leonidas Mavroeidis
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London SW3 6JZ, UK
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Radaelli S, Merlini A, Khan M, Gronchi A. Progress in histology specific treatments in soft tissue sarcoma. Expert Rev Anticancer Ther 2024; 24:845-868. [PMID: 39099398 DOI: 10.1080/14737140.2024.2384584] [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: 05/07/2024] [Accepted: 07/22/2024] [Indexed: 08/06/2024]
Abstract
INTRODUCTION Soft tissue sarcomas (STS) represent a heterogenous group of rare tumors, primarily treated with surgery. Preoperative radiotherapy is often recommended for extremity high-risk STS. Neoadjuvant chemotherapy, typically based on doxorubicin with ifosfamide, has shown efficacy in limbs and trunk wall STS. Second-line chemotherapy, commonly utilized in the metastatic setting, is mostly histology-driven. Molecular targeted agents are used across various histologies, and although the use of immunotherapy in STS is still in its early stages, there is increasing interest in exploring its potential. AREAS COVERED This article involved an extensive recent search on PubMed. It explored the current treatment landscape for localized and metastatic STS, focusing on the combined use of radiotherapy and chemotherapy for both extremity and retroperitoneal tumors, and with a particular emphasis on the most innovative histopathology driven therapeutic approaches. Additionally, ongoing clinical trials identified via clinicaltrials.gov are included. EXPERT OPINION Recently there have been advancements in the treatment of STS, largely driven by the outcomes of clinical trials. However further research is imperative to comprehend the effect of chemotherapy, targeted therapy and immunotherapy in various STS, as well as to identify biomarkers able to predict which patients are most likely to benefit from these treatments.
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Affiliation(s)
- Stefano Radaelli
- Sarcoma Service, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Merlini
- Department of Oncology, University of Turin, Orbassano, Italy
- Department of Oncology, San Luigi Gonzaga University Hospital, Orbassano, Italy
| | - Misbah Khan
- Surgery, East Sussex NHS Healthcare, East Sussex, UK
| | - Alessandro Gronchi
- Sarcoma Service, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Zhang L, Guan L, Wang Y, Niu MM, Yan J. Discovery of a dual-target DYRK2 and HDAC8 inhibitor for the treatment of hepatocellular carcinoma. Biomed Pharmacother 2024; 177:116839. [PMID: 38889633 DOI: 10.1016/j.biopha.2024.116839] [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: 04/05/2024] [Revised: 05/12/2024] [Accepted: 05/26/2024] [Indexed: 06/20/2024] Open
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and histone deacetylase 8 (HDAC8) have been shown to be associated with the development of several cancers. Here, we identified a dual-target DYRK2/HDAC8 inhibitor (DYC-1) through a combined virtual screening protocol. DYC-1 exhibited nanomolar inhibitory activity against both DYRK2 (IC50 = 5.27 ± 0.13 nM) and HDAC8 (IC50 = 8.06 ± 0.47 nM). Molecular dynamics simulations showed that DYC-1 had positive binding stability with DYRK2 and HDAC8. Importantly, the cytotoxicity assay indicated that DYC-1 exhibited superior antiproliferative activity against human liver cancer, especially SK-HEP-1 cells, and had no significant inhibition on normal liver cells. Moreover, DYC-1 showed a strong inhibitory effect on the growth of SK-HEP-1 xenograft tumors with no significant side effects. These data suggest that DYC-1 is a high-efficacy and low-toxic antitumor agent for the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Li Zhang
- Department of Pharmacy, Changzhi People's Hospital, Changzhi Medical College, Changzhi 046000, China.
| | - Lixia Guan
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
| | - Yuting Wang
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
| | - Miao-Miao Niu
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
| | - Jinhu Yan
- Department of Pain Treatment, Changzhi Hospital of Traditional Chinese Medicine, Changzhi 046000, China.
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M S A, K C, Bhargavan RV, Somanathan T, Subhadradevi L. An overview on liposarcoma subtypes: Genetic alterations and recent advances in therapeutic strategies. J Mol Histol 2024; 55:227-240. [PMID: 38696048 DOI: 10.1007/s10735-024-10195-4] [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: 07/24/2023] [Accepted: 04/18/2024] [Indexed: 05/21/2024]
Abstract
Liposarcoma (LPS) is a rare malignancy of adipocytic differentiation. According to World Health Organization classification, LPS comprises of four principle subtypes Atypical lipomatous tumor/Well-differentiated liposarcoma (ATL/WDLPS), Dedifferentiated liposarcoma (WDLPS), Myxoid liposarcoma (MLPS), and Pleomorphic liposarcoma (PLPS). Each subtype can develop at any location and shows distinct clinical behavior and treatment sensitivity. ATL/ WDLPS subtype has a higher incidence rate, low recurrence, and is insensitive to radiation and chemotherapy. DDLPS is the focal progression of WDLPS, which is aggressive and highly metastasizing. MLPS is sensitive to radiation and chemotherapy, with a higher recurrence rate and metastasis. PLPS subtype is highly metastasizing, has a poor prognosis, and exhibiting higher recurrence rate. Initial histological analysis provides information for the characterization of LPS subtypes', further molecular and genetic analysis provides certain subtype specifications, such as gene amplifications and gene fusions. Such molecular genetic alterations will be useful as therapeutic targets in various cancers, including the LPS subtypes. A wide range of novel therapeutic agents based on genetic alterations that aim to target LPS subtypes specifically are under investigation. This review summarizes the LPS subtype classification, their molecular genetic characteristics, and the implications of genetic alterations in therapeutics.
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Affiliation(s)
- Anju M S
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India
| | - Chandramohan K
- Division of Surgical Oncology, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India
| | - Rexeena V Bhargavan
- Division of Surgical Oncology, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India
| | - Thara Somanathan
- Division of Pathology, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India
| | - Lakshmi Subhadradevi
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India.
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Ewongwo A, Hui C, Moding EJ. Opportunity in Complexity: Harnessing Molecular Biomarkers and Liquid Biopsies for Personalized Sarcoma Care. Semin Radiat Oncol 2024; 34:195-206. [PMID: 38508784 DOI: 10.1016/j.semradonc.2023.12.002] [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: 03/22/2024]
Abstract
Due to their rarity and complexity, sarcomas represent a substantial therapeutic challenge. However, the incredible diversity within and across sarcoma subtypes presents an opportunity for personalized care to maximize efficacy and limit toxicity. A deeper understanding of the molecular alterations that drive sarcoma development and treatment response has paved the way for molecular biomarkers to shape sarcoma treatment. Genetic, transcriptomic, and protein biomarkers have become critical tools for diagnosis, prognostication, and treatment selection in patients with sarcomas. In the future, emerging biomarkers like circulating tumor DNA analysis offer the potential to improve early detection, monitoring response to treatment, and identifying mechanisms of resistance to personalize sarcoma treatment. Here, we review the current state of molecular biomarkers for sarcomas and highlight opportunities and challenges for the implementation of new technologies in the future.
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Affiliation(s)
- Agnes Ewongwo
- Department of Radiation Oncology, Stanford University, Stanford, CA
| | - Caressa Hui
- Department of Radiation Oncology, Stanford University, Stanford, CA
| | - Everett J Moding
- Department of Radiation Oncology, Stanford University, Stanford, CA.; Stanford Cancer Institute, Stanford University, Stanford, CA..
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11
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Mori T, Iwasaki T, Sonoda H, Kawaguchi K, Tomonaga T, Furukawa H, Sato C, Shiraishi S, Taguchi K, Tamiya S, Yoneda R, Oshiro Y, Matsunobu T, Abe C, Kuboyama Y, Ueki N, Kohashi K, Yamamoto H, Nakashima Y, Oda Y. DDIT3-amplified or low-polysomic pleomorphic sarcomas without MDM2 amplification: Clinicopathological review and immunohistochemical profile of nine cases. Hum Pathol 2024; 145:56-62. [PMID: 38401716 DOI: 10.1016/j.humpath.2024.02.007] [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: 11/09/2023] [Revised: 02/17/2024] [Accepted: 02/20/2024] [Indexed: 02/26/2024]
Abstract
Several high-grade pleomorphic sarcoma cases that cannot be classified into any existing established categories have been reported. These cases were provisionally classified into undifferentiated pleomorphic sarcoma (UPS). Some dedifferentiated liposarcoma (DDLS) cases may also have been classified into the UPS category due to the absence of MDM2 amplification or an atypical lipomatous tumor/well-differentiated liposarcoma component. We retrieved and reviewed 77 high-grade pleomorphic sarcoma cases, initially diagnosed as UPS in 66 cases and DDLS in 11 cases. Fluorescence in situ hybridization (FISH) analyses of DDIT3 and MDM2 were performed for available cases. Of the cases successfully subjected to DDIT3 FISH (n = 56), nine (7 UPS and 2 DDLS) showed DDIT3 amplification but no MDM2 amplification. Two UPS cases showed both telomeric (5') and centromeric (3') amplification of DDIT3 or low polysomy of chromosome 12, whereas 5 UPS and 2 DDLS cases showed 5'-predominant DDIT3 amplification. Histopathologically, all cases showed UPS-like proliferation of atypical pleomorphic tumor cells. Immunohistochemically, only one case showed focal nuclear positivity for DDIT3, supporting the previous finding that DDIT3 expression was not correlated with DDIT3 amplification. All three cases with focal MDM2 expression involved 5'-predominant amplification, two of which showed DDLS-like histological features. The majority of cases (7/9) showed decreased expression in p53 staining, suggesting that DDIT3 amplification regulates the expression of TP53 like MDM2. From a clinicopathological perspective, we hypothesize that DDIT3-amplified sarcoma, especially with 5'-predominant amplification, can be reclassified out of the UPS category.
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Affiliation(s)
- Taro Mori
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Iwasaki
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroki Sonoda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kengo Kawaguchi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takumi Tomonaga
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Furukawa
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Chiaki Sato
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sakura Shiraishi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichi Taguchi
- Department of Pathology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Sadafumi Tamiya
- Department of Pathology, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Reiko Yoneda
- Department of Pathology, Hamanomachi Hospital, Fukuoka, Japan
| | - Yumi Oshiro
- Department of Pathology, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Tomoya Matsunobu
- Department of Orthopaedic Surgery, Kyushu Rosai Hospital, Fukuoka, Japan
| | - Chie Abe
- Department of Diagnostic Pathology, Fukuokahigashi Medical Center, Fukuoka, Japan
| | - Yusuke Kuboyama
- Department of Pathology, Oita Red Cross Hospital, Oita, Japan
| | - Nozomi Ueki
- Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kenichi Kohashi
- Department of Humanpathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hidetaka Yamamoto
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yasuharu Nakashima
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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12
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Xing D, Meyer CF, Gross JM, Argani P, Hung CF, Wu TC, Vang R, Armstrong DK, Gaillard SL. Uterine MEIS1::NCOA2 Fusion Sarcoma With Lung Metastasis: A Case Report and Review of the Literature. Int J Gynecol Pathol 2024; 43:47-55. [PMID: 37043646 PMCID: PMC10497720 DOI: 10.1097/pgp.0000000000000951] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
MEIS1::NCOA1/2 fusion sarcomas are a recently described novel entity arising in a variety of locations with a predilection for the genitourinary tract and gynecologic organs. Despite multiple locoregional recurrences, these tumors are thought to behave in a low-grade malignant manner. Here we report a uterine MEIS1::NCOA2 fusion sarcoma with lung metastasis. The patient was a 47-yr-old woman with a history of abnormal uterine bleeding who was found to have a myometrial mass confirmed by pathology to be uterine sarcoma. The tumor was predominantly composed of monotonous spindle cells with scant cytoplasm, crowded nuclei, and brisk mitotic activity, growing in a fascicular and streaming pattern. The morphologic and immunophenotypic features were nonspecific and a diagnosis of high-grade uterine sarcoma with a differential of leiomyosarcoma versus high-grade endometrial stromal sarcoma was rendered. At the 27-mo follow-up, the patient was found to have a lung metastasis consisting of a monotonous round cell sarcoma. A retrospective RNA-based and DNA-based next-generation sequencing of the primary uterine sarcoma revealed a MEIS1::NCOA2 gene fusion, a c.94G>C/p.D32H mutation in exon 3 of CTNNB1 gene, HMGA2 , and CDK4 gene amplification, and an intermediate/marginal level of MDM2 gene amplification. Polymerase chain reaction-based molecular analysis further demonstrated that the MEIS1::NCOA2 gene fusion and CTNNB1 somatic mutation were also present in the lung metastasis. This case represents the first case of such gynecologic sarcoma with distant (lung) metastasis, and the second metastatic case among all reported MEIS1::NCOA1/2 fusion sarcomas, highlighting the malignant metastatic potential of this emerging entity. Our case also indicates that HMGA2/CDK4/MDM2 region amplification and CTNNB1 somatic mutation might be recurrent genetic events in this rare sarcoma subtype.
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Somaiah N, Tap W. MDM2-p53 in liposarcoma: The need for targeted therapies with novel mechanisms of action. Cancer Treat Rev 2024; 122:102668. [PMID: 38104352 DOI: 10.1016/j.ctrv.2023.102668] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 12/19/2023]
Abstract
Well-differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS) are rare tumors that arise from lipocytes in soft tissue. There is a high unmet need in patients with these liposarcomas given poor outcomes, particularly for DDLPS. WDLPS and DDLPS share important genetic and histological characteristics - most notably, the amplification of the 2 genes MDM2 and CDK4. Both genes are considered oncogenes because of their ability to shut down tumor suppressor pathways. There are multiple therapeutic approaches that aim to target MDM2 and CDK4 activity for the purpose of restoring intrinsic tumor suppressor cellular response and terminating oncogenesis. However, current understanding of the molecular mechanisms involved in WDLPS and DDLPS pathology is limited. In recent years, significant efforts have been made to refine and implement targeted therapy for this patient population. The use of patient-derived cell and tumor xenograft models has been an important tool for recapitulating WDLPS and DDLPS biology. These models also offer valuable insights for drug development and drug combination studies. Here we offer a review of the current understanding of WDLPS and DDLPS biology and its therapeutic implications.
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Affiliation(s)
- Neeta Somaiah
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, United States.
| | - William Tap
- Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
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14
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Ji K, Li L, Liu H, Shen Y, Jiang J, Zhang M, Teng H, Yan X, Zhang Y, Cai Y, Zhou H. Unveiling the role of GAS41 in cancer progression. Cancer Cell Int 2023; 23:245. [PMID: 37853482 PMCID: PMC10583379 DOI: 10.1186/s12935-023-03098-z] [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: 05/10/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023] Open
Abstract
GAS41, a member of the human YEATS domain family, plays a pivotal role in human cancer development. It serves as a highly promising epigenetic reader, facilitating precise regulation of cell growth and development by recognizing essential histone modifications, including histone acetylation, benzoylation, succinylation, and crotonylation. Functional readouts of these histone modifications often coincide with cancer progression. In addition, GAS41 functions as a novel oncogene, participating in numerous signaling pathways. Here, we summarize the epigenetic functions of GAS41 and its role in the carcinoma progression. Moving forward, elucidating the downstream target oncogenes regulated by GAS41 and the developing small molecule inhibitors based on the distinctive YEATS recognition properties will be pivotal in advancing this research field.
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Affiliation(s)
- Kangkang Ji
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Li Li
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Hui Liu
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Yucheng Shen
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Jian Jiang
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Minglei Zhang
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Hongwei Teng
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Xun Yan
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Yanhua Zhang
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Yong Cai
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Hai Zhou
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China.
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15
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Țigăran AE, Abu-Baker A, Ion DE, Peligrad T, Gheoca-Mutu DE, Avino A, Anghel AW, Balcangiu-Stroescu AE, Toma A, Răducu L. Extremely Rare Type of Breast Cancer-Dedifferentiated Breast Liposarcoma-Diagnosis and Treatment. J Pers Med 2023; 13:1451. [PMID: 37888062 PMCID: PMC10608349 DOI: 10.3390/jpm13101451] [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: 09/07/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/28/2023] Open
Abstract
Primary liposarcoma of the breast is an uncommon soft tissue malignant tumor, comprising only 0.003% of all malignant breast tumors. The main differential diagnosis of this mass consists of malignant phyllodes tumor and metaplastic breast carcinoma. The objective of this paper is to report a case of dedifferentiated breast liposarcoma, therapeutic approach and outcome. We present a case of a 79-year-old woman complaining of a large mass in her left breast which had increased in size over the last 6 months. Physical examination revealed an enlarged left breast, and a total body CT scan showed a large tumor in contact with the musculature of the anterior thoracic wall, with no metastatic lesions. The histopathology report of a fine needle biopsy described a high-grade sarcoma. The Oncological Tumor Board recommended neoadjuvant radiotherapy sessions and reevaluation by MRI and CT scans. The patient underwent radical mastectomy with latissimus dorsi myo-cutaneous flap reconstruction. The final histopathology diagnosis was a grade 3 dedifferentiated liposarcoma (FNCLCC), with certain response to radiotherapy and positive MDM2, CDK4 markers. The postoperative period was uneventful; 12 months after surgery, the follow-up CT scan showed multiple pulmonary lesions with metastatic characteristics. Liposarcoma is a very rare type of breast cancer, and the most important treatment for breast sarcoma is surgery, the role of axillary lymph node removal, chemotherapy and radiotherapy still being controversial. Considering such cases are scarce and the development of surgical guidelines is difficult, reporting any new case is crucial.
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Affiliation(s)
- Andrada-Elena Țigăran
- Department of Plastic and Reconstructive Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania; (A.-E.Ț.); (A.A.-B.); (D.-E.I.); (T.P.); (D.-E.G.-M.); (L.R.)
| | - Abdalah Abu-Baker
- Department of Plastic and Reconstructive Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania; (A.-E.Ț.); (A.A.-B.); (D.-E.I.); (T.P.); (D.-E.G.-M.); (L.R.)
- Doctoral School, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Daniela-Elena Ion
- Department of Plastic and Reconstructive Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania; (A.-E.Ț.); (A.A.-B.); (D.-E.I.); (T.P.); (D.-E.G.-M.); (L.R.)
| | - Teodora Peligrad
- Department of Plastic and Reconstructive Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania; (A.-E.Ț.); (A.A.-B.); (D.-E.I.); (T.P.); (D.-E.G.-M.); (L.R.)
| | - Daniela-Elena Gheoca-Mutu
- Department of Plastic and Reconstructive Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania; (A.-E.Ț.); (A.A.-B.); (D.-E.I.); (T.P.); (D.-E.G.-M.); (L.R.)
- Discipline of Anatomy, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Adelaida Avino
- Department of Plastic and Reconstructive Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania; (A.-E.Ț.); (A.A.-B.); (D.-E.I.); (T.P.); (D.-E.G.-M.); (L.R.)
- Doctoral School, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Discipline of Plastic Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania
| | - Andrei-Wilhelm Anghel
- Department of Radiotherapy, Elias University Emergency Hospital, 011461 Bucharest, Romania;
- Department of Radiotherapy, MedEuropa, 022343 Bucharest, Romania
| | - Andra-Elena Balcangiu-Stroescu
- Discipline of Physiology, Faculty of Dental Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Anca Toma
- Department of Anatomic Pathology, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania;
| | - Laura Răducu
- Department of Plastic and Reconstructive Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania; (A.-E.Ț.); (A.A.-B.); (D.-E.I.); (T.P.); (D.-E.G.-M.); (L.R.)
- Discipline of Plastic Surgery, ‘Prof. Dr Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania
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16
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Musa J, Willis F, Harnoss JM, Rompen IF, Sauerteig C, Kochendoerfer SM, Grünewald TGP, Al-Saeedi M, Schneider M, Harnoss JC. A century of retroperitoneal soft-tissue sarcoma research: From single center experience to precision oncology? A bibliometric analysis of past, present, and future perspectives. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:106948. [PMID: 37286428 DOI: 10.1016/j.ejso.2023.05.023] [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: 05/04/2023] [Accepted: 05/31/2023] [Indexed: 06/09/2023]
Abstract
BACKGROUND Increasing publication numbers in the biomedical field led to an improvement of patient care in many aspects but are challenging for scientists when integratively processing data of their fields. Using bibliometric analyses, the present study assesses the productivity and predominant topics in retroperitoneal soft-tissue sarcoma (RPS) research across the past 122 years, thereby identifying crucial questions to address in future RPS research. METHODS Using the Web of Science Core Collection, 1018 RPS-associated publications from 1900 to 2022 were identified and analyzed regarding key bibliometric variables using the Bibliometrix R package and the VOSviewer software. RESULTS A continuous increase in RPS-associated publication numbers can be noticed over the time, which is strongly pronounced from 2005 onwards, and is characterized by a multinationally driven collaborative clinical research focus. The research primarily reflects progression regarding surgical techniques, histology-based therapy, radiotherapy regimens, and identification of prognostic clinicopathological factors. This progression is accompanied with improved overall survival of RPS patients. However, a paucity of RPS-specific basic/translational research indicates that such research might be additionally needed to better understand the pathophysiology of RPS and with that to enable the development of personalized therapies and to further improve patient outcome. CONCLUSION Increasing publication numbers of multinationally driven clinical RPS research are accompanied with improved overall survival of RPS patients, highlighting the importance of international collaborations to facilitate future clinical trials. However, this bibliometric analysis reveals a lack of RPS-specific basic/translational research which is needed to further improve patient outcome in the context of precision oncology.
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Affiliation(s)
- Julian Musa
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany; Division of Translational Pediatric Sarcoma Research (B410), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany
| | - Franziska Willis
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Jonathan M Harnoss
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Ingmar F Rompen
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Christine Sauerteig
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Sarah M Kochendoerfer
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas G P Grünewald
- Division of Translational Pediatric Sarcoma Research (B410), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Mohammed Al-Saeedi
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Julian-C Harnoss
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
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17
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Xian Q, Song Y, Gui C, Zhou Y. Mechanistic insights into genomic structure and functions of a novel oncogene YEATS4. Front Cell Dev Biol 2023; 11:1192139. [PMID: 37435030 PMCID: PMC10332269 DOI: 10.3389/fcell.2023.1192139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/12/2023] [Indexed: 07/13/2023] Open
Abstract
As a novel oncogene, the role of YEATS domain-containing protein 4 (YEATS4) in the occurrence, development, and treatment of tumors is now beginning to be appreciated. YEATS4 plays an important role in regulating DNA repair during replication. The upregulation of YEAST4 promotes DNA damage repair and prevents cell death, whereas its downregulation inhibits DNA replication and induces apoptosis. Additionally, accumulating evidence indicates that the aberrant activation of YEATS4 leads to changes in drug resistance, epithelial-mesenchymal transition and also in the migration and invasion capacity of tumor cells. Therefore, specific inhibition of the expression or activity of YEATS4 protein may be an effective strategy for inhibiting the proliferation, motility, differentiation, and/or survival of tumor cells. Taken together, YEATS4 has emerged as a potential target for multiple cancers and is an attractive protein for the development of small-molecule inhibitors. However, research on YEAST4 in tumor-related fields is limited and its biological functions, metabolism, and the regulatory mechanism of YEATS4 in numerous cancers remain undetermined. This review comprehensively and extensively summarizes the functions, structure and oncogenic roles of YEATS4 in cancer progression and aims to further contribute to the study of its underlying molecular mechanism and targeted drugs.
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Affiliation(s)
- Qingqing Xian
- Department of Clinical Laboratory Diagnosis, Shandong University, Jinan, Shandong, China
| | - Yiying Song
- Department of Clinical Laboratory Diagnosis, Shandong University, Jinan, Shandong, China
| | - Chengzhi Gui
- Department of Clinical Laboratory Diagnosis, Shandong First Medical University, Jinan, Shandong, China
| | - Yunying Zhou
- Department of Clinical Laboratory Diagnosis, Shandong University, Jinan, Shandong, China
- Department of Clinical Laboratory Diagnosis, Shandong First Medical University, Jinan, Shandong, China
- Medical Research and Laboratory Diagnostic Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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18
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Watson S, Gruel N, Le Loarer F. New developments in the pathology and molecular biology of retroperitoneal sarcomas. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:1053-1060. [PMID: 35151525 DOI: 10.1016/j.ejso.2022.02.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/22/2022] [Accepted: 02/02/2022] [Indexed: 02/07/2023]
Abstract
Retroperitoneal sarcomas (RPS) refer to a heterogeneous group of malignancies of mesenchymal origin developing from retroperitoneal tissues and vessels. The most frequent RPS are well differentiated/dedifferentiated liposarcomas and leiomyosarcomas, but other rare histological subtypes can be observed. Over the last decade, significant advances have been made in the pathological and molecular characterization of sarcomas. These advances have led to major changes in their diagnostic management as well as in the development of new therapeutic strategies based on tumor biology and microenvironment. This review describes the current knowledge and recent findings in the pathology and molecular biology of the most frequent RPS subtypes.
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Affiliation(s)
- Sarah Watson
- INSERM U830, Équipe Labellisée Ligue Nationale Contre le Cancer, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Medical Oncology, Institut Curie Hospital, Paris, France.
| | - Nadege Gruel
- INSERM U830, Équipe Labellisée Ligue Nationale Contre le Cancer, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France
| | - François Le Loarer
- Department of Pathology, Institut Bergonie, Bordeaux, France; INSERM U1218, Unité ACTION, Institut Bergonie, Bordeaux, France; University of Bordeaux, Talence, France
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19
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Zhou MY, Bui NQ, Charville GW, Ganjoo KN, Pan M. Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy. Int J Mol Sci 2023; 24:ijms24119571. [PMID: 37298520 DOI: 10.3390/ijms24119571] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 05/30/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
Well-differentiated/de-differentiated liposarcoma (WDLPS/DDLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS); however, treatment options remain limited. WDLPS and DDLPS both exhibit the characteristic amplification of chromosome region 12q13-15, which contains the genes CDK4 and MDM2. DDLPS exhibits higher amplification ratios of these two and carries additional genomic lesions, including the amplification of chromosome region 1p32 and chromosome region 6q23, which may explain the more aggressive biology of DDLPS. WDLPS does not respond to systemic chemotherapy and is primarily managed with local therapy, including multiple resections and debulking procedures whenever clinically feasible. In contrast, DDLPS can respond to chemotherapy drugs and drug combinations, including doxorubicin (or doxorubicin in combination with ifosfamide), gemcitabine (or gemcitabine in combination with docetaxel), trabectedin, eribulin, and pazopanib. However, the response rate is generally low, and the response duration is usually short. This review highlights the clinical trials with developmental therapeutics that have been completed or are ongoing, including CDK4/6 inhibitors, MDM2 inhibitors, and immune checkpoint inhibitors. This review will also discuss the current landscape in assessing biomarkers for identifying tumors sensitive to immune checkpoint inhibitors.
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Affiliation(s)
- Maggie Y Zhou
- Sarcoma Program, Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Nam Q Bui
- Sarcoma Program, Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Gregory W Charville
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Kristen N Ganjoo
- Sarcoma Program, Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Minggui Pan
- Sarcoma Program, Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA
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20
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Aydin B, Beklen H, Arga KY, Bayrakli F, Turanli B. Epigenomic and transcriptomic landscaping unraveled candidate repositioned therapeutics for non-functioning pituitary neuroendocrine tumors. J Endocrinol Invest 2023; 46:727-747. [PMID: 36306107 DOI: 10.1007/s40618-022-01923-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 09/12/2022] [Indexed: 10/31/2022]
Abstract
PURPOSE Non-functioning pituitary neuroendocrine tumors are challengingly diagnosed tumors in the clinic. Transsphenoidal surgery remains the first-line treatment. Despite the development of state-of-the-art techniques, no drug therapy is currently approved for the treatment. There are also no randomized controlled trials comparing therapeutic strategies or drug therapy for the management after surgery. Therefore, novel therapeutic interventions for the therapeutically challenging NF-PitNETs are urgently needed. METHODS We integrated epigenome and transcriptome data (both coding and non-coding) that elucidate disease-specific signatures, in addition to biological and pharmacological data, to utilize rational pathway and drug prioritization in NF-PitNETs. We constructed an epigenome- and transcriptome-based PPI network and proposed hub genes. The signature-based drug repositioning based on the integration of multi-omics data was performed. RESULTS The construction of a disease-specific network based on three different biological levels revealed DCC, DLG5, ETS2, FOXO1, HBP1, HMGA2, PCGF3, PSME4, RBPMS, RREB1, SMAD1, SOCS1, SOX2, YAP1, ZFHX3 as hub proteins. Signature-based drug repositioning using hub proteins yielded repositioned drug candidates that were confirmed in silico via molecular docking. As a result of molecular docking simulations, palbociclib, linifanib, trametinib, eplerenone, niguldipine, and zuclopenthixol showed higher binding affinities with hub genes compared to their inhibitors and were proposed as potential repositioned therapeutics for the management of NF-PitNETs. CONCLUSION The proposed systems' biomedicine-oriented multi-omics data integration for drug repurposing to provide promising results for the construction of effective clinical therapeutics. To the best of our knowledge, this is the first study reporting epigenome- and transcriptome-based drug repositioning for NF-PitNETs using in silico confirmations.
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Affiliation(s)
- B Aydin
- Department of Bioengineering, Faculty of Engineering and Architecture, Konya Food and Agriculture University, Konya, Turkey
| | - H Beklen
- Department of Bioengineering, Faculty of Engineering, Marmara University, RTE Basibuyuk Campus, 34720, Istanbul, Turkey
| | - K Y Arga
- Department of Bioengineering, Faculty of Engineering, Marmara University, RTE Basibuyuk Campus, 34720, Istanbul, Turkey
- Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
| | - F Bayrakli
- Department of Neurosurgery, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Institute of Neurological Sciences, Marmara University, Istanbul, Turkey
| | - B Turanli
- Department of Bioengineering, Faculty of Engineering, Marmara University, RTE Basibuyuk Campus, 34720, Istanbul, Turkey.
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21
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Menon AA, Deshpande V, Suster D. MDM2 for the practicing pathologist: a primer. J Clin Pathol 2023; 76:285-290. [PMID: 36898827 DOI: 10.1136/jcp-2022-208687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2023] [Indexed: 03/12/2023]
Abstract
The mouse double minute 2 (MDM2) gene is located on the long arm of chromosome 12 and is the primary negative regulator of p53. The MDM2 gene encodes an E3 ubiquitin-protein ligase that mediates the ubiquitination of p53, leading to its degradation. MDM2 enhances tumour formation by inactivating the p53 tumour suppressor protein. The MDM2 gene also has many p53-independent functions. Alterations of MDM2 may occur through various mechanisms and contribute to the pathogenesis of many human tumours and some non-neoplastic diseases. Detection of MDM2 amplification is used in the clinical practice setting to help diagnose multiple tumour types, including lipomatous neoplasms, low-grade osteosarcomas and intimal sarcoma, among others. It is generally a marker of adverse prognosis, and MDM2-targeted therapies are currently in clinical trials. This article provides a concise overview of the MDM2 gene and discusses practical diagnostic applications pertaining to human tumour biology.
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Affiliation(s)
- Aswathy Ashok Menon
- Department of Pathology, Neuberg Anand Reference Laboratory, Bengaluru, Karnataka, India
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David Suster
- Department of Pathology, Rutgers University New Jersey Medical School, Newark, New Jersey, USA
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22
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Merlini A, Pavese V, Manessi G, Rabino M, Tolomeo F, Aliberti S, D’Ambrosio L, Grignani G. Targeting cyclin-dependent kinases in sarcoma treatment: Current perspectives and future directions. Front Oncol 2023; 13:1095219. [PMID: 36741019 PMCID: PMC9893281 DOI: 10.3389/fonc.2023.1095219] [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: 11/10/2022] [Accepted: 01/03/2023] [Indexed: 01/20/2023] Open
Abstract
Effective treatment of advanced/metastatic bone and soft tissue sarcomas still represents an unmet medical need. Recent advances in targeted therapies have highlighted the potential of cyclin-dependent kinases (CDK) inhibitors in several cancer types, including sarcomas. CDKs are master regulators of the cell cycle; their dysregulation is listed among the "hallmarks of cancer" and sarcomas are no exception to the rule. In this review, we report both the molecular basis, and the potential therapeutic implications for the use of CDK inhibitors in sarcoma treatment. What is more, we describe and discuss the possibility and biological rationale for combination therapies with conventional treatments, target therapy and immunotherapy, highlighting potential avenues for future research to integrate CDK inhibition in sarcoma treatment.
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Affiliation(s)
- Alessandra Merlini
- Candiolo Cancer Institute, IRCCS-FPO, Turin, Italy,Department of Oncology, University of Turin, Turin, Italy
| | - Valeria Pavese
- Department of Oncology, University of Turin, Turin, Italy
| | - Giulia Manessi
- Department of Oncology, University of Turin, Turin, Italy
| | - Martina Rabino
- Department of Oncology, University of Turin, Turin, Italy
| | | | | | - Lorenzo D’Ambrosio
- Department of Oncology, University of Turin, Turin, Italy,Medical Oncology, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Turin, Italy,*Correspondence: Lorenzo D’Ambrosio,
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Traweek RS, Cope BM, Roland CL, Keung EZ, Nassif EF, Erstad DJ. Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma. Front Oncol 2022; 12:1006959. [PMID: 36439412 PMCID: PMC9684653 DOI: 10.3389/fonc.2022.1006959] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/19/2022] [Indexed: 10/12/2023] Open
Abstract
Dedifferentiated liposarcoma (DDLPS) is an aggressive adipogenic cancer with poor prognosis. DDLPS tumors are only modestly sensitive to chemotherapy and radiation, and there is a need for more effective therapies. Genetically, DDLPS is characterized by a low tumor mutational burden and frequent chromosomal structural abnormalities including amplification of the 12q13-15 chromosomal region and the MDM2 gene, which are defining features of DDLPS. The MDM2 protein is an E3 ubiquitin ligase that targets the tumor suppressor, p53, for proteasomal degradation. MDM2 amplification or overexpression in human malignancies is associated with cell-cycle progression and worse prognosis. The MDM2-p53 interaction has thus garnered interest as a therapeutic target for DDLPS and other malignancies. MDM2 binds p53 via a hydrophobic protein interaction that is easily accessible with synthetic analogues. Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Preclinical in vitro and animal models have shown promising results with MDM2 inhibition, resulting in robust p53 reactivation and cancer cell death. However, multiple early-phase clinical trials have failed to show a benefit with MDM2 pathway inhibition for DDLPS. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS.
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Affiliation(s)
- Raymond S. Traweek
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Brandon M. Cope
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Christina L. Roland
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Emily Z. Keung
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elise F. Nassif
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Derek J. Erstad
- Division of Surgical Oncology, Baylor College of Medicine, Houston, TX, United States
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Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup. Sci Rep 2022; 12:12420. [PMID: 35859155 PMCID: PMC9300649 DOI: 10.1038/s41598-022-16455-1] [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: 08/20/2021] [Accepted: 07/11/2022] [Indexed: 11/08/2022] Open
Abstract
In neuroblastoma, MYCN amplification and 11q-deletion are important, although incomplete, markers of high-risk disease. It is therefore relevant to characterize additional alterations that can function as prognostic and/or predictive markers. Using SNP-microarrays, a group of neuroblastoma patients showing amplification of one or multiple 12q loci was identified. Two loci containing CDK4 and MDM2 were commonly co-amplified, although amplification of either locus in the absence of the other was observed. Pharmacological inhibition of CDK4/6 with ribociclib or abemaciclib decreased proliferation in a broad set of neuroblastoma cell lines, including CDK4/MDM2-amplified, whereas MDM2 inhibition by Nutlin-3a was only effective in p53wild-type cells. Combined CDK4/MDM2 targeting had an additive effect in p53wild-type cell lines, while no or negative additive effect was observed in p53mutated cells. Most 12q-amplified primary tumors were of abdominal origin, including those of intrarenal origin initially suspected of being Wilms' tumor. An atypical metastatic pattern was also observed with low degree of bone marrow involvement, favoring other sites such as the lungs. Here we present detailed biological data of an aggressive neuroblastoma subgroup hallmarked by 12q amplification and atypical clinical presentation for which our in vitro studies indicate that CDK4 and/or MDM2 inhibition also could be beneficial.
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25
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Noncanonical roles of p53 in cancer stemness and their implications in sarcomas. Cancer Lett 2022; 525:131-145. [PMID: 34742870 DOI: 10.1016/j.canlet.2021.10.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 09/24/2021] [Accepted: 10/25/2021] [Indexed: 12/25/2022]
Abstract
Impairment of the prominent tumor suppressor p53, well known for its canonical role as the "guardian of the genome", is found in almost half of human cancers. More recently, p53 has been suggested to be a crucial regulator of stemness, orchestrating the differentiation of embryonal and adult stem cells, suppressing reprogramming into induced pluripotent stem cells, or inhibiting cancer stemness (i.e., cancer stem cells, CSCs), which underlies the development of therapy-resistant tumors. This review addresses these noncanonical roles of p53 and their implications in sarcoma initiation and progression. Indeed, dysregulation of p53 family proteins is a common event in sarcomas and is associated with poor survival. Additionally, emerging studies have demonstrated that loss of wild-type p53 activity hinders the terminal differentiation of mesenchymal stem cells and leads to the development of aggressive sarcomas. This review summarizes recent findings on the roles of aberrant p53 in sarcoma development and stemness and further describes therapeutic approaches to restore normal p53 activity as a promising anti-CSC strategy to treat refractory sarcomas.
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Thway K. What’s new in adipocytic neoplasia? Histopathology 2021; 80:76-97. [DOI: 10.1111/his.14548] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 12/22/2022]
Affiliation(s)
- Khin Thway
- Sarcoma Unit Royal Marsden Hospital London UK
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27
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Abdul Razak AR, Bauer S, Suarez C, Lin CC, Quek R, Hütter-Krönke ML, Cubedo R, Ferretti S, Guerreiro N, Jullion A, Orlando EJ, Clementi G, Sand Dejmek J, Halilovic E, Fabre C, Blay JY, Italiano A. Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results From a Proof-of-Concept, Phase Ib Study. Clin Cancer Res 2021; 28:1087-1097. [PMID: 34921024 DOI: 10.1158/1078-0432.ccr-21-1291] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/28/2021] [Accepted: 12/13/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53-MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy. METHODS In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A (4-week cycle: siremadlin once daily [QD] and ribociclib QD, [2 weeks on, 2 weeks off]); Regimen B (3-week cycle: siremadlin once every 3 weeks; ribociclib QD [2 weeks on, 1 week off]); Regimen C (4-week cycle: siremadlin once every 4 weeks; ribociclib QD [2 weeks on, 2 weeks off]). The primary objective was to determine the maximum tolerated dose and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens. RESULTS As of 16 October 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1-174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity. CONCLUSION Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.
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Affiliation(s)
| | - Sebastian Bauer
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany; DKTK partner site Essen and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Cristina Suarez
- Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO)
| | - Chia-Chi Lin
- Department of Oncology, National Taiwan University Hospital
| | | | | | - Ricardo Cubedo
- Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda
| | | | | | | | | | - Giorgia Clementi
- Translational Clinical Oncology, Novartis Institutes for BioMedical Research
| | | | | | | | - Jean-Yves Blay
- Medecine, Centre Leon Bérard, Univ Claude Bernard, Unicancer
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Expression of FRS2 in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: an immunohistochemical analysis of 182 cases with genetic data. Diagn Pathol 2021; 16:96. [PMID: 34696768 PMCID: PMC8543942 DOI: 10.1186/s13000-021-01161-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 10/06/2021] [Indexed: 02/08/2023] Open
Abstract
Background The fibroblast growth factor receptor substrate 2 (FRS2) gene is located close to MDM2 and CDK4 within the 12q13-15 chromosomal region. FRS2 gene was recently found to be consistently amplified in atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DDL), suggesting the detection of FRS2 amplification could be a diagnostic tool for ALT/WDL/DDLs. However, the expression of FRS2 protein and diagnostic value of FRS2 immunohistochemistry (IHC) has not been evaluated in a large cohort of ALT/WDL/DDLs. Methods A SNOMED search of hospital surgical pathology files from January 2007 to July 2020 identified 182 ALT/WDL/DDLs with available materials. FRS2 fluorescence in situ hybridization (FISH) and IHC were performed on 182 ALT/WDL/DDLs and 64 control samples. The expression of FRS2 was also compared with that of classic immunomarkers (MDM2 and CDK4) of this tumor entity. Results This study included 91 ALT/WDLs and 91 DDLs. The FISH results showed 172 of 182 (94.5%) cases were FRS2-amplified, and 10 cases were FRS2-nonamplified. Immunostaining results showed 171 (94.0%) ALT/WDL/DDLs were positive for FRS2 and 11 cases (6.0%) were FRS2-immunonegative. In 172 FRS2-amplified cases, 166 (96.5%) were FRS2-immunopositive, and 6 (3.5%) were negative. Among 10 FRS2-nonamplified ALT/WDL/DDL cases, 5 cases were FRS2-immunonegative, and 5 tumors displayed 1+ staining for this marker. In 64 control cases, none of them exhibited FRS2 amplification. Forty-seven (73.5%) control cases were negative for FRS2 immunostaining, while 17 cases (26.5%) were FRS2-immunopositive. Fifteen of these false positive samples (15/17, 88.2%) showed 1+ positivity and only 2 cases (2/17, 11.8%) displayed 2+ positivity. In ALT/WDL/DDLs, the sensitivity of FRS2 immunostaining was slightly lower than MDM2 (FRS2 vs. MDM2: 94.0% vs 100.0%) and CDK4 (FRS2 vs. CDK4: 94.0% vs 97.0%). However, the specificity of FRS2 (73.5%) was slightly higher than that of MDM2 (67.8%) and CDK4 (64.4%). Conclusion This study indicated that FRS2 IHC had relatively good consistency with FRS2 FISH, suggesting that FRS2 immunostaining could be utilized as an additional screening tool for the diagnosis of ALT/WDL/DDL. It must be emphasized that MDM2/CDK4/FRS2 especially MDM2 FISH remains the gold standard and the most recommended method to diagnose this entity.
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Establishment and Characterization of NCC-DDLPS4-C1: A Novel Patient-Derived Cell Line of Dedifferentiated Liposarcoma. J Pers Med 2021; 11:jpm11111075. [PMID: 34834427 PMCID: PMC8618493 DOI: 10.3390/jpm11111075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 12/23/2022] Open
Abstract
Dedifferentiated liposarcoma (DDLPS) is a highly malignant sarcoma characterized by the co-amplification of MDM2 and CDK4. Although systemic chemotherapy is recommended for unresectable or metastatic cases, DDLPS is insensitive to conventional chemotherapy, leading to an unfavorable prognosis. Therefore, novel treatment methods are urgently required. Patient-derived cell lines are essential in preclinical studies. Recently, large-scale screening studies using a number of cell lines have been actively conducted for the development of new therapeutic drugs. However, the DDLPS cell line cannot be obtained from public cell banks owing to its rarity, hindering screening studies. As such, novel DDLPS cell lines need to be established. Accordingly, this study aimed to establish a novel DDLPS cell line from surgical specimens. The cell line was named NCC-DDLPS4-C1. NCC-DDLPS4-C1 cells retained copy number alterations corresponding to the original tumors. Further, the cells demonstrated constant growth, spheroid formation, and equivalent invasiveness to MG63 osteosarcoma cells. We also conducted drug screening and integrated the results with those of the previously reported DDLPS cell lines. Consequently, we identified the histone deacetylase inhibitor romidepsin as a novel candidate drug. In conclusion, the NCC-DDLPS4-C1 cell line is a useful tool for the basic study of DDLPS.
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30
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Tyler R, Dilworth MP, James J, Blakeway D, Stockton JD, Morton DG, Taniere P, Gourevitch D, Desai A, Beggs AD. The molecular landscape of well differentiated retroperitoneal liposarcoma. J Pathol 2021; 255:132-140. [PMID: 34156092 DOI: 10.1002/path.5749] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/14/2021] [Accepted: 06/18/2021] [Indexed: 11/09/2022]
Abstract
Well differentiated liposarcoma (WD-LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy- and radiotherapy-resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD-LPS via whole genome sequencing, RNA sequencing, and methylation array analysis. A recurrent mutation within exon 1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p.Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair, and hypoxia-associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31, and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumourigenesis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Robert Tyler
- Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Mark P Dilworth
- Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Jonathan James
- Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Daniel Blakeway
- Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Joanne D Stockton
- Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Dion G Morton
- Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Phillipe Taniere
- Midland Abdominal Retroperitoneal Sarcoma Unit (MARSU), University Hospital Birmingham, Birmingham, UK
| | - David Gourevitch
- Midland Abdominal Retroperitoneal Sarcoma Unit (MARSU), University Hospital Birmingham, Birmingham, UK
| | - Anant Desai
- Midland Abdominal Retroperitoneal Sarcoma Unit (MARSU), University Hospital Birmingham, Birmingham, UK
| | - Andrew D Beggs
- Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Vargas AC, Joy C, Cheah AL, Jones M, Bonar F, Brookwell R, Garrone B, Talbot J, Harraway J, Gill AJ, Maclean FM. Lessons learnt from MDM2 fluorescence in-situ hybridisation analysis of 439 mature lipomatous lesions with an emphasis on atypical lipomatous tumour/well-differentiated liposarcoma lacking cytological atypia. Histopathology 2021; 80:369-380. [PMID: 34523152 DOI: 10.1111/his.14558] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/30/2021] [Accepted: 09/04/2021] [Indexed: 11/30/2022]
Abstract
AIMS Amplification of the murine double minute-2 (MDM2) gene, which is usually detected with fluorescence in-situ hybridisation (FISH), is the key driving event for atypical lipomatous tumours (ALTs)/well-differentiated liposarcomas (WDLs). We sought to determine the concordance between the histopathological findings and MDM2 FISH in the diagnosis of ALT/WDL, and to identify the histological features of MDM2-amplified tumours lacking classic atypia. METHODS AND RESULTS We performed a retrospective analysis of all mature lipomatous lesions subjected to MDM2 FISH analysis at our institution. MDM2 FISH analysis was performed on 439 mature lipomatous lesions: 364 (82.9%) were negative and 75 (17%) were positive. In 17 of 75 (22.6%) ALTs/WDLs, cytological atypia was not identified on initial histological assessment, thus favouring lipoma. On review, these cases shared common histological features, consisting of a very low number of relatively small stromal cells within the tumour lobules, with mildly coarse chromatin and oval nuclei, admixed with unremarkable adipocytes in a tumour background devoid of fibroconnective septa, areas of fibrosis, or blood vessels. These cells matched the cells in which FISH showed MDM2 amplification. In contrast, 13 cases (3.5%) regarded as suspicious for ALT/WDL on the basis of histology lacked MDM2 amplification and were reclassified following the FISH findings. CONCLUSIONS We conclude that a subset of lipoma-like ALTs/WDLs are not associated with any of the features typically described in ALT/WDL. Our study also showed that tumours >100 mm are more likely to be ALT/WDL; however, a history of recurrence or concerning clinical/radiological features was not significantly associated with classification as ALT/WDL.
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Affiliation(s)
- Ana Cristina Vargas
- Department of Anatomical Pathology, Sonic Healthcare-Douglass Hanly Moir Pathology, Macquarie Park, Australia.,Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Australia.,Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Christopher Joy
- Department of Cytogenetics, Sullivan Nicolaides Pathology, Brisbane, Queensland, Australia
| | - Alison L Cheah
- Department of Anatomical Pathology, Sonic Healthcare-Douglass Hanly Moir Pathology, Macquarie Park, Australia
| | - Martin Jones
- Department of Anatomical Pathology, Sonic Healthcare-Douglass Hanly Moir Pathology, Macquarie Park, Australia
| | - Fiona Bonar
- Department of Anatomical Pathology, Sonic Healthcare-Douglass Hanly Moir Pathology, Macquarie Park, Australia
| | - Ross Brookwell
- Department of Cytogenetics, Sullivan Nicolaides Pathology, Brisbane, Queensland, Australia
| | - Bernadette Garrone
- Department of Cytogenetics, Sullivan Nicolaides Pathology, Brisbane, Queensland, Australia
| | - Joel Talbot
- Department of Anatomical Pathology, Sonic Healthcare-Douglass Hanly Moir Pathology, Macquarie Park, Australia
| | - James Harraway
- Department of Cytogenetics, Sullivan Nicolaides Pathology, Brisbane, Queensland, Australia
| | - Anthony J Gill
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Australia.,Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.,Department of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Fiona M Maclean
- Department of Anatomical Pathology, Sonic Healthcare-Douglass Hanly Moir Pathology, Macquarie Park, Australia.,Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Australia.,Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
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Pei J, Flieder DB, Talarchek JN, Cooper HS, Patchefsky AS, Wei S. Clinical Application of Chromosome Microarray Analysis in the Diagnosis of Lipomatous Tumors. Appl Immunohistochem Mol Morphol 2021; 29:592-598. [PMID: 33734108 DOI: 10.1097/pai.0000000000000923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/27/2021] [Indexed: 11/25/2022]
Abstract
Well-differentiated liposarcoma/atypical lipomatous tumor (WDLS/ALT) and dedifferentiated liposarcoma (DDLS) have characteristic supernumerary ring and giant marker chromosomes involving the chromosomal region 12q13-15 which contains MDM2 (12q15), CDK4 (12q14.1), HMGA2 (12q14.3), YEATS4 (12q15), CPM (12q15), and FRS2 (12q15). Detecting MDM2 amplification by fluorescence in situ hybridization (FISH) is considered to be the gold standard for the diagnosis of WDLS/ALT and DDLS. In this study, formalin fixed paraffin embedded clinical specimens (16 liposarcomas and 19 benign lipomatous tumors) were used to detect MDM2 amplification and other chromosomal alterations in WDLS/ALT and DDLS by single nucleotide polymorphism-based chromosome microarray (CMA). All 16 liposarcomas showed MDM2 amplification with a MDM2/cep12 ratio from 2.4 to 8.4 by CMA. Ten (62.5%) of these cases had CDK4/cep12 ratio ≥2.0. All the cases without CDK4 amplification were from the thigh. The MDM2/cep12 ratio of all the benign lipomatous tumors (19/19) was within the normal limits. Twenty-one of the 35 benign lipomatous tumors and liposarcomas were also tested for MDM2 amplification by FISH. All the FISH results were consistent with the CMA results (100%). Along with MDM2 amplification, all 16 liposarcomas (100%) also showed amplification of YEATS4, CPM and FRS2. Only 11 of 16 (69%) cases showed HMGA2 amplification. In conclusion, this study demonstrated that CMA on routine formalin fixed paraffin embedded tissue is a sensitive and specific clinical test for detection of MDM2 gene amplification. Moreover, CMA allows simultaneous detection of genomic changes of interest including CDK4 and others, which provides enriched information for diagnosing lipomatous tumors.
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Affiliation(s)
- Jianming Pei
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA
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Nishio J, Nakayama S, Nabeshima K, Yamamoto T. Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives. J Clin Med 2021; 10:3230. [PMID: 34362013 PMCID: PMC8348700 DOI: 10.3390/jcm10153230] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/16/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
Dedifferentiated liposarcoma (DDL) is defined as the transition from well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) to non-lipogenic sarcoma, which arises mostly in the retroperitoneum and deep soft tissue of proximal extremities. It is characterized by a supernumerary ring and giant marker chromosomes, both of which contain amplified sequences of 12q13-15 including murinedouble minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) cell cycle oncogenes. Detection of MDM2 (and/or CDK4) amplification serves to distinguish DDL from other undifferentiated sarcomas. Recently, CTDSP1/2-DNM3OS fusion genes have been identified in a subset of DDL. However, the genetic events associated with dedifferentiation of WDL/ALT remain to be clarified. The standard treatment for localized DDL is surgery, with or without radiotherapy. In advanced disease, the standard first-line therapy is an anthracycline-based regimen, with either single-agent anthracycline or anthracycline in combination with the alkylating agent ifosfamide. Unfortunately, this regimen has not necessarily led to a satisfactory clinical outcome. Recent advances in the understanding of the pathogenesis of DDL may allow for the development of more-effective innovative therapeutic strategies. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology and treatment of DDL.
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Affiliation(s)
- Jun Nishio
- Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan; (S.N.); (T.Y.)
| | - Shizuhide Nakayama
- Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan; (S.N.); (T.Y.)
| | - Kazuki Nabeshima
- Department of Pathology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan;
| | - Takuaki Yamamoto
- Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan; (S.N.); (T.Y.)
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Kuczkiewicz-Siemion O, Wiśniewski P, Dansonka-Mieszkowska A, Grabowska-Kierył M, Olszewska K, Goryń T, Prochorec-Sobieszek M, Rutkowski P, Szumera-Ciećkiewicz A. The utility of fluorescence in situ hybridization (FISH) in determining DNA damage-inducible transcript 3 (DDIT3) amplification in dedifferentiated liposarcomas - an important diagnostic pitfall. Pathol Res Pract 2021; 225:153555. [PMID: 34325315 DOI: 10.1016/j.prp.2021.153555] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND OBJECTIVE Dedifferentiated liposarcoma (DDLPS) is characterized by non-lipogenic sarcoma fields coexisting with adipocyte-rich well-differentiated areas. Amplification of the 12q13-15 region includes the MDM2 and DDIT3 genes. MDM2 amplification is considered a genetic hallmark of DDLPS, while DDIT3 is typically rearranged in myxoid liposarcoma. Recent studies showed that DDIT3 amplification is associated with myxoid liposarcoma-like (LPS-like) morphology in DDLPS. Our study aimed to evaluate the status of MDM2 and DDIT3 by FISH in DDLPS and correlate it with MLPS-like features. MATERIAL AND METHODS Six patients with MLPS-like morphology DDLPS were investigated pathologically, immunohistochemically, and genetically. The control groups of patients with classical DDLPS morphology and well-differentiated liposarcoma (WDLPS) were established and molecularly assessed as well. Fluorescence in situ hybridization (FISH) used in routine diagnostics was performed to determine the status of MDM2 and DDIT3 genes. RESULTS The patient's mean age was 64 (range from 43 to 85 years) with a 5:4 male to female ratio. Tumors were localized retroperitoneally (15) and extra-retroperitoneally (3). All cases demonstrated amplification of the 12q15 region containing MDM2 gene and co-amplification of the 5' DDIT3 FISH Probe representing DDIT3 telomeric tag. However, we did not find the relation of myxoid LPS-like morphology with DDIT3 amplification as previously reported. CONCLUSIONS The biopsy material from DDLPS with myxoid areas can be misclassified as myxoid liposarcoma. Indeed, according to the histological image, DDIT3 status may be evaluated first. In these cases, we show that the DDIT3 telomeric tag amplification assessed by FISH, is a common, nonspecific feature, which is also found in classical DDLPS and WDLPS. Therefore, we believe that co-amplification of DDIT3 and MDM2 may be considered a spectrum of the 12q13-15 region amplification due to the specification of FISH methodology.
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Affiliation(s)
- Olga Kuczkiewicz-Siemion
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland; Institute of Hematology and Transfusion Medicine, Diagnostic Hematology Department, Warsaw, Poland
| | - Piotr Wiśniewski
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland
| | - Agnieszka Dansonka-Mieszkowska
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland
| | - Magdalena Grabowska-Kierył
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland
| | - Katarzyna Olszewska
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland
| | - Tomasz Goryń
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma, Warsaw, Poland
| | - Monika Prochorec-Sobieszek
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland; Institute of Hematology and Transfusion Medicine, Diagnostic Hematology Department, Warsaw, Poland
| | - Piotr Rutkowski
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma, Warsaw, Poland
| | - Anna Szumera-Ciećkiewicz
- Maria Skłodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland; Institute of Hematology and Transfusion Medicine, Diagnostic Hematology Department, Warsaw, Poland.
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Listunov D, Linhares BM, Kim E, Winkler A, Simes ML, Weaver S, Cho HJ, Rizo A, Zolov S, Keshamouni VG, Grembecka J, Cierpicki T. Development of potent dimeric inhibitors of GAS41 YEATS domain. Cell Chem Biol 2021; 28:1716-1727.e6. [PMID: 34289376 DOI: 10.1016/j.chembiol.2021.06.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 04/26/2021] [Accepted: 06/28/2021] [Indexed: 12/14/2022]
Abstract
GAS41 is an emerging oncogene overexpressed and implicated in multiple cancers, including non-small cell lung cancer (NSCLC). GAS41 is a dimeric protein that contains the YEATS domain, which is involved in the recognition of lysine-acylated histones. Here, we report the development of GAS41 YEATS inhibitors by employing a fragment-based screening approach. These inhibitors bind to GAS41 YEATS domain in a channel constituting a recognition site for acylated lysine on histone proteins. To enhance inhibitory activity, we developed a dimeric analog with nanomolar activity that blocks interactions of GAS41 with acetylated histone H3. Our lead compound engages GAS41 in cells, blocks proliferation of NSCLC cells, and modulates expression of GAS41-dependent genes, validating on-target mechanism of action. This study demonstrates that disruption of GAS41 protein-protein interactions may represent an attractive approach to target lung cancer cells. This work exemplifies the use of bivalent inhibitors as a general strategy to block challenging protein-protein interactions.
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Affiliation(s)
- Dymytrii Listunov
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Brian M Linhares
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - EunGi Kim
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Alyssa Winkler
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Miranda L Simes
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Sidney Weaver
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Hyo Je Cho
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Alexandrea Rizo
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA
| | - Sergey Zolov
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2670, USA
| | - Venkateshwar G Keshamouni
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2670, USA
| | - Jolanta Grembecka
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA.
| | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA.
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Chen J, Hang Y, Gao Q, Huang X. Surgical Diagnosis and Treatment of Primary Retroperitoneal Liposarcoma. Front Surg 2021; 8:672669. [PMID: 34150840 PMCID: PMC8211986 DOI: 10.3389/fsurg.2021.672669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/10/2021] [Indexed: 12/30/2022] Open
Abstract
Background: Primary retroperitoneal liposarcoma (PRPLS) is the most common soft tissue sarcoma of the retroperitoneum with high recurrence rate and short overall survival (OS). Methods: A retrospective review of 51 patients with PRPLS, treated between September 1, 2009 and November 30, 2020, was conducted to evaluate clinical outcomes of PRPLS resection. Patient demographics, histopathologic subtypes, overall survival (OS), progression-free survival (PFS), disease recurrence rate, and tumor stage were reviewed and analyzed. Univariate analysis was done to identify factors potentially affecting OS and PFS of PRPLS patients. Multivariate Cox proportional hazards analysis was used to evaluate the impact of various clinicopathological factors on OS and PFS of PRPLS patients. Results: Fifty-one PRPLS patients (28 Males, 23 Females; mean age 56.25 years) were evaluated. There was no significant effect of age, gender, contiguous organ resection, degree of differentiation and tumor size on the OS and PFS of the patients. Univariate analysis showed that negative surgical margin and early tumor stage significantly correlated with OS and PFS (all P < 0.001). Multivariate analysis showed that tumor stage [hazard ratio (HR) = 1.177, P = 0.001] was an independent predictors of poor progression-free survival, and surgical margins [HR = 4.0674 P = 0.038] and tumor stage [HR = 1.167 P = 0.001] were identified as independent predictors of poor overall survival. Conclusion: Negative surgical margin is a prognostic factor of OS, and can prolong the postoperative survival time of PRPLS patients. Tumor stage is a prognostic factor for OS and PFS, and can influence the survival of PRPLS patients. Earlier tumor stages of PRPLS are associated with significantly better outcomes.
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Affiliation(s)
- Jie Chen
- Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ying Hang
- Department of Emergency, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Qi Gao
- Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xinyu Huang
- Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China
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37
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Renne SL, Di Tommaso L. Poorly-differentiated and undifferentiated sarcomas of the mediastinum: a bag of tricks. MEDIASTINUM (HONG KONG, CHINA) 2021; 5:3. [PMID: 35118309 PMCID: PMC8794417 DOI: 10.21037/med-20-54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 09/24/2020] [Indexed: 11/29/2022]
Abstract
Mediastinum is a Pandora's Box containing many different structures that can give origin to several cancer types. Our aims are to provide a general framework to make a diagnosis of an undifferentiated pleomorphic sarcoma and to highlight relevant immunohistochemical and molecular techniques that can help in the differential diagnosis. We, therefore, provide a simple three-step algorithmic approach to diagnose pleomorphic sarcoma, emphasizing the role of clinicopathological correlations and advocating for a "relative frequency" method, especially when the material for the diagnosis is scarce, as in small biopsies. In the first place, if clinical and/or radiological features make a non-sarcoma diagnosis more likely, it should be ruled in. Next, even if no specific non-sarcomatous diagnoses are suspected, they should always be ruled out. Lastly, since many sarcomas can have a pleomorphic appearance, specific entities should also be ruled out because their identification might affect prognosis and treatment. We then cover selected immunohistochemical and molecular ancillary tests that can come at hand in the diagnosis, highlighting the pros and cons; in particular the use and the limitations of H3K27me3 immunohistochemistry, the meaning of MDM2 amplification in the mediastinum and the implication of muscle differentiation-either smooth or skeletal-in sarcomas. The main take home messages are to always rule-out more frequent lesion first and always include clinical and radiological information in the diagnostic process.
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Affiliation(s)
- Salvatore Lorenzo Renne
- Pathology Department, Humanitas Clinical and Research Center- IRCCS-, Via Manzoni 56, 20089 Rozzano (Mi), Italy
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele – Milan, Italy
| | - Luca Di Tommaso
- Pathology Department, Humanitas Clinical and Research Center- IRCCS-, Via Manzoni 56, 20089 Rozzano (Mi), Italy
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele – Milan, Italy
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38
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Wang XQ, Wang XQ, Hsu ATYW, Goytain A, Ng TLT, Nielsen TO. A Rapid and Cost-Effective Gene Expression Assay for the Diagnosis of Well-Differentiated and Dedifferentiated Liposarcomas. J Mol Diagn 2020; 23:274-284. [PMID: 33346147 DOI: 10.1016/j.jmoldx.2020.11.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 10/26/2020] [Accepted: 11/17/2020] [Indexed: 12/22/2022] Open
Abstract
Histologic examination neither reliably distinguishes benign lipomas from atypical lipomatous tumor/well-differentiated liposarcoma, nor dedifferentiated liposarcoma from other pleomorphic sarcomas, entities with different prognoses and management. Molecular confirmation of pathognomonic 12q13-15 amplifications leading to MDM2 overexpression is a diagnostic gold standard. Currently the most commonly used assay for this purpose is fluorescence in situ hybridization (FISH), but this is labor intensive. This study assessed whether newer NanoString-based technology could allow for more rapid and cost-efficient diagnosis of liposarcomas on standard formalin-fixed tissues through gene expression. Leveraging large-scale transcriptome data from The Cancer Genome Atlas, 20 genes were identified, most from the 12q13-15 amplicon, that distinguish dedifferentiated liposarcoma from other sarcomas and can be measured within a single NanoString assay. Using 21 cases of histologically ambiguous low-grade adipocytic tumors with available MDM2 amplification status, a machine learning-based analytical pipeline was built that assigns a given sample as negative or positive for liposarcoma based on quantitative gene expression. The effectiveness of the assay was validated on an independent set of 100 sarcoma samples (including 40 incident prospective cases), where histologic examination was considered insufficient for clinical diagnosis. The NanoString assay had a 93% technical success rate, and an accuracy of 97.8% versus an MDM2 amplification FISH gold standard. NanoString had a considerably faster turnaround time and was cheaper than FISH.
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Affiliation(s)
- Xiu Q Wang
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Xue Q Wang
- Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Anika T Y W Hsu
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Angela Goytain
- Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tony L T Ng
- Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada
| | - Torsten O Nielsen
- Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
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39
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Yamashita K, Kohashi K, Yamada Y, Akatsuka S, Ikuta K, Nishida Y, Toyokuni S, Oda Y. Prognostic significance of the MDM2/HMGA2 ratio and histological tumor grade in dedifferentiated liposarcoma. Genes Chromosomes Cancer 2020; 60:26-37. [PMID: 33111425 DOI: 10.1002/gcc.22899] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 01/13/2023] Open
Abstract
Dedifferentiated liposarcoma (DDLPS) is a relatively common soft tissue sarcoma that results from the progression of well-differentiated liposarcoma (WDLPS). This study aimed to investigate the progression process and to clarify the pathological and genetic factors related to poor prognosis in DDLPS. In 32 DDLPS cases and five WDLPS cases, genetic factors were analyzed by custom comparative genomic hybridization (CGH) array, which was designed to densely cover gene regions known to be frequently amplified in WD/DDLPS. The analyses comparing primary and metastatic lesions and those comparing histologically different areas in the same tumor revealed intra-tumoral genetic heterogeneity and progression. According to a prognostic analysis comparing the good-prognosis and the poor-prognosis groups, we selected MDM2 and HMGA2 as candidate genes associated with poor and good prognosis, respectively. The ratios of the amplification or gain levels of MDM2 and HMGA2 expressed in log ratios (log[MDM2/HMGA2] = log[MDM2]-log[HMGA2]) were significantly associated with prognosis. An amplification or gain level of MDM2 that was more than twice that of HMGA2 (MDM2/HMGA2 > 2, log[MDM2/HMGA2] > 1) was strongly related to poor OS (P < .001) and poor distant metastasis-free survival (DMFS) (P < .001). In the pathological analysis of 44 cases of DDLPS, histological tumor grade, cellular atypia, and MDM2 immunoreactivity were related to overall survival (OS), while HMGA2 immunoreactivity tended to be associated with OS. Cellular atypia was also associated with DMFS. In conclusion, histological grade and MDM2 expression were determined to be prognostically important, and the MDM2/HMGA2 amplification or gain ratio was found to have significant prognostic value by the custom CGH array analysis.
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Affiliation(s)
- Kyoko Yamashita
- Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuichi Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinya Akatsuka
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kunihiro Ikuta
- Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, Nagoya, Japan.,Medical Genomic Center, Nagoya University Hospital, Nagoya, Japan
| | - Yoshihiro Nishida
- Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, Nagoya, Japan.,Department of Rehabilitation, Nagoya University Hospital, Nagoya, Japan
| | - Shinya Toyokuni
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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40
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Tsuchiya R, Yoshimatsu Y, Noguchi R, Sei A, Takeshita F, Sugaya J, Fukushima S, Yoshida A, Ohtori S, Kawai A, Kondo T. Establishment and characterization of NCC-DDLPS1-C1: a novel patient-derived cell line of dedifferentiated liposarcoma. Hum Cell 2020; 34:260-270. [PMID: 32949334 DOI: 10.1007/s13577-020-00436-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/13/2020] [Indexed: 12/21/2022]
Abstract
Dedifferentiated liposarcoma (DDLPS) is one of the four subtypes of liposarcomas; it is characterized by the amplification of the 12q13-15 region, which includes MDM2 and CDK4 genes. DDLPS has an extremely high local recurrence rate and is refractory to chemotherapy and radiation, which leads to poor prognosis. Therefore, a novel therapeutic strategy should be urgently established for improving the prognosis of DDLPS. Although patient-derived cell lines are important tools for basic research, there are no DDLPS cell lines available from public cell banks. Here, we report the establishment of a novel DDLPS cell line. Using the surgically resected tumor tissue from a patient with DDLPS, we established a cell line and named it NCC-DDLPS1-C1. The NCC-DDLPS1-C1 cells contained 12q13-15, 1p32, and 1q23 amplicons and highly expressed MDM2 and CDK4 proteins. NCC-DDLPS-C1 cells exhibited constant growth, spheroid formation, aggressive invasion, and tumorigenesis in mice. By screening a drug library, we identified that the proteasome inhibitor, bortezomib, had inhibitory effects on the proliferation of NCC-DDLPS1-C1 cells. We concluded that the NCC-DDLPS1-C1 cell line may serve as a useful tool for basic and pre-clinical studies of DDLPS.
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Affiliation(s)
- Ryuto Tsuchiya
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Yuki Yoshimatsu
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Rei Noguchi
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akane Sei
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Fumitaka Takeshita
- Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Jun Sugaya
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Suguru Fukushima
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akihiko Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Seiji Ohtori
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Akira Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tadashi Kondo
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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Boni J, Rubio-Perez C, López-Bigas N, Fillat C, de la Luna S. The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities. Cancers (Basel) 2020; 12:cancers12082106. [PMID: 32751160 PMCID: PMC7465136 DOI: 10.3390/cancers12082106] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 07/24/2020] [Accepted: 07/27/2020] [Indexed: 12/15/2022] Open
Abstract
DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available.
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Affiliation(s)
- Jacopo Boni
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr Aiguader 88, 08003 Barcelona, Spain;
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain
| | - Carlota Rubio-Perez
- Cancer Science Programme, Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain; (C.R.-P.); (N.L.-B.)
| | - Nuria López-Bigas
- Cancer Science Programme, Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain; (C.R.-P.); (N.L.-B.)
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain
| | - Cristina Fillat
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036 Barcelona, Spain;
| | - Susana de la Luna
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr Aiguader 88, 08003 Barcelona, Spain;
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
- Correspondence: ; Tel.: +34-933-160-144
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Tyler R, Wanigasooriya K, Taniere P, Almond M, Ford S, Desai A, Beggs A. A review of retroperitoneal liposarcoma genomics. Cancer Treat Rev 2020; 86:102013. [PMID: 32278233 DOI: 10.1016/j.ctrv.2020.102013] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/22/2022]
Abstract
Retroperitoneal liposarcomas are rare tumours that carry a poorer prognosis than their extremity counterparts. Within their subtypes - well differentiated (WDL), dedifferentiated (DDL), myxoid (MLS) and pleomorphic (PLS) - they exhibit a diverse genomic landscape. With recent advances in next generation sequencing, the number of studies exploring this have greatly increased. The recent literature has deepened our understanding of the hallmark MDM2/CDK4 amplification in WDL/DDL and addressed concerns about toxicity and resistance when targeting this. The FUS-DDIT3 fusion gene remains the primary focus of interest in MLS with additional potential targets described. Whole genome sequencing has driven identification of novel genes and pathways implicated in WDL/DDL outside of the classic 12q13-15 amplicon. Due to their rarity; anatomical location and histologic subtype are infrequently mentioned when reporting the results of these studies. Reports can include non-adipogenic or extremity tumours, making it difficult to draw specific retroperitoneal conclusions. This narrative review aims to provide a summary of retroperitoneal liposarcoma genomics and the implications for therapeutic targeting.
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Affiliation(s)
- Robert Tyler
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
| | - Kasun Wanigasooriya
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
| | - Philippe Taniere
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham B15 2TH, United Kingdom.
| | - Max Almond
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham B15 2TH, United Kingdom.
| | - Samuel Ford
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham B15 2TH, United Kingdom.
| | - Anant Desai
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham B15 2TH, United Kingdom.
| | - Andrew Beggs
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
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Abstract
OPINION STATEMENT Over the last several years, the systemic treatment landscape for dedifferentiated liposarcoma (DDLPS) has notably expanded. Historically, systemic therapy options have been limited to cytotoxic chemotherapy agents, including doxorubicin, ifosfamide, gemcitabine, and docetaxel, that were shown to have efficacy in unselected populations of patients with soft tissue sarcomas. More recently, however, there have been phase II and III trials establishing clinical benefit of the cytotoxic agents trabectedin and eribulin along with the tyrosine kinase inhibitor pazopanib in patients with advanced liposarcoma and DDLPS. Additionally, there are several investigational targeted therapies that have incorporated advances in the understanding of DDLPS disease biology, exploiting the fact that nearly all such tumors include highly amplified expression of MDM2 and CDK4. Recent clinical trials have supported the benefit of the CDK4 inhibitor abemaciclib and the nuclear export inhibitor selinexor and support continued development of anti-MDM2 therapies, with particular attention to the bone marrow toxicity and resultant thrombocytopenia that has thus far limited their use. In contrast, the checkpoint inhibitors pembrolizumab and nivolumab remain of questionable benefit, although these immunotherapy drugs may have a role when combined with other therapeutic agents. Ongoing phase III trials will clarify the role of these novel agents. Future directions include directly comparing current standard-of-care options and newer therapies, developing synergistic combinations of novel agents, and evaluating their role in patients with localized DDLPS.
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44
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Yang L, Chen S, Luo P, Yan W, Wang C. Liposarcoma: Advances in Cellular and Molecular Genetics Alterations and Corresponding Clinical Treatment. J Cancer 2020; 11:100-107. [PMID: 31892977 PMCID: PMC6930414 DOI: 10.7150/jca.36380] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 09/12/2019] [Indexed: 12/12/2022] Open
Abstract
Liposarcoma is a malignant tumor of mesenchymal origin with significant tissue diversity. It is composed of adipocytes with different degrees of differentiation and different degrees of heteromorphosis. It is not sensitive to traditional radiotherapy and chemotherapy and has a poor prognosis. In recent years, with the rapid development of basic immunology, molecular genetics and tumor molecular biology, the histological classification of liposarcoma has become increasingly clear. More and more new methods and technologies, such as gene expression profile analysis, the whole genome sequencing, miRNA expression profile analysis and RNA sequencing, have been successfully applied to liposarcoma, bringing about a deeper understanding of gene expression changes and molecular pathogenic mechanisms in the occurrence and development of liposarcoma. This study reviews the present research status and progress of cellular and molecular alterations of liposarcoma and corresponding clinical treatment progress.
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Affiliation(s)
- Lingge Yang
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shiqi Chen
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Peng Luo
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wangjun Yan
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chunmeng Wang
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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45
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Integrated exome and RNA sequencing of dedifferentiated liposarcoma. Nat Commun 2019; 10:5683. [PMID: 31831742 PMCID: PMC6908635 DOI: 10.1038/s41467-019-13286-z] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 10/28/2019] [Indexed: 01/06/2023] Open
Abstract
The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management. Understanding the genomic features of dedifferentiated liposarcoma (DDLPS) is likely to uncover new options for management. Here, the authors reveal three prognostic groups, and highlight molecular markers associated with malignant transformation.
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46
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Abstract
Objective:to conduct a systematic literature review of the published studies on retroperitoneal non-organ liposarcomas.Material and Methods.A literature search was performed using Pubmed, Elibrary, COSMIC databases. The data of retrospective and prospective clinical trials were analyzed. Results. The article reviews contemporary data on epidemiology, classification, clinicalmorphological and molecular-genetic characteristics, as well as diagnosis and treatment of retroperitoneal non-organ liposarcomas. Conclusion. Retroperitoneal sarcomas account for about 13 % of all types of soft tissue sarcomas. Liposarcoma is the most common retroperitoneal mesenchymal tumor. Diagnosis and treatment of non-organ retroperitoneal liposarcoma remain challenging due to poor long-term treatment outcomes. As experience is gained with the diagnosis and treatment of retroperitoneal nonorganic liposarcomas, changes occur in the system of understanding the problem that determines the strategy for providing medical care in this category of patients. The article presents modern concept of retroperitoneal non-organ liposarcomas.
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Affiliation(s)
- A. Yu. Volkov
- N. N. Blokhin National Medical Research Centre of Oncology, Health Ministry of Russia
| | - S. N. Nered
- N. N. Blokhin National Medical Research Centre of Oncology, Health Ministry of Russia
| | - L. N. Lyubchenko
- N. N. Blokhin National Medical Research Centre of Oncology, Health Ministry of Russia; I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation
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Wardelmann E, Hartmann W. [Tumors with predominantly adipocytic morphology]. DER PATHOLOGE 2019; 40:339-352. [PMID: 31240452 DOI: 10.1007/s00292-019-0624-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
More than 20% of soft-tissue tumors belong to the group of adipocytic neoplasms. Difficulties may occur in the differential diagnosis of lipomas versus atypical lipomatous tumors/well-differentiated liposarcomas, in the distinction of dedifferentiated liposarcomas from other soft-tissue sarcoma entities and in the detailed subtyping of liposarcomas. Especially in biopsies, the correct diagnosis and grading may be hampered due to limited tissue. Because of the ever-increasing molecular-pathological knowledge of soft-tissue tumors and the rising distribution of molecular diagnostic assays in institutes of pathology, differential diagnosis has been facilitated, as more than 90% of adipocytic tumors carry more or less specific genomic alterations. In the following, the most important subtypes of adipocytic tumors are described morphologically and genomically.
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Affiliation(s)
- E Wardelmann
- Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude D17, 48149, Münster, Deutschland.
| | - W Hartmann
- Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude D17, 48149, Münster, Deutschland.,Sektion für Translationale Pathologie, Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Münster, Deutschland
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48
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Dufresne A, Brahmi M, Karanian M, Blay JY. Using biology to guide the treatment of sarcomas and aggressive connective-tissue tumours. Nat Rev Clin Oncol 2019; 15:443-458. [PMID: 29666441 DOI: 10.1038/s41571-018-0012-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Sarcomas are a heterogeneous group of malignancies that arise from cells of a mesenchymal origin. Surgery forms the mainstay of the treatment of most patients with localized sarcoma and might be followed or preceded by chemotherapy and/or radiotherapy. In the metastatic setting, systemic treatments tend to improve survival and control symptoms. However, the adverse events and sometimes disappointing outcomes associated with these empirical approaches to treatment indicate a need for new approaches. The advent of next-generation sequencing (NGS) has enabled more targeted treatment of many malignancies based on the presence of specific alterations. NGS analyses of sarcomas have revealed the presence of many alterations that can be targeted using therapies that are already used in patients with other forms of cancer. In this Review, we describe the genomic alterations considered to define specific nosological subgroups of sarcoma and whose contribution to oncogenesis provides a biological rationale for the use of a specific targeted therapy. We also report several less successful examples that should guide researchers and clinicians to better define the extent to which the identification of driver molecular alterations should influence the development of novel treatments.
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Affiliation(s)
- Armelle Dufresne
- Department of Medical Oncology, Centre Leon Berard, Lyon, France.
| | - Mehdi Brahmi
- Department of Medical Oncology, Centre Leon Berard, Lyon, France
| | - Marie Karanian
- Department of Pathology, Centre Leon Berard, Lyon, France
| | - Jean-Yves Blay
- Department of Medical Oncology, Centre Leon Berard, Lyon, France
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49
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Abstract
Well-differentiated liposarcoma (WDL)/atypical lipomatous tumor and dedifferentiated liposarcoma (DDL) together comprise the largest subgroup of liposarcomas, and constitute a histologic and behavioral spectrum of one disease. WDL and DDL typically occur in middle-aged to older adults, particularly within the retroperitoneum or extremities. WDL closely resembles mature adipose tissue, but typically shows fibrous septation with variable nuclear atypia and enlargement. WDL does not metastasize, but can dedifferentiate to DDL, which is associated with more aggressive clinical behavior, with a greater propensity for local recurrence and the capacity for metastasis. Although distant metastasis is rarer in DDL compared with other pleomorphic sarcomas, behavior is related to location, with a significantly worse outcome in retroperitoneal tumors. DDL typically has the appearance of undifferentiated pleomorphic or spindle cell sarcoma, and is usually a non-lipogenic sarcoma that is adjacent to WDL, occurs as a recurrence of WDL or which can arise de novo. WDL and DDL share similar background genetic aberrations; both are associated with high-level amplifications in the chromosomal 12q13-15 region, which includes the CDK4 and MDM2 cell cycle oncogenes. In addition, DDL harbor further genetic changes, particularly 6q23 and 1p32 coamplifications. While surgical excision remains the treatment mainstay with limited medical options for patients with aggressive recurrent disease or metastases, novel targeted therapies towards the gene products of chromosome 12 are being evaluated. This review summarizes the pathology of WDL and DDL, discussing morphology, immunohistochemistry, genetics and the differential diagnosis.
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Affiliation(s)
- Khin Thway
- Sarcoma Unit, Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ, United Kingdom.
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50
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Abstract
Adipocytic neoplasms include a diversity of both benign tumors (lipomas) and malignancies (liposarcomas), and each tumor type is characterized by its own unique molecular alterations driving tumorigenesis. Work over the past 30 years has established the diagnostic utility of several of these characteristic molecular alterations (e.g. MDM2 amplification in well- and dedifferentiated liposarcoma, FUS/EWSR1-DDIT3 gene fusions in myxoid liposarcoma, RB1 loss in spindle cell/pleomorphic lipoma). More recent studies have focused on additional molecular alterations which may have therapeutic or prognostic impact. This review will summarize several of the important molecular findings in adipocytic tumors that have been described over the past 10 years.
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Affiliation(s)
- Elizabeth G Demicco
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
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