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Zhang C, Li C, Su JZ, Zhao K, Shao L, Deng J. The genomic landscape of esophageal squamous cell carcinoma cell lines. Cancer Cell Int 2025; 25:174. [PMID: 40346668 PMCID: PMC12065367 DOI: 10.1186/s12935-025-03686-1] [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: 07/28/2024] [Accepted: 02/10/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND Research on the genomic characteristics of common esophageal squamous cell carcinoma (ESCC) cell lines, including exome mutations and mRNA expression, is limited. This study aims to elucidate the malignancy, invasion capability, classical cancer-related signaling pathways, and immune status of ESCC cell lines, providing a detailed genomic landscape and highlighting the unique features of each cell line. METHODS Whole exome and RNA sequencing were conducted on ESCC cell lines TE-1, ECA-109, KYSE-30, KYSE-150, KYSE-180, KYSE-450, and KYSE-510, with the normal epithelium cell line Het-1a as a comparison. Bioinformatics methods analyzed gene mutation types, mutation frequencies, RNA expression, and classical cancer-related signaling pathways. Specific analyses were also performed on tumor burden, genes related to differentiation, invasion, immunity, and gene enrichment in each cell line. RESULTS The highest tumor mutation burden (TMB) was 70.4 mutations per megabase (mut/MB) in KYSE-150, while the lowest was 48.7 mut/MB in KYSE-510. Mutations in the Hippo, Notch, PI3K, RTK-Ras, and Wnt signaling pathways were present in all cancer cell lines. Mutations were significantly enriched in signature 3, associated with defective homologous recombination deficiency (HRD). The NRF2 signaling pathway exhibited mutations in KYSE-180, KYSE-450, and TE-1 cell lines. The cell cycle gene mutation frequency was low, occurring only in KYSE-30 and TE-1 cell lines. The expression profiles of KYSE-510 and ECA-109 were similar. The KYSE-150 cell line showed up-regulated invasion genes, while the KYSE-450 cell line had significantly down-regulated poor differentiation-related genes. Immune-related genes were up-regulated in the ECA-109 cell line. CONCLUSION The molecular profiles generated in this study provide detailed information on gene mutations and expression in common ESCC cell lines. The KYSE-150 cell line exhibited a prominent invasion capability, while the ECA-109 cell line showed up-regulated immune properties. This genomic landscape offers valuable insights for future research and therapeutic strategies in ESCC.
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Affiliation(s)
- Chao Zhang
- Departments of Thoracic Surgery, State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Chenghao Li
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150006, Heilongjiang, China
| | - Jian Zhong Su
- School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325011, China
| | - Kuaile Zhao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Longlong Shao
- Departments of Thoracic Surgery, State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Jiaying Deng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China.
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China.
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Zhu J, Du L, Li H, Ran X, Zeng H, Wei W. Clinicopathological and therapeutic comparisons of esophageal cancer between China and the USA: a multicenter hospital-based study. JOURNAL OF THE NATIONAL CANCER CENTER 2024; 4:318-325. [PMID: 39735444 PMCID: PMC11674431 DOI: 10.1016/j.jncc.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/24/2024] [Accepted: 04/01/2024] [Indexed: 12/31/2024] Open
Abstract
Background Esophageal cancer (EC) remains a global health challenge due to its poor prognosis. China and the United States of America (USA) represent two distinct epicenters of EC burden. Understanding the EC disparities in these two countries is vital for tailoring prevention strategies, optimizing treatment, and enhancing outcomes in both countries. Yet, there lacks a comprehensive comparison of EC characteristics between the two countries. Methods In this multicenter, retrospective hospital-based study, we enrolled primary EC patients who received their initial treatment at one of 23 hospitals in China during 2016-2017. Using electronic medical records and cancer registration records, information on demographics, lifestyle, and clinicopathological characteristics (including tumor site, pathology, stage, metastases, differentiation, and treatment) were collected. Additionally, we compared these data with the clinicopathological information of invasive EC patients diagnosed in 2016-2017 from the Surveillance, Epidemiology, and End Results (SEER) database in the USA. Results A total of 6,658 EC patients in China and 8,555 EC patients in the USA were included finally. 85.5% (n = 5,694) of EC were esophageal squamous cell carcinoma (ESCC) in China, while esophageal adenocarcinoma (EAC) was prominent in the USA (58.9%, n = 5,041). Among EC patients with known staging, the proportion of early stage was higher in China compared to the USA (48.3% vs. 30.5%). Among ESCC patients, early-stage cases were higher in China than in the USA (49.8% vs. 31.8%), while among EAC patients, late-stage cases were higher in China than in the USA (77.3% vs. 68.5%) (all P < 0.001). In China, EC mainly occurred in the middle third (60.2%) of the esophagus, whereas in the USA, it was more common in the lower third (59.9%) of the organ. Compared with EC patients with known metastatic status in the USA, China had fewer cases of lymph node metastases (51.4% vs. 57.7%) and distant metastases (7.9% vs. 33.8%). Regarding treatment, China had more surgical therapy (53.7% vs. 22.6%), less radiotherapy (35.6% vs. 53.3%), and less chemotherapy (46.7% vs. 59.7%) compared to the USA. Conclusions This study reveals notable disparities in EC between China and the USA, encompassing epidemiological, clinicopathological, and treatment dimensions. These findings provide insight for tailored strategies addressing regional variations in clinicopathological and therapeutic characteristics.
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Affiliation(s)
- Juan Zhu
- Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lingbin Du
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huizhang Li
- Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Xianhui Ran
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongmei Zeng
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenqiang Wei
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Mahmud M, Munjal A, Savani M, Win H, Rozell U, Arshad J. Biomarker Testing and Role of Tyrosine Kinase Inhibitors and Immunotherapy for Esophageal Squamous Cell Carcinoma. FOREGUT: THE JOURNAL OF THE AMERICAN FOREGUT SOCIETY 2024; 4:467-474. [DOI: 10.1177/26345161241238748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Esophageal squamous cell carcinoma (ESCC) constitutes an aggressive subset of esophageal cancers that portends a poor prognosis. Management of ESCC has been historically challenging due to the limited effective therapeutic options. Broadening our understanding of the molecular landscape and identifying reliable biomarkers are essential in early detection, monitoring disease response and advancing treatment strategies. Recently, immunotherapy and tyrosine kinase inhibitors have changed the treatment algorithm of ESCC. In this review, we explore the molecular landscape and biomarkers that can aid in the management of ESCC and discuss the role of immunotherapy and tyrosine kinase inhibitors in the treatment of ESCC.
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Affiliation(s)
| | | | - Malvi Savani
- University of Arizona Cancer Center, Tucson, AZ, USA
| | - Hninyee Win
- University of Arizona Cancer Center, Tucson, AZ, USA
| | | | - Junaid Arshad
- University of Arizona Cancer Center, Tucson, AZ, USA
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Gupta P, Zhu S, Gui Y, Zhou D. Metabolic Chaos in Kidney Disease: Unraveling Energy Dysregulation. J Clin Med 2024; 13:6772. [PMID: 39597916 PMCID: PMC11594442 DOI: 10.3390/jcm13226772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/08/2024] [Accepted: 11/09/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Acute kidney injury (AKI) and chronic kidney disease (CKD) share a fundamental disruption: metabolic dysfunction. METHODS A literature review was performed to determine the metabolic changes that occur in AKI and CKD as well as potential therapeutic targets related to these changes. RESULTS In AKI, increased energy demand in proximal tubular epithelial cells drives a shift from fatty acid oxidation (FAO) to glycolysis. Although this shift offers short-term support, it also heightens cellular vulnerability to further injury. As AKI progresses to CKD, metabolic disruption intensifies, with both FAO and glycolysis becoming downregulated, exacerbating cellular damage and fibrosis. These metabolic alterations are governed by shifts in gene expression and protein signaling pathways, which can now be precisely analyzed through advanced omics and histological methods. CONCLUSIONS This review examines these metabolic disturbances and their roles in disease progression, highlighting therapeutic interventions that may restore metabolic balance and enhance kidney function. Many metabolic changes that occur in AKI and CKD can be utilized as therapeutic targets, indicating a need for future studies related to the clinical utility of these therapeutics.
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Affiliation(s)
- Priya Gupta
- School of Medicine, University of Connecticut, Farmington, CT 06030, USA;
| | - Saiya Zhu
- Division of Nephrology, Department of Medicine, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (S.Z.); (Y.G.)
| | - Yuan Gui
- Division of Nephrology, Department of Medicine, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (S.Z.); (Y.G.)
| | - Dong Zhou
- Division of Nephrology, Department of Medicine, School of Medicine, University of Connecticut, Farmington, CT 06030, USA; (S.Z.); (Y.G.)
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Naviwala MSS, Samar MR, Shoaib D, Akbar F, Idrees R, Rashid YA. Esophageal squamous cell carcinoma in a patient with BRCA1 mutation: a rare association. Ecancermedicalscience 2024; 18:1730. [PMID: 39421182 PMCID: PMC11484678 DOI: 10.3332/ecancer.2024.1730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Indexed: 10/19/2024] Open
Abstract
Background Esophageal neoplasms rank as the 7th most common cancers in the world. Squamous cell carcinomas of esophagus (SCCE) are the predominant subset, linked to a number of genetic alterations. Gene-driven tumour pathways are being increasingly identified with the emerging role of next-generation sequencing. Case presentation We report a case of an 82-year-old male patient who was diagnosed with SCCE involving the cervical region. He received definitive concurrent chemoradiotherapy with Carboplatin and Paclitaxel. To trace the family history of malignancy, a genetic test was carried out which turned out to be a pathogenic BRCA1 variant. Conclusion SCCE arising in the context of known BRCA1 mutation has been rarely reported to date. Testing for these mutations should be considered in patients who present with esophageal cancer, especially in the backdrop of familial neoplasms.
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Affiliation(s)
| | - Mirza Rameez Samar
- Department of Medical Oncology, Aga Khan University Hospital, Karachi 74800, Pakistan
| | - Daania Shoaib
- Department of Medical Oncology, Aga Khan University Hospital, Karachi 74800, Pakistan
| | - Fizza Akbar
- Department of Women and Child Health, Aga Khan University Hospital, Karachi 74800, Pakistan
| | - Romana Idrees
- Department of Pathology, Aga Khan University Hospital, Karachi 74800, Pakistan
| | - Yasmin Abdul Rashid
- Department of Medical Oncology, Aga Khan University Hospital, Karachi 74800, Pakistan
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杨 泽, 张 秀, 张 旭, 柳 颖, 张 嘉, 原 翔. [ Porphyromonas gingivalis infection facilitates immune escape of esophageal cancer by enhancing YTHDF2-mediated Fas degradation]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2024; 44:1159-1165. [PMID: 38977346 PMCID: PMC11237310 DOI: 10.12122/j.issn.1673-4254.2024.06.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Indexed: 07/10/2024]
Abstract
OBJECTIVE To investigate the effect of Porphyromonas gingivalis (Pg) infection on immune escape of oesophageal cancer cells and the role of YTHDF2 and Fas in this regulatory mechanism. METHODS We examined YTHDF2 and Fas protein expressions in esophageal squamous cell carcinoma (ESCC) tissues with and without Pg infection using immunohistochemistry and in Pg-infected KYSE150 cells using Western blotting. The interaction between YTHDF2 and Fas was investigated by co-immunoprecipitation (Co-IP). Pg-infected KYSE150 cells with lentivirus-mediated YTHDF2 knockdown were examined for changes in expression levels of YTHDF2, cathepsin B (CTSB), Fas and FasL proteins, and the effect of E64 (a cathepsin inhibitor) on these proteins were observed. After Pg infection and E64 treatment, KYSE150 cells were co-cultured with human peripheral blood mononuclear cells (PBMCs), and the expressions of T cell-related effector molecules were detected by flow cytometry. RESULTS ESCC tissues and cells with Pg infection showed significantly increased YTHDF2 expression and lowered Fas expression. The results of Co-IP demonstrated a direct interaction between YTHDF2 and Fas. In Pg-infected KYSE150 cells with YTHDF2 knockdown, the expression of CTSB was significantly reduced while Fas and FasL expressions were significantly increased. E64 treatment of KYSE150 cells significantly decreased the expression of CTSB without affecting YTHDF2 expression and obviously increased Fas and FasL expressions. Flow cytometry showed that in Pg-infected KYSE150 cells co-cultured with PBMCs, the expressions of Granzyme B and Ki67 were significantly decreased while PD-1 expression was significantly enhanced. CONCLUSION Pg infection YTHDF2-dependently regulates the expression of Fas to facilitate immune escape of esophageal cancer and thus promoting cancer progression, suggesting the key role of YTHDF2 in regulating immune escape of esophageal cancer.
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Deboever N, Jones CM, Yamashita K, Ajani JA, Hofstetter WL. Advances in diagnosis and management of cancer of the esophagus. BMJ 2024; 385:e074962. [PMID: 38830686 DOI: 10.1136/bmj-2023-074962] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
Esophageal cancer is the seventh most common malignancy worldwide, with over 470 000 new cases diagnosed each year. Two distinct histological subtypes predominate, and should be considered biologically separate disease entities.1 These subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Outcomes remain poor regardless of subtype, with most patients presenting with late stage disease.2 Novel strategies to improve early detection of the respective precursor lesions, squamous dysplasia, and Barrett's esophagus offer the potential to improve outcomes. The introduction of a limited number of biologic agents, as well as immune checkpoint inhibitors, is resulting in improvements in the systemic treatment of locally advanced and metastatic esophageal cancer. These developments, coupled with improvements in minimally invasive surgical and endoscopic treatment approaches, as well as adaptive and precision radiotherapy technologies, offer the potential to improve outcomes still further. This review summarizes the latest advances in the diagnosis and management of esophageal cancer, and the developments in understanding of the biology of this disease.
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Affiliation(s)
- Nathaniel Deboever
- Department of Thoracic and Cardiovascular Surgery, MD Anderson Cancer Center, Houston, TX, USA
| | - Christopher M Jones
- Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Kohei Yamashita
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Wayne L Hofstetter
- Department of Thoracic and Cardiovascular Surgery, MD Anderson Cancer Center, Houston, TX, USA
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Li R, Luo Q, Gutierrez ID. Asian Americans have higher 30-day surgical complications after esophagectomy: A propensity-score matched study from ACS-NSQIP database. Am J Surg 2024; 232:75-80. [PMID: 38199873 DOI: 10.1016/j.amjsurg.2024.01.005] [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: 10/09/2023] [Revised: 12/28/2023] [Accepted: 01/04/2024] [Indexed: 01/12/2024]
Abstract
BACKGROUND Despite Asian Americans having a heightened risk profile for esophageal cancer, racial disparities within this group have not been investigated. This study seeks to evaluate the 30-day postoperative outcomes for Asian Americans following esophagectomy. METHODS A retrospective analysis was performed using ACS-NSQIP esophagectomy targeted database 2016-2021. A 1:3 propensity-score matching was applied to Asian Americans and Caucasians who underwent esophagectomy to compare their 30-day outcomes. RESULTS There were 229 Asian Americans and 5303 Caucasians identified. Asian Americans were more likely to have squamous cell carcinoma than adenocarcinoma. After matching, 687 Caucasians were included. Asian Americans had higher pulmonary complications (22.27 % vs 16.01 %, p = 0.04) especially pneumonia (16.59 % vs 11.06 %, p = 0.04), renal dysfunction (2.62 % vs 0.44 %, p = 0.01) especially progressive renal insufficiency (1.31 % vs 0.15 %, p < 0.05), and bleeding events (18.34 % vs 9.02 %, p < 0.01). In addition, Asian Americans had longer LOS (11.83 ± 9.39 vs 10.23 ± 7.34 days, p = 0.03). CONCLUSION Asian Americans were found to face higher 30-day surgical complications following esophagectomy. Continued investigation into the underlying causes and potential mitigation strategies for these disparities are needed.
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Affiliation(s)
- Renxi Li
- The George Washington University School of Medicine and Health Sciences, United States; Division of Cardiovascular and Thoracic Surgery, Department of Surgery, University of Minnesota Medical School, United States.
| | - Qianyun Luo
- Division of Cardiovascular and Thoracic Surgery, Department of Surgery, University of Minnesota Medical School, United States
| | - Ilitch Diaz Gutierrez
- Division of Cardiovascular and Thoracic Surgery, Department of Surgery, University of Minnesota Medical School, United States
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Zhao YX, Zhao HP, Zhao MY, Yu Y, Qi X, Wang JH, Lv J. Latest insights into the global epidemiological features, screening, early diagnosis and prognosis prediction of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:2638-2656. [PMID: 38855150 PMCID: PMC11154680 DOI: 10.3748/wjg.v30.i20.2638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/27/2024] Open
Abstract
As a highly invasive carcinoma, esophageal cancer (EC) was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020. Esophageal squamous cell carcinoma (ESCC) is the major histological subtype of EC, and its incidence and mortality rates are decreasing globally. Due to the lack of specific early symptoms, ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis, and the incidence and mortality rates are still high in many countries, especially in China. Therefore, enormous challenges still exist in the management of ESCC, and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC. Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated, certain promising biomarkers are being investigated to facilitate clinical decision-making. With the advent and advancement of high-throughput technologies, such as genomics, proteomics and metabolomics, valuable biomarkers with high sensitivity, specificity and stability could be identified for ESCC. Herein, we aimed to determine the epidemiological features of ESCC in different regions of the world, especially in China, and focused on novel molecular biomarkers associated with ESCC screening, early diagnosis and prognosis prediction.
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Affiliation(s)
- Yi-Xin Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Meng-Yao Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Xi Qi
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Ji-Han Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
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Zhang J, Chen W, Chen G, Flannick J, Fikse E, Smerin G, Degner K, Yang Y, Xu C, Consortium AMP-T2D-GENES, Li Y, Hanover JA, Simonds WF. Ancestry-specific high-risk gene variant profiling unmasks diabetes-associated genes. Hum Mol Genet 2024; 33:655-666. [PMID: 36255737 PMCID: PMC11000659 DOI: 10.1093/hmg/ddac255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 09/28/2022] [Accepted: 10/10/2022] [Indexed: 11/15/2022] Open
Abstract
How ancestry-associated genetic variance affects disparities in the risk of polygenic diseases and influences the identification of disease-associated genes warrants a deeper understanding. We hypothesized that the discovery of genes associated with polygenic diseases may be limited by the overreliance on single-nucleotide polymorphism (SNP)-based genomic investigation, as most significant variants identified in genome-wide SNP association studies map to introns and intergenic regions of the genome. To overcome such potential limitations, we developed a gene-constrained, function-based analytical method centered on high-risk variants (hrV) that encode frameshifts, stopgains or splice site disruption. We analyzed the total number of hrV per gene in populations of different ancestry, representing a total of 185 934 subjects. Using this analysis, we developed a quantitative index of hrV (hrVI) across 20 428 genes within each population. We then applied hrVI analysis to the discovery of genes associated with type 2 diabetes mellitus (T2DM), a polygenic disease with ancestry-related disparity. HrVI profiling and gene-to-gene comparisons of ancestry-specific hrV between the case (20 781 subjects) and control (24 440 subjects) populations in the T2DM national repository identified 57 genes associated with T2DM, 40 of which were discoverable only by ancestry-specific analysis. These results illustrate how a function-based, ancestry-specific analysis of genetic variations can accelerate the identification of genes associated with polygenic diseases. Besides T2DM, such analysis may facilitate our understanding of the genetic basis for other polygenic diseases that are also greatly influenced by environmental and behavioral factors, such as obesity, hypertension and Alzheimer's disease.
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Affiliation(s)
- Jianhua Zhang
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Weiping Chen
- Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
- Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Guanjie Chen
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD 20892, United States
| | - Jason Flannick
- Metabolism Program, Broad Institute, Cambridge, MA 02142, United States
| | - Emma Fikse
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Glenda Smerin
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Katherine Degner
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - Yanqin Yang
- Laboratory of Transplantation Genomics, National Heart Lung and Blood Institute; National Institutes of Health, Bethesda, MD 20892, United States
| | - Catherine Xu
- Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | | | - Yulong Li
- Milton S. Hershey Medical Center, Division of Endocrinology, Diabetes and Metabolism, Penn State University, Hershey, PA 17033, United States
| | - John A Hanover
- Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
| | - William F Simonds
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States
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Zhang J, Pandey M, Awe A, Lue N, Kittock C, Fikse E, Degner K, Staples J, Mokhasi N, Chen W, Yang Y, Adikaram P, Jacob N, Greenfest-Allen E, Thomas R, Bomeny L, Zhang Y, Petros TJ, Wang X, Li Y, Simonds WF. The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function. Am J Hum Genet 2024; 111:473-486. [PMID: 38354736 PMCID: PMC10940018 DOI: 10.1016/j.ajhg.2024.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 02/16/2024] Open
Abstract
Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gβ5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases.
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Affiliation(s)
- Jianhua Zhang
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Mritunjay Pandey
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Adam Awe
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicole Lue
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Claire Kittock
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Emma Fikse
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Katherine Degner
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jenna Staples
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Neha Mokhasi
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Weiping Chen
- Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bldg. 8/Rm 1A11, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yanqin Yang
- Laboratory of Transplantation Genomics, National Heart Lung and Blood Institute, Bldg. 10/Rm 7S261, National Institutes of Health, Bethesda, MD 20892, USA
| | - Poorni Adikaram
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nirmal Jacob
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Emily Greenfest-Allen
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rachel Thomas
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Laura Bomeny
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yajun Zhang
- Unit on Cellular and Molecular Neurodevelopment, Bldg. 35/Rm 3B 1002, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Timothy J Petros
- Unit on Cellular and Molecular Neurodevelopment, Bldg. 35/Rm 3B 1002, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Xiaowen Wang
- Partek Incorporated, 12747 Olive Boulevard, St. Louis, MO 63141, USA
| | - Yulong Li
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA
| | - William F Simonds
- Metabolic Diseases Branch, Bldg. 10/Rm 8C-101, National Institutes of Health, Bethesda, MD 20892, USA.
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Chuwdhury GS, Guo Y, Chiang CL, Lam KO, Kam NW, Liu Z, Dai W. ImmuneMirror: A machine learning-based integrative pipeline and web server for neoantigen prediction. Brief Bioinform 2024; 25:bbae024. [PMID: 38343325 PMCID: PMC10859690 DOI: 10.1093/bib/bbae024] [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: 09/08/2023] [Revised: 12/05/2023] [Accepted: 01/16/2024] [Indexed: 02/15/2024] Open
Abstract
Neoantigens are derived from somatic mutations in the tumors but are absent in normal tissues. Emerging evidence suggests that neoantigens can stimulate tumor-specific T-cell-mediated antitumor immune responses, and therefore are potential immunotherapeutic targets. We developed ImmuneMirror as a stand-alone open-source pipeline and a web server incorporating a balanced random forest model for neoantigen prediction and prioritization. The prediction model was trained and tested using known immunogenic neopeptides collected from 19 published studies. The area under the curve of our trained model was 0.87 based on the testing data. We applied ImmuneMirror to the whole-exome sequencing and RNA sequencing data obtained from gastrointestinal tract cancers including 805 tumors from colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma patients. We discovered a subgroup of microsatellite instability-high (MSI-H) CRC patients with a low neoantigen load but a high tumor mutation burden (> 10 mutations per Mbp). Although the efficacy of PD-1 blockade has been demonstrated in advanced MSI-H patients, almost half of such patients do not respond well. Our study identified a subset of MSI-H patients who may not benefit from this treatment with lower neoantigen load for major histocompatibility complex I (P < 0.0001) and II (P = 0.0008) molecules, respectively. Additionally, the neopeptide YMCNSSCMGV-TP53G245V, derived from a hotspot mutation restricted by HLA-A02, was identified as a potential actionable target in ESCC. This is so far the largest study to comprehensively evaluate neoantigen prediction models using experimentally validated neopeptides. Our results demonstrate the reliability and effectiveness of ImmuneMirror for neoantigen prediction.
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Affiliation(s)
- Gulam Sarwar Chuwdhury
- Department of Clinical Oncology, Center of Cancer Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (SAR), P. R. China
| | - Yunshan Guo
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA
| | - Chi-Leung Chiang
- Department of Clinical Oncology, Center of Cancer Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (SAR), P. R. China
| | - Ka-On Lam
- Department of Clinical Oncology, Center of Cancer Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (SAR), P. R. China
| | - Ngar-Woon Kam
- Department of Clinical Oncology, Center of Cancer Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (SAR), P. R. China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Hong Kong Science Park, Shatin, Hong Kong
| | - Zhonghua Liu
- Department of Biostatistics, Columbia University, New York, NY, USA
| | - Wei Dai
- Department of Clinical Oncology, Center of Cancer Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (SAR), P. R. China
- University of Hong Kong-Shenzhen Hospital, Shenzhen, P. R. China
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13
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Liu Z, Zhang Y, Ma N, Yang Y, Ma Y, Wang F, Wang Y, Wei J, Chen H, Tartarone A, Velotta JB, Dayyani F, Gabriel E, Wakefield CJ, Kidane B, Carbonelli C, Long L, Liu Z, Su J, Li Z. Progenitor-like exhausted SPRY1 +CD8 + T cells potentiate responsiveness to neoadjuvant PD-1 blockade in esophageal squamous cell carcinoma. Cancer Cell 2023; 41:1852-1870.e9. [PMID: 37832554 DOI: 10.1016/j.ccell.2023.09.011] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 08/15/2023] [Accepted: 09/18/2023] [Indexed: 10/15/2023]
Abstract
Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset of exhausted CD8+ T cells expressing SPRY1 (CD8+ Tex-SPRY1) that displays a progenitor exhausted T cell (Tpex) phenotype and correlates with complete response to ICB. We validate CD8+ Tex-SPRY1 cells as an ICB-specific predictor of improved response and survival using independent ICB-/non-ICB cohorts and demonstrate that expression of SPRY1 in CD8+ T cells enforces Tpex phenotype and enhances ICB efficacy. Additionally, CD8+ Tex-SPRY1 cells contribute to proinflammatory phenotype of macrophages and functional state of B cells, which thereby promotes antitumor immunity by enhancing CD8+ T cell effector functions. Overall, our findings unravel progenitor-like CD8+ Tex-SPRY1 cells' role in effective responses to ICB for ESCC and inform mechanistic biomarkers for future individualized immunotherapy.
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Affiliation(s)
- Zhichao Liu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai 200030, China
| | - Yaru Zhang
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China; Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang 325101, China
| | - Ning Ma
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai 200030, China
| | - Yang Yang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai 200030, China
| | - Yunlong Ma
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Feng Wang
- State Key Laboratory of Oncogenes and Related Genes, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yan Wang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Jinzhi Wei
- Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Hongyan Chen
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Alfredo Tartarone
- Division of Medical Oncology, Department of Onco-Hematology, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ) 85028, Italy
| | - Jeffrey B Velotta
- Department of Thoracic Surgery, Kaiser Permanente Oakland Medical Center, Kaiser Permanente Northern California, Oakland, CA 94611, USA
| | - Farshid Dayyani
- Chao Comprehensive Cancer Center, University of California Irvine, Orange, CA 92868, USA
| | - Emmanuel Gabriel
- Department of Surgery, Division of Surgical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Connor J Wakefield
- Department of Internal Medicine, Brooke Army Medical Center, Fort Sam Houston, TX 78234, USA
| | - Biniam Kidane
- Section of Thoracic Surgery, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Cristiano Carbonelli
- Pneumology Unit, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo 71013, Italy
| | - Lingyun Long
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Jianzhong Su
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China; Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang 325101, China.
| | - Zhigang Li
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai 200030, China.
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14
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Van Loon K, Mmbaga EJ, Mushi BP, Selekwa M, Mwanga A, Akoko LO, Mwaiselage J, Mosha I, Ng DL, Wu W, Silverstein J, Mulima G, Kaimila B, Gopal S, Snell JM, Benz SC, Vaske C, Sanborn Z, Sedgewick AJ, Radenbaugh A, Newton Y, Collisson EA. A Genomic Analysis of Esophageal Squamous Cell Carcinoma in Eastern Africa. Cancer Epidemiol Biomarkers Prev 2023; 32:1411-1420. [PMID: 37505926 PMCID: PMC11578543 DOI: 10.1158/1055-9965.epi-22-0775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 04/19/2023] [Accepted: 07/26/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) comprises 90% of all esophageal cancer cases globally and is the most common histology in low-resource settings. Eastern Africa has a disproportionately high incidence of ESCC. METHODS We describe the genomic profiles of 61 ESCC cases from Tanzania and compare them to profiles from an existing cohort of ESCC cases from Malawi. We also provide a comparison to ESCC tumors in The Cancer Genome Atlas (TCGA). RESULTS We observed substantial transcriptional overlap with other squamous histologies via comparison with TCGA PanCan dataset. DNA analysis revealed known mutational patterns, both genome-wide as well as in genes known to be commonly mutated in ESCC. TP53 mutations were the most common somatic mutation in tumors from both Tanzania and Malawi but were detected at lower frequencies than previously reported in ESCC cases from other settings. In a combined analysis, two unique transcriptional clusters were identified: a proliferative/epithelial cluster and an invasive/migrative/mesenchymal cluster. Mutational signature analysis of the Tanzanian cohort revealed common signatures associated with aging and cytidine deaminase activity (APOBEC) and an absence of signature 29, which was previously reported in the Malawi cohort. CONCLUSIONS This study defines the molecular characteristics of ESCC in Tanzania, and enriches the Eastern African dataset, with findings of overall similarities but also some heterogeneity across two unique sites. IMPACT Despite a high burden of ESCC in Eastern Africa, investigations into the genomics in this region are nascent. This represents the largest comprehensive genomic analysis ESCC from sub-Saharan Africa to date.
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Affiliation(s)
- Katherine Van Loon
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - Elia J Mmbaga
- Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Beatrice P Mushi
- Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Msiba Selekwa
- Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Ally Mwanga
- Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Larry O Akoko
- Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | | | | | - Dianna L Ng
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - Wei Wu
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - Jordyn Silverstein
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
| | | | | | - Satish Gopal
- UNC Project-Malawi, Lilongwe, Malawi
- University of North Carolina, Chapel Hill, North Carolina
| | - Jeff M Snell
- University of North Carolina, Chapel Hill, North Carolina
| | | | | | - Zack Sanborn
- NantOmics/NantHealth, Inc., El Segundo, California
| | | | | | - Yulia Newton
- NantOmics/NantHealth, Inc., El Segundo, California
| | - Eric A Collisson
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
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Jiang H, Makelike K, Chen B, Xi M, Li Q, Hu Y, Zhu Y. Definitive concurrent chemoradiotherapy with docetaxel plus cisplatin versus 5-fluorouracil plus cisplatin in patients with esophageal squamous cell carcinoma: long-term follow-up results of a phase II randomized controlled trial. Radiat Oncol 2023; 18:150. [PMID: 37700348 PMCID: PMC10498519 DOI: 10.1186/s13014-023-02339-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Definitive radiotherapy plus concurrent chemotherapy has been a standard treatment for esophagus patients who are unfit to undergo surgery. However, there are a variety of concurrent chemotherapy regimens with varying efficacy. In this phase II prospective study, we compared the efficacy and toxicity of DP (docetaxel and cisplatin) and PF (cisplatin and 5-fluorouracil) regimens with concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC) and analyzed the 5-year overall survival (OS) and progression free survival (PFS). We also summarized the salvage treatments and late toxicities. METHODS We enrolled 86 patients with clinical stage II-IVA from the Sun Yat-sen University Cancer Center. The patients were divided into two groups: PF group (41) and DP group (45). Statistics were analyzed using SPSS version 19.0. RESULTS The 5-year OS rates were 62.9% ± 7.6% in PF group, and 52.7% ± 7.5% in DP group (P = 0.131), respectively. The 5-year PFS rates were 43.9% ± 7.8% for PF group, and 40.0% ± 7.3% for DP group (P = 0.398), respectively. Sixteen patients in the DP group and thirteen in the PF group received salvage treatment. For those patients with local residual or local recurrent disease, the median survival time after salvage treatment was 13.5 months and the 1, 2, and 3-year survival rates were 79.0%, 50.3%, and 43.1%, respectively. For all patients, thirteen (15.1%) had Grade 2 late cardiac toxicities. One patient had Grade 2 pleural effusion and required diuretic. Most patients with pneumonia are mild, and only one patient in PF group had Grade 2 pneumonia. One patient in the DP group developed tracheoesophageal fistula. CONCLUSIONS The 5-year follow-up confirmed that definitive CCRT with the DP regimen did not improve the treatment response, OS, or PFS in patients with ESCC compared to the PF regimen. The PF regimen remains the standard regimen for definitive CCRT for patients with locally advanced ESCC. Long-term follow-up also suggested that appropriate and active salvage treatment has a survival benefit for some patients, and late cardiopulmonary toxicities should be noticed during follow-up. TRIAL REGISTRATION The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT02969473, October 2010).
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Affiliation(s)
- Hui Jiang
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, P.R. China
| | - Kanjiebubi Makelike
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, P.R. China
| | - Baoqing Chen
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, P.R. China
| | - Mian Xi
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, P.R. China
| | - Qiaoqiao Li
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, P.R. China
| | - Yonghong Hu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, P.R. China
| | - Yujia Zhu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, P.R. China.
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16
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Cheng M, Xin Q, Ma S, Ge M, Wang F, Yan X, Jiang B. Advances in the Theranostics of Oesophageal Squamous Carcinoma. ADVANCED THERAPEUTICS 2023; 6. [DOI: 10.1002/adtp.202200251] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Indexed: 01/04/2025]
Abstract
AbstractOesophageal squamous carcinoma (ESCC) is one of the most lethal human malignancies, and it is a more aggressive form of oesophageal cancer (EC) that comprises over 90% of all EC cases in China compared with oesophageal adenocarcinoma (EAC). The high mortality of ESCC is attributed to the late‐stage diagnosis, chemoradiotherapy resistance, and lack of appropriate therapeutic targets and corresponding therapeutic formulations. Recently, emerging clinical and translational investigations have involved genome analyses, diagnostic biomarkers, and targeted therapy for ESCC, and these studies provide a new horizon for improving the clinical outcomes of patients with ESCC. Here, the latest research advances in the theranostics of ESCC are reviewed and the unique features of ESCC (including differences from EAC, genomic alterations, and microbe infections), tissue and circulating biomarkers, chemoradiotherapy resistance, clinical targeted therapy for ESCC, identification of novel therapeutic targets, and designation of nanotherapeutic systems for ESCC are particularly focused on. Finally, the perspectives for future clinical and translational theranostic research of ESCC are discussed and the obstacles that must be overcome in ESCC theranostics are described.
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Affiliation(s)
- Miaomiao Cheng
- Nanozyme Medical Center School of Basic Medical Sciences Zhengzhou University Zhengzhou 450001 China
| | - Qi Xin
- Nanozyme Medical Center School of Basic Medical Sciences Zhengzhou University Zhengzhou 450001 China
| | - Saiyu Ma
- Nanozyme Medical Center School of Basic Medical Sciences Zhengzhou University Zhengzhou 450001 China
| | - Mengyue Ge
- Nanozyme Medical Center School of Basic Medical Sciences Zhengzhou University Zhengzhou 450001 China
| | - Feng Wang
- Oncology Department The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan 450000 China
| | - Xiyun Yan
- Nanozyme Medical Center School of Basic Medical Sciences Zhengzhou University Zhengzhou 450001 China
- State Key Laboratory of Esophageal Cancer Prevention &Treatment Zhengzhou Henan 450001 China
- CAS Engineering Laboratory for Nanozyme Key Laboratory of Protein and Peptide Pharmaceuticals Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China
| | - Bing Jiang
- Nanozyme Medical Center School of Basic Medical Sciences Zhengzhou University Zhengzhou 450001 China
- State Key Laboratory of Esophageal Cancer Prevention &Treatment Zhengzhou Henan 450001 China
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Tang G, Peng J, Huo L, Yin W. An N6-methyladenosine regulation- and mRNAsi-related prognostic index reveals the distinct immune microenvironment and immunotherapy responses in lower-grade glioma. BMC Bioinformatics 2023; 24:225. [PMID: 37264314 DOI: 10.1186/s12859-023-05328-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 05/10/2023] [Indexed: 06/03/2023] Open
Abstract
BACKGROUND N6-methyladenosine (m6A) modification is involved in tumorigenesis and progression as well as closely correlated with stem cell differentiation and pluripotency. Moreover, tumor progression includes the acquisition of stemness characteristics and accumulating loss of differentiation phenotype. Therefore, we integrated m6A modification and stemness indicator mRNAsi to classify patients and predict prognosis for LGG. METHODS We performed consensus clustering, weighted gene co-expression network analysis, and least absolute shrinkage and selection operator Cox regression analysis to identify an m6A regulation- and mRNAsi-related prognostic index (MRMRPI). Based on this prognostic index, we also explored the differences in immune microenvironments between high- and low-risk populations. Next, immunotherapy responses were also predicted. Moreover, single-cell RNA sequencing data was further used to verify the expression of these genes in MRMRPI. At last, the tumor-promoting and tumor-associated macrophage polarization roles of TIMP1 in LGG were validated by in vitro experiments. RESULTS Ten genes (DGCR10, CYP2E1, CSMD3, HOXB3, CABP4, AVIL, PTCRA, TIMP1, CLEC18A, and SAMD9) were identified to construct the MRMRPI, which was able to successfully classify patients into high- and low-risk group. Significant differences in prognosis, immune microenvironment, and immunotherapy responses were found between distinct groups. A nomogram integrating the MRMRPI and other prognostic factors were also developed to accurately predict prognosis. Moreover, in vitro experiments illustrated that inhibition of TIMP1 could inhibit the proliferation, migration, and invasion of LGG cells and also inhibit the polarization of tumor-associated macrophages. CONCLUSION These findings provide novel insights into understanding the interactions of m6A methylation regulation and tumor stemness on LGG development and contribute to guiding more precise immunotherapy strategies.
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Affiliation(s)
- Guihua Tang
- Department of Clinical Laboratory, Hunan Provincial People's Hospital (The first affiliated hospital of Hunan Normal University, The College of Clinical Medicine of Human Normal University), Changsha, 410005, Hunan Province, People's Republic of China.
| | - Jianqiao Peng
- Department of Clinical Laboratory, Hunan Provincial People's Hospital (The first affiliated hospital of Hunan Normal University, The College of Clinical Medicine of Human Normal University), Changsha, 410005, Hunan Province, People's Republic of China
| | - Longwei Huo
- Department of Neurosurgery, Yulin First Hospital Affiliated to Xi'an Jiao Tong University, Yulin, 719000, People's Republic of China
| | - Wen Yin
- Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, Hunan Province, People's Republic of China.
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18
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Fang X, Sun P, Dong Y, Huang Y, Lu JJ, Kong L. In vitro evaluation of photon and carbon ion radiotherapy in combination with cisplatin in head and neck squamous cell carcinoma cell lines. Front Oncol 2023; 13:896142. [PMID: 37081974 PMCID: PMC10110960 DOI: 10.3389/fonc.2023.896142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/21/2023] [Indexed: 04/07/2023] Open
Abstract
BackgroundHeavy ion radiotherapy, such as carbon ion radiotherapy (CIRT), has multiple advantages over conventional photon therapy. Cisplatin, as a classic anti-tumor drugs, has been tested and discovered as a photon radiosensitizer in several cell lines, including head and neck squamous cell carcinoma (HNSCC). Hence, the aim of our study is to evaluate whether cisplatin can sensitize CIRT towards HNSCC cell lines in vitro.MethodsHuman nasopharyngeal carcinoma cell line CNE-2, human tongue squamous carcinoma cell line TCA 8113 and human hypopharynx squamous carcinoma cell line FADU were all irradiated with photon beam of 2, 4, 6, 8 Gy (physical dose) and carbon ion beam of 1, 2, 3, 4 Gy (physical dose) and treated with cisplatin. Cell survival was assessed by clonogenic survival assay.ResultsCIRT showed significantly stronger cytotoxic effect than standard photon radiotherapy. The relative biological effectiveness (RBE) of carbon ion beam at 10% survival (RBE10) was calculated 3.07 for CNE-2, 2.33 for TCA 8113 and 2.36 for FADU. Chemoradiotherapy (both photon radiotherapy and CIRT) was more effective than radiotherapy alone. In vitro sensitizer enhancement ratios (SERs) of cisplatin in CNE-2, TCA 8113 and FA DU cell lines after photon irradiation were 1.33, 1.14 and 1.21, while after carbon ion irradiation were 1.02, 1.00 and 0.96, showed that cisplatin sensitized photon irradiation but showed no sensitization effect in carbon ion irradiation in all tested cell lines.ConclusionsIn conclusion, high linear energy transfer (LET) CIRT was more effective than photon irradiation to prevent the proliferation of HNSCC cell lines. Additional treatment with cisplatin could sensitize photon irradiation but showed no effect on carbon ion irradiation.
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Affiliation(s)
- Xumeng Fang
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Pian Sun
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Yuanli Dong
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Yangle Huang
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Jiade Jay Lu
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
- *Correspondence: Jiade Jay Lu, ; Lin Kong,
| | - Lin Kong
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
- *Correspondence: Jiade Jay Lu, ; Lin Kong,
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Chen YX, Wang ZX, Jin Y, Zhao Q, Liu ZX, Zuo ZX, Ju HQ, Cui C, Yao J, Zhang Y, Li M, Feng J, Tian L, Xia XJ, Feng H, Yao S, Wang FH, Li YH, Wang F, Xu RH. An immunogenic and oncogenic feature-based classification for chemotherapy plus PD-1 blockade in advanced esophageal squamous cell carcinoma. Cancer Cell 2023; 41:919-932.e5. [PMID: 37059106 DOI: 10.1016/j.ccell.2023.03.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/18/2022] [Accepted: 03/22/2023] [Indexed: 04/16/2023]
Abstract
Although chemotherapy plus PD-1 blockade (chemo+anti-PD-1) has become the standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC), reliable biomarkers for this regimen are lacking. Here we perform whole-exome sequencing on tumor samples from 486 patients of the JUPITER-06 study and develop a copy number alteration-corrected tumor mutational burden that depicts immunogenicity more precisely and predicts chemo+anti-PD-1 efficacy. We identify several other favorable immunogenic features (e.g., HLA-I/II diversity) and risk oncogenic alterations (e.g., PIK3CA and TET2 mutation) associated with chemo+anti-PD-1 efficacy. An esophageal cancer genome-based immuno-oncology classification (EGIC) scheme incorporating these immunogenic features and oncogenic alterations is established. Chemo+anti-PD-1 achieves significant survival improvements in EGIC1 (immunogenic feature-favorable and oncogenic alteration-negative) and EGIC2 (either immunogenic feature-favorable or oncogenic alteration-negative) subgroups, but not the EGIC3 subgroup (immunogenic feature-unfavorable and oncogenic alteration-positive). Thus, EGIC may guide future individualized treatment strategies and inform mechanistic biomarker research for chemo+anti-PD-1 treatment in patients with advanced ESCC.
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Affiliation(s)
- Yan-Xing Chen
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China; Bioinformatics Platform, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zi-Xian Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China
| | - Ying Jin
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China
| | - Qi Zhao
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China; Bioinformatics Platform, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Ze-Xian Liu
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China; Bioinformatics Platform, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zhi-Xiang Zuo
- Bioinformatics Platform, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Huai-Qiang Ju
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China; Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Chengxu Cui
- Cancer Hospital Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Jun Yao
- The First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471000, China
| | - Yanqiao Zhang
- Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Mengxia Li
- Army Medical Center of PLA, Chongqing 400042, China
| | - Jifeng Feng
- Jiangsu Cancer Hospital, Nanjing 210009, China
| | - Lin Tian
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Xiao-Jun Xia
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Hui Feng
- Shanghai Junshi Biosciences, Shanghai 200126, China; TopAlliance Biosciences, Rockville, MD 20850, USA
| | - Sheng Yao
- Shanghai Junshi Biosciences, Shanghai 200126, China; TopAlliance Biosciences, Rockville, MD 20850, USA
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Feng Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China.
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China.
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20
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Zheng SJ, Zheng CP, Zhai TT, Xu XE, Zheng YQ, Li ZM, Li EM, Liu W, Xu LY. Development and Validation of a New Staging System for Esophageal Squamous Cell Carcinoma Patients Based on Combined Pathological TNM, Radiomics, and Proteomics. Ann Surg Oncol 2023; 30:2227-2241. [PMID: 36587172 DOI: 10.1245/s10434-022-13026-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/06/2022] [Indexed: 01/02/2023]
Abstract
OBJECTIVE This study aimed to construct a new staging system for patients with esophageal squamous cell carcinoma (ESCC) based on combined pathological TNM (pTNM) stage, radiomics, and proteomics. METHODS This study collected patients with radiomics and pTNM stage (Cohort 1, n = 786), among whom 103 patients also had proteomic data (Cohort 2, n = 103). The Cox regression model with the least absolute shrinkage and selection operator, and the Cox proportional hazards model were used to construct a nomogram and predictive models. Concordance index (C-index) and the integrated area under the time-dependent receiver operating characteristic (ROC) curve (IAUC) were used to evaluate the predictive models. The corresponding staging systems were further assessed using Kaplan-Meier survival curves. RESULTS For Cohort 1, the RadpTNM4c staging systems, constructed based on combined pTNM stage and radiomic features, outperformed the pTNM4c stage in both the training dataset 1 (Train1; IAUC 0.711 vs. 0.706, p < 0.001) and the validation dataset 1 (Valid1; IAUC 0.695 vs. 0.659, p < 0.001; C-index 0.703 vs. 0.674, p = 0.029). For Cohort 2, the ProtRadpTNM2c staging system, constructed based on combined pTNM stage, radiomics, and proteomics, outperformed the pTNM2c stage in both the Train2 (IAUC 0.777 vs. 0.610, p < 0.001; C-index 0.898 vs. 0.608, p < 0.001) and Valid2 (IAUC 0.746 vs. 0.608, p < 0.001; C-index 0.889 vs. 0.641, p = 0.009) datasets. CONCLUSIONS The ProtRadpTNM2c staging system, based on combined pTNM stage, radiomic, and proteomic features, improves the predictive performance of the classical pTNM staging system.
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Affiliation(s)
- Shao-Jun Zheng
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
- Department of Surgical Oncology, Shantou Central Hospital, Shantou, 515041, Guangdong, China
| | - Chun-Peng Zheng
- Department of Surgical Oncology, Shantou Central Hospital, Shantou, 515041, Guangdong, China.
| | - Tian-Tian Zhai
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Xiu-E Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Ya-Qi Zheng
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Zhi-Mao Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Wei Liu
- College of Science, Heilongjiang Institute of Technology, Harbin, Heilongjiang, China
| | - Li-Yan Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
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21
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Wu HX, Pan YQ, He Y, Wang ZX, Guan WL, Chen YX, Yao YC, Shao NY, Xu RH, Wang F. Clinical Benefit of First-Line Programmed Death-1 Antibody Plus Chemotherapy in Low Programmed Cell Death Ligand 1-Expressing Esophageal Squamous Cell Carcinoma: A Post Hoc Analysis of JUPITER-06 and Meta-Analysis. J Clin Oncol 2023; 41:1735-1746. [PMID: 36473145 PMCID: PMC10022847 DOI: 10.1200/jco.22.01490] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/10/2022] [Accepted: 10/13/2022] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Pembrolizumab or nivolumab plus chemotherapy was approved as a first-line treatment for high programmed cell death ligand 1 (PD-L1)-expressing esophageal squamous cell carcinoma (ESCC) by the European Medicines Agency, whereas the US Food and Drug Administration approved this regimen regardless of PD-L1 expression. The superiority of programmed death-1 (PD-1) antibody plus chemotherapy over chemotherapy alone in patients with low PD-L1-expressing ESCC remains debatable. METHODS Post hoc analysis of the Chinese JUPITER-06 study focusing on efficacy stratified by PD-L1 tumor proportion score (TPS; using JS311 antibody) was conducted. Electronic databases were searched to identify eligible randomized controlled trials for meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for overall survival and progression-free survival and odds ratios for objective response rate according to PD-L1 expression were performed. RESULTS The post hoc analysis of JUPITER-06 showed more prominent clinical benefit with PD-1 antibody plus chemotherapy than with chemotherapy alone in both the high and low PD-L1-expressing subgroups. Five randomized controlled trials were included in the meta-analysis, and two PD-L1 expression scoring criteria, TPS (≥ 1%/< 1%) and combined positive score (CPS, ≥ 10/< 10), were analyzed. Significant overall survival benefit by adding PD-1 antibody to chemotherapy was observed in both the TPS < 1% (HR, 0.74; 95% CI, 0.56 to 0.97) and CPS < 10 (HR, 0.77; 95% CI, 0.66 to 0.89) subgroups. Similarly, significantly prolonged progression-free survival was observed in both the TPS < 1% (HR, 0.66; 95% CI, 0.50 to 0.86) and CPS < 10 (HR, 0.63; 95% CI, 0.47 to 0.84) subgroups. In addition, the objective response rate of the TPS < 1% subgroup was significantly improved (odds ratio, 1.71; 95% CI, 1.27 to 2.29). In all high PD-L1-expressing subgroups, the pooled benefit of PD-1 antibody plus chemotherapy was significantly better than that of chemotherapy. CONCLUSION This study provided novel evidence supporting the superiority of PD-1 antibody plus chemotherapy to chemotherapy alone in patients with advanced ESCC with low PD-L1 expression. Further studies of predictive biomarkers are warranted.
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Affiliation(s)
- Hao-Xiang Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Yi-Qian Pan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Ye He
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Zi-Xian Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Wen-Long Guan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Yan-Xing Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Yi-Chen Yao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Ning-Yi Shao
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau, China
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Feng Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
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22
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Onishi T, Komori O, Ando T, Fukutomi M, Tobaru T. Effectiveness of high implantation of SAPIEN 3 in preventing pacemaker implantation: A propensity score analysis. Arch Cardiovasc Dis 2023; 116:79-87. [PMID: 36641243 DOI: 10.1016/j.acvd.2022.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/04/2022] [Accepted: 11/07/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND In transcatheter aortic valve implantation, high implantation on the aortic annulus may prevent conduction pathway injury, leading to a decrease in the rate of permanent pacemaker implantation. AIM To assess the impact of high implantation of SAPIEN 3 on the prevention of permanent pacemaker implantation. METHODS Since August 2020, we have performed high implantation by fluoroscopically positioning the lower part of the lucent line at the virtual basal ring line on a coplanar view before valve implantation. Patients treated before the adoption of this method were defined as the conventional group. We compared the high implantation group with the conventional group using propensity score analysis. RESULTS Overall, the high implantation group (n=95) showed a significantly shorter ventricular strut length than the conventional group (n=85): median 1.3 (interquartile range 0.2-2.4) mm vs 2.8 (1.8-4.1) mm (P<0.001). The permanent pacemaker implantation rate was significantly lower in the high implantation group than in the conventional group (2.1% vs 11.8%; P=0.009). According to 100 propensity score analyses based on multiple imputation and the selection of appropriate covariates, the median P value for the comparison of permanent pacemaker implantation rates after transcatheter aortic valve implantation between the high implantation group and the conventional group ranged between 0.001 and 0.017, indicating a more significant reduction in the permanent pacemaker implantation rate in the high implantation group than in the conventional group. Neither valve dislodgement nor the need for a second valve was observed in either group. CONCLUSIONS The high implantation of SAPIEN 3 successfully decreases ventricular strut length, reducing the permanent pacemaker implantation rate after transcatheter aortic valve implantation.
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Affiliation(s)
- Takayuki Onishi
- Department of Cardiology, Kawasaki Heart Centre, Kawasaki Saiwai Hospital, Saiwai-ku, Kawasaki-shi, 212-0014 Kanagawa, Japan.
| | - Osamu Komori
- Department of Computer and Information Science, Faculty of Science and Technology, Seikei University, Musashino-shi, 180-8633 Tokyo, Japan; School of Statistical Thinking, The Institute of Statistical Mathematics, Tachikawa, 190-8562 Tokyo, Japan
| | - Tomo Ando
- Department of Cardiology, Kawasaki Heart Centre, Kawasaki Saiwai Hospital, Saiwai-ku, Kawasaki-shi, 212-0014 Kanagawa, Japan
| | - Motoki Fukutomi
- Department of Cardiology, Kawasaki Heart Centre, Kawasaki Saiwai Hospital, Saiwai-ku, Kawasaki-shi, 212-0014 Kanagawa, Japan
| | - Tetsuya Tobaru
- Department of Cardiology, Kawasaki Heart Centre, Kawasaki Saiwai Hospital, Saiwai-ku, Kawasaki-shi, 212-0014 Kanagawa, Japan
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23
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Xu H, Wu J, Zhang L, Li Y, Gao L, Cheng Y. The measurement of NRF2 and TP53 in blood expects radiotherapeutic sensitivity in patients with esophageal cancer. Mol Cell Probes 2022; 66:101860. [PMID: 36116599 DOI: 10.1016/j.mcp.2022.101860] [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: 05/02/2022] [Revised: 08/10/2022] [Accepted: 09/07/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE This study investigates the relationship between the mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and Tumor protein p53 (TP53) in circulating tumor cells (CTC) and sensitivity to radiotherapy in patients with esophageal cancer. To investigate the relationship between cytokines IL-6, CD8+, and NRF2 during patient treatment and their predictive role for treatment. METHODS Radiosensitivity was assessed by measuring a morphological or functional change in the tumor in response to ionizing radiation. Fasting venous anticoagulated blood (EDTA anticoagulation) was drawn from patients, and the Trizol-chloroform two-step method was used for RNA extraction. Data were collected from 45 patients admitted with radiotherapy alone from January 2018 to December 2021. The expression levels of NRF2mRNA (Messenger Ribose Nucleic Acid) and TP53mRNA in CTCs were detected by reverse transcription-polymerase chain reaction (RT-PCR). Pre- and post-treatment changes in IL-6 and CD8+ were recorded. The correlation between their expression level and the clinical stage, radiotherapy sensitivity, and efficacy of patients was analyzed. RESULTS Twenty-six cases were sensitive to radiotherapy, and 19 were resistant, for a radiotherapy sensitivity rate of 58.8%. NRF2mRNA and TP53mRNA values increased in 19 radiotherapy-resistant patients and decreased in 26 radiotherapy-sensitive patients compared with those before radiotherapy (P = 0.001, P＜0.05). The ΔCT values of NRF2mRNA and TP53mRNA before treatment were moderately correlated with prognosis (P < 0.002). Inflammatory cytokine IL-6 was elevated in 22 of 45 patients after radiation, P = 0.04. NRF2 mRNA level was consistently elevated with CD8+ in 10 patients, P = 0.02. CONCLUSIONS The expression of NRF2mRNA and TP53mRNA in the CTCs found in the peripheral blood of patients with esophageal squamous carcinoma was significantly associated with the sensitivity to radiotherapy. NRF2 mRNA level was consistently elevated with CD8+ and IL-6 in patients.
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Affiliation(s)
- Huiqin Xu
- Radiotherapy Center, Qilu hospital of Shandong University, Jinan city, Shandong Province, 25000, China; Radiotherapy Department, The Second Affiliated Hospital of Xuzhou Medical University (Xuzhou Mining Group General Hospital), Xuzhou City, Jiangsu Province, 221000, China.
| | - Jinchang Wu
- Radiotherapy Department, The Second Affiliated Hospital of Xuzhou Medical University (Xuzhou Mining Group General Hospital), Xuzhou City, Jiangsu Province, 221000, China
| | - Lansheng Zhang
- Radiotherapy Department, The Second Affiliated Hospital of Xuzhou Medical University (Xuzhou Mining Group General Hospital), Xuzhou City, Jiangsu Province, 221000, China
| | - Yang Li
- Radiotherapy Department, The Second Affiliated Hospital of Xuzhou Medical University (Xuzhou Mining Group General Hospital), Xuzhou City, Jiangsu Province, 221000, China
| | - Liyan Gao
- Xuzhou Medical University, Xuzhou City, Jiangsu Province, 221000, China
| | - Yufeng Cheng
- Radiotherapy Center, Qilu hospital of Shandong University, Jinan city, Shandong Province, 25000, China.
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24
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Ma Y, Xin Y, Su D, Zhou Y, Li H, Zou H, Yu X, Yang Q, Cui J, Wang C, Zhang Y. Comparative efficacy and toxicity of immune checkpoint inhibitors in combination with or without chemotherapy treatment for advanced esophageal squamous cell carcinoma: A systematic review and meta-analysis. Front Oncol 2022; 12:958783. [PMID: 36530991 PMCID: PMC9748809 DOI: 10.3389/fonc.2022.958783] [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: 06/01/2022] [Accepted: 10/31/2022] [Indexed: 09/19/2023] Open
Abstract
Introduction We did a systematic review and meta-analysis to assess the efficacy and safety of immune checkpoint inhibitors combined with or without chemotherapies in patients with esophageal squamous cell carcinoma. Methods Data related to the treatment of esophageal squamous cell carcinoma with immune checkpoint inhibitors therapy were retrieved from the database construction to August 2022. The risk of bias was assessed using the Cochrane Manual standard and RevMan 5.3 software for data synthesis. The outcome measures observed included overall survival, 12-month survival, disease control rate, objective response rate, treatment-related adverse events of grade 3 or higher, and progression-free survival. The adverse reactions included fatigue, diarrhea, hypothyroidism, rash, anemia, and anorexia. Results In this meta-analysis, a total of 17 randomized controlled trials were included. In first-line therapy, immune checkpoint inhibitors combined with or without chemotherapy in the treatment of esophageal squamous cell carcinoma was more effective than chemotherapy alone. Overall survival, 12-month survival rate, and objective response rate were statistically significant. Among second-line treatments, immune checkpoint inhibitors combined with or without chemotherapy in the treatment of esophageal squamous cell carcinoma had statistically significant overall survival, 12-month survival, objective response rate, treatment-related adverse events of grade 3 or higher, and progression-free survival compared with chemotherapy alone. Conclusion Both first- and second-line immune checkpoint inhibitors are effective for esophageal squamous cell carcinoma, and the adverse reactions are controllable and safe. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021282586.
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Affiliation(s)
- Yue Ma
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Xin
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dan Su
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuxin Zhou
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hongxu Li
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Haoyi Zou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xuefan Yu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qing Yang
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jie Cui
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Changsong Wang
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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25
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Characterization of somatic structural variations in 528 Chinese individuals with Esophageal squamous cell carcinoma. Nat Commun 2022; 13:6296. [PMID: 36272974 PMCID: PMC9588063 DOI: 10.1038/s41467-022-33994-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/05/2022] [Indexed: 12/25/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) demonstrates high genome instability. Here, we analyze 528 whole genomes to investigate structural variations' mechanisms and biological functions. SVs show multi-mode distributions in size, indicating distinct mutational processes. We develop a tool and define five types of complex rearrangements with templated insertions. We highlight a type of fold-back inversion, which is associated with poor outcomes. Distinct rearrangement signatures demonstrate variable genomic metrics such as replicating time, spatial proximity, and chromatin accessibility. Specifically, fold-back inversion tends to occur near the centrosome; TD-c2 (Tandem duplication-cluster2) is significantly enriched in chromatin-accessibility and early-replication region compared to other signatures. Analyses of TD-c2 signature reveal 9 TD hotspots, of which we identify a hotspot consisting of a super-enhancer of PTHLH. We confirm the oncogenic effect of the PTHLH gene and its interaction with enhancers through functional experiments. Finally, extrachromosomal circular DNAs (ecDNAs) are present in 14% of ESCCs and have strong selective advantages to driver genes.
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26
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Integrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics. Nat Commun 2022; 13:5268. [PMID: 36071046 PMCID: PMC9452532 DOI: 10.1038/s41467-022-32962-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 08/25/2022] [Indexed: 11/08/2022] Open
Abstract
Esophageal squamous cell cancer (ESCC) is the major pathologic type of esophageal cancer in Asian population. To systematically evaluate the mutational features underlying clinical characteristics, we establish the integrated dataset of ESCC-META that consists of 1930 ESCC genomes from 33 datasets. The data process pipelines lead to well homogeneity of this integrated cohort for further analysis. We identified 11 mutational signatures in ESCC, some of which are related to clinical features, and firstly detect the significant mutated hotspots in TGFBR2 and IRF2BPL. We screen the survival related mutational features and found some genes had different prognostic impacts between early and late stage, such as PIK3CA and NFE2L2. Based on the results, an applicable approach of mutational score is proposed and validated to predict prognosis in ESCC. As an open-sourced, quality-controlled and updating mutational landscape, the ESCC-META dataset could facilitate further genomic and translational study in this field.
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Xu J, Bai Y, Li E, Xu N, Shi D, Qian J. Efficacy and safety of chemotherapy regimens for first-line treatment of advanced esophageal squamous cell carcinoma in asia: a systematic review. Expert Rev Anticancer Ther 2022; 22:981-998. [PMID: 35950848 DOI: 10.1080/14737140.2022.2110470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION There is currently no consensus on the optimal chemotherapy regimen in the palliative first-line setting for East Asian patients with advanced esophageal squamous cell carcinoma (ESCC). AREAS COVERED We conducted a systematic review using a literature search of PubMed, Embase, and the Cochrane Library without date restrictions, and abstracts from major oncology congresses. Studies meeting the following criteria were included: East Asian patients ≥18 years old with pathologically proven metastatic or locally advanced unresectable ESCC; first-line chemotherapy; reporting of overall survival, progression-free survival, duration of response, overall response rate, and/or safety; randomized controlled trials, non-randomized controlled trials, and prospective or retrospective comparative studies. In total, 39 articles were identified for the following regimens: platinum plus fluoropyrimidine (n=9), platinum plus taxane (n=16), platinum plus fluoropyrimidine plus taxane (n=7), platinum plus fluoropyrimidine plus other (n=3), irinotecan plus platinum (n=2), taxane plus fluoropyrimidine (n=1). EXPERT OPINION The available data supports both taxane plus platinum regimens and fluoropyrimidine plus platinum regimens in the first-line treatment of East Asian patients with ESCC. Compared with data from doublet chemotherapy studies, triplet chemotherapy appeared to improve ORR, but did not seem to prolong OS, possibly due to an increased incidence of adverse events.
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Affiliation(s)
- Jianming Xu
- The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Enxiao Li
- The First Affiliated Hospital of Xi'An Jiaotong University, Xi'An, China
| | - Nong Xu
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Wang F, Shu X, Pal T, Berlin J, Nguyen SM, Zheng W, Bailey CE, Shu XO. Racial/Ethnic Disparities in Mortality Related to Access to Care for Major Cancers in the United States. Cancers (Basel) 2022; 14:3390. [PMID: 35884451 PMCID: PMC9318931 DOI: 10.3390/cancers14143390] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 12/04/2022] Open
Abstract
Importance: The reasons underlying racial/ethnic mortality disparities for cancer patients remain poorly understood, especially regarding the role of access to care. Participants: Over five million patients with a primary diagnosis of lung, breast, prostate, colon/rectum, pancreas, ovary, or liver cancer during 2004-2014, were identified from the National Cancer Database. Cox proportional hazards models were applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for total mortality associated with race/ethnicity, and access to care related factors (i.e., socioeconomic status [SES], insurance, treating facility, and residential type) for each cancer. Results: Racial/ethnic disparities in total mortality were observed across seven cancers. Compared with non-Hispanic (NH)-white patients, NH-black patients with breast (HR = 1.27, 95% CI: 1.26 to 1.29), ovarian (HR = 1.20, 95% CI: 1.17 to 1.23), prostate (HR = 1.31, 95% CI: 1.30 to 1.33), colorectal (HR = 1.11, 95% CI: 1.10 to 1.12) or pancreatic (HR = 1.03, 95% CI: 1.02 to 1.05) cancers had significantly elevated mortality, while Asians (13-31%) and Hispanics (13-19%) had lower mortality for all cancers. Racial/ethnic disparities were observed across all strata of access to care related factors and modified by those factors. NH-black and NH-white disparities were most evident among patients with high SES or those with private insurance, while Hispanic/Asian versus NH-white disparities were more evident among patients with low SES or those with no/poor insurance. Conclusions and Relevance: Racial/ethnic mortality disparities for major cancers exist across all patient groups with different access to care levels. The influence of SES or insurance on mortality disparity follows different patterns for racial/ethnic minorities versus NH-whites. Impact: Our study highlights the need for racial/ethnic-specific strategies to reduce the mortality disparities for major cancers.
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Affiliation(s)
- Fei Wang
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA or (F.W.); (S.M.N.); or (W.Z.)
- Department of Breast Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China
| | - Xiang Shu
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Tuya Pal
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA;
| | - Jordan Berlin
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA;
| | - Sang M. Nguyen
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA or (F.W.); (S.M.N.); or (W.Z.)
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA or (F.W.); (S.M.N.); or (W.Z.)
| | - Christina E. Bailey
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37203, USA;
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA or (F.W.); (S.M.N.); or (W.Z.)
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Thyroid Dysfunction as a Predictive Indicator in Camrelizumab of Advanced Esophageal Squamous Cell Carcinoma. J Immunol Res 2022; 2022:4015897. [PMID: 35832645 PMCID: PMC9273411 DOI: 10.1155/2022/4015897] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/26/2022] [Indexed: 12/23/2022] Open
Abstract
Thyroid dysfunction (TD) induced by programmed death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has been widely reported. However, the effects of ICI-induced TD on the survival of patients with esophageal squamous cell carcinoma (ESCC) have not been described. Herein, a retrospective study was conducted, which 82 patients with advanced metastatic or recurrent ESCC treated with camrelizumab were enrolled. Twenty patients (24.4%) experienced TD during camrelizumab treatment with or without chemotherapy. The median onset time of TD was 1.7 months. The incidence of TD was 35.6% in patients who previously received thoracic radiotherapy versus 10.8% in patients who did not (P =0.009). Patients with TD had significantly longer median progression-free survival (5.5 months vs 3.5 months, P =0.035) and overall survival (26.7 months vs 11.5 months, P <0.001). TD is frequently observed in ESCC patients treated with camrelizumab and especially in patients who received radiotherapy previously. ESCC patients with TD during ICIs treatment often have better prognosis.
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Genomic analyses reveal SCN7A is associated with the prognosis of esophageal squamous cell carcinoma. Esophagus 2022; 19:303-315. [PMID: 34993672 DOI: 10.1007/s10388-021-00898-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 11/22/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and occurs with high frequency in China. In particular, Fujian is one of the high-incidence areas of ESCC in China and the somatic mutation profile of ESCC there remains unclear. PATIENTS AND METHODS Whole-exome sequencing (WES) was performed in 49 matched ESCC tumor-normal specimens to examine the somatic mutation profiles. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between mutational profile and survival were derived from Cox regression model. RESULTS We constructed a preliminary somatic mutation profiling of ESCC in Fujian. Exome sequencing data showed that the main base substitutions in ESCC were C > T transformation (close to 50%), C > A and T > C transversion. The study identified 21 significantly mutated genes, including 8 driver genes and 11 predicted driver genes. Among the 19 driver or predicted driver genes, 9 are novel (OBSCN, PKHD1L1, FSIP2, HRNR, CUBN, CELSR3, SCN7A, TULP4, SRRM2) and 10 have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including Signature_15, Signature_4 and Signature_6, of which Signature_15 was related to prognosis of ESCC (HR 2.81, 95% CI 1.30-6.05; p = 0.008). Survival analysis showed that SCN7A was correlated to overall survival with an HR of 2.76 (95% CI 0.96-7.90, p = 0.058). After controlling for confounding factors such as age, gender, stage and location, the correlation between SCN7A and survival was statistically significant based on multivariate COX regression analysis (HR 4.76, 95% CI 1.20-18.85; p = 0.026, padjust = 0.053). The tumor vascular invasion was associated with SCN7A of ESCC patients (p = 0.028). CONCLUSION In summary, this study provided comprehensive analysis of the somatic mutation profiles of ESCC, and identified SCN7A and Signature_15 for the prognosis of ESCC for the first time. The findings might serve as a conceptual basis for molecular diagnosis and prevention of ESCC.
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Park KH, Choi JY, Lim AR, Kim JW, Choi YJ, Lee S, Sung JS, Chung HJ, Jang B, Yoon D, Kim S, Sa JK, Kim YH. Genomic Landscape and Clinical Utility in Korean Advanced Pan-Cancer Patients from Prospective Clinical Sequencing: K-MASTER Program. Cancer Discov 2022; 12:938-948. [PMID: 34862196 PMCID: PMC9387587 DOI: 10.1158/2159-8290.cd-21-1064] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 10/13/2021] [Accepted: 11/30/2021] [Indexed: 01/07/2023]
Abstract
The fundamental principle of precision oncology is centralized on the identification of therapeutically exploitable targets that provides individual patients with cancer an opportunity to make informed decisions on a personalized level. To facilitate and adopt such concepts within clinical practice, we have initiated a nationwide, multi-institutional precision oncology screening program to examine and enroll patients into the most appropriate clinical trial based on their tumor's unique molecular properties. To determine the prevalence of essential major driver mutations and to explore their dynamic associations at both molecular and pathway levels, we present a comprehensive overview on the genomic properties of East Asian patients with cancer. We further delineate the extent of genomic diversity as well as clinical actionability in patients from Western and Eastern cultures at the pan-cancer and single-tumor entity levels. To support fellow oncology communities in future investigations involving large-scale analysis, all data have been made accessible to the public (https://kmportal.or.kr). SIGNIFICANCE We present a comprehensive overview of molecular properties of East Asian pan-cancer patients and demonstrate significant diversity in terms of genomic characteristics as well as clinical utility compared with patients with European ancestry. The results of this study will lay the groundwork for designing personalized treatments in the clinical setting. See related commentary by Moyers and Subbiah, p. 886. This article is highlighted in the In This Issue feature, p. 873.
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Affiliation(s)
- Kyong Hwa Park
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jung Yoon Choi
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ah-Reum Lim
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ju Won Kim
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yoon Ji Choi
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Soohyeon Lee
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jae Sook Sung
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hee-Joon Chung
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Byunghyun Jang
- BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
| | - Dayoung Yoon
- BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
| | - Sukwon Kim
- BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jason K. Sa
- BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
- Corresponding Authors: Jason K. Sa, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul, Republic of Korea. Phone: 822-2286-1468; E-mail: ; and Yeul Hong Kim,
| | - Yeul Hong Kim
- Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- K-MASTER Cancer Precision Medicine Diagnosis and Treatment Enterprise, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
- Corresponding Authors: Jason K. Sa, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul, Republic of Korea. Phone: 822-2286-1468; E-mail: ; and Yeul Hong Kim,
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Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer. Cell Death Dis 2022; 13:392. [PMID: 35449126 PMCID: PMC9023472 DOI: 10.1038/s41419-022-04838-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 12/01/2022]
Abstract
Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially the comparative analysis between higher metastatic-potential (HMP) group with T1 stage and lymph-node metastasis, and lower metastatic-potential (LMP) group without lymph-nodes or distant metastasis. HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, more immune cell infiltration than LMP group. An integrated mRNA-lncRNA signature based on differentially expressed genes was constructed and its prognostic value was better than traditional TNM stage. We identified 176 candidate prometastatic mutations by WES and selected 8 genes for following TES. Mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. We further demonstrated that mutated MADCAM1 could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages by regulating CCL2 through Akt/mTOR axis. In conclusion, GCs with different metastatic-potential are distinguishable at the genetic level and we revealed a number of potential metastatic driver mutations. Driver mutations in early-onset metastatic GC could promote metastasis by establishing an immunosuppressive microenvironment. This study provided possibility for future target therapy of GC.
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Lin S, Chen Y, Wang J, Cai Y, Chen X, Chen Y, Shi Y, Chen G, Zhu K. Multi-Region Genomic Landscape Analysis for the Preoperative Prediction of Lymph Node Metastasis in Esophageal Carcinoma. Front Genet 2022; 13:830601. [PMID: 35401692 PMCID: PMC8986126 DOI: 10.3389/fgene.2022.830601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Esophageal cancer is an aggressive malignant tumor, with 90 percent of the patients prone to recurrence and metastasis. Although recent studies have identified some potential biomarkers, these biomarkers’ clinical or pathological significance is still unclear. Therefore, it is urgent to further identify and study novel molecular changes occurring in esophageal cancer. It has positive clinical significance to identify a tumor-specific mutation in patients after surgery for an effective intervention to improve the prognosis of patients.Methods: In this study, we performed whole-exome sequencing (WES) on 33 tissue samples from six esophageal cancer patients with lymph node metastasis, compared the differences in the genomic and evolutionary maps in different tissues, and then performed pathway enrichment analysis on non-synonymous mutation genes. Finally, we sorted out the somatic mutation data of all patients to analyze the subclonality of each tumor.Results: There were significant differences in somatic mutations between the metastatic lymph nodes and primary lesions in the six patients. Clustering results of pathway enrichment analysis indicated that the metastatic lymph nodes had certain commonalities. Tumors of the cloned exploration results illustrated that five patients showed substantial heterogeneity.Conclusion: WES technology can be used to explore the differences in regional evolutionary maps, heterogeneity, and detect patients’ tumor-specific mutations. In addition, an in-depth understanding of the ontogeny and phylogeny of tumor heterogeneity can help to further find new molecular changes in esophageal cancer, which can improve the prognosis of EC patients and provide a valuable reference for their diagnosis.
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Affiliation(s)
- Shaofeng Lin
- Department of Thoracic Surgery, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Yanping Chen
- Department of Pathology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Jianchao Wang
- Department of Pathology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Yibin Cai
- Department of Thoracic Surgery, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Xiaohui Chen
- Department of Thoracic Surgery, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Yuanmei Chen
- Department of Thoracic Surgery, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Yi Shi
- Department of Molecular Pathology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
| | - Gang Chen
- Department of Pathology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
- *Correspondence: Gang Chen, ; Kunshou Zhu,
| | - Kunshou Zhu
- Department of Thoracic Surgery, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, China
- *Correspondence: Gang Chen, ; Kunshou Zhu,
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Pape M, Vissers PA, de Vos‐Geelen J, Hulshof MC, Gisbertz SS, Jeene PM, van Laarhoven HW, Verhoeven RH. Treatment patterns and survival in advanced unresectable esophageal squamous cell cancer: A population-based study. Cancer Sci 2022; 113:1038-1046. [PMID: 34986523 PMCID: PMC8898723 DOI: 10.1111/cas.15262] [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: 11/18/2021] [Revised: 12/18/2021] [Accepted: 12/19/2021] [Indexed: 11/27/2022] Open
Abstract
Data on treatment and survival of patients with advanced unresectable esophageal squamous cell carcinoma (ESCC) from Western populations are limited. Here we describe treatment and survival in patients with advanced unresectable ESCC: patients with cT4b disease without metastases (cT4b), metastases limited to the supraclavicular lymph nodes (SCLNM) or distant metastatic ESCC at the population level. All patients with unresectable (cT4b) or synchronous metastatic ESCC at primary diagnosis (2015-2018) or patients with metachronous metastases after primary non-metastatic diagnosis in 2015-2016 were selected from the Netherlands Cancer Registry. Fifteen percent of patients had cT4b disease (n = 146), 12% SCLNM (n = 118) and 72% distant metastases (n = 681). Median overall survival (OS) time was 6.3, 11.2, and 4.4 months in patients with cT4b, SCLNM, and distant metastases, respectively (P < .001). Multivariable Cox regression showed that patients with cT4b (hazard ratio 1.44, 95% CI 1.04-1.99) and patients with distant metastases (hazard ratio 1.42, 95% CI 1.12-1.80) had a worse survival time compared with patients with SCLNM. Among patients who received chemoradiotherapy and/or underwent resection (primary tumor and/or metastases), median OS was 11.9, 16.1, and 14.0 months in patients with cT4b, SCLNM, and distant metastases, respectively (P = .76). Patients with SCLNM had a better survival time compared with patients with cT4b and patients with distant metastases. Survival of patients with advanced unresectable ESCC in clinical practice was poor, even in patients treated with curative intent.
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Affiliation(s)
- Marieke Pape
- Department of Research & DevelopmentNetherlands Comprehensive Cancer Organisation (IKNL)UtrechtThe Netherlands
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Pauline A.J. Vissers
- Department of Research & DevelopmentNetherlands Comprehensive Cancer Organisation (IKNL)UtrechtThe Netherlands
- Department of SurgeryRadboud University Medical CentreNijmegenThe Netherlands
| | - Judith de Vos‐Geelen
- Division of Medical OncologyDepartment of Internal MedicineGROW–School for Oncology and Developmental BiologyMaastricht UMC+MaastrichtThe Netherlands
| | | | - Suzanne S. Gisbertz
- Department of SurgeryAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Paul M. Jeene
- Department of RadiotherapyAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Radiotherapiegroep, location DeventerDeventerThe Netherlands
| | - Hanneke W.M. van Laarhoven
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Rob H.A. Verhoeven
- Department of Research & DevelopmentNetherlands Comprehensive Cancer Organisation (IKNL)UtrechtThe Netherlands
- Department of Medical OncologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
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Long J, Wang D, Wang A, Chen P, Lin Y, Bian J, Yang X, Zheng M, Zhang H, Zheng Y, Sang X, Zhao H. A mutation-based gene set predicts survival benefit after immunotherapy across multiple cancers and reveals the immune response landscape. Genome Med 2022; 14:20. [PMID: 35197093 PMCID: PMC8867854 DOI: 10.1186/s13073-022-01024-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/08/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of many cancers. However, the limited population that benefits from ICI therapy makes it necessary to screen predictive biomarkers for stratifying patients. Currently, many biomarkers, such as tumor mutational burden (TMB), have been used in the clinic as indicative biomarkers. However, some high-TMB patients with mutations in genes that are closely related to immunotherapeutic resistance are not sensitive to ICI therapy. Thus, there is a need to move beyond TMB and identify specific genetic determinants of the response to ICI therapy. In this study, we established a comprehensive mutation-based gene set across different tumor types to predict the efficacy of ICI therapy. METHODS We constructed and validated a mutational signature to predict the prognosis of patients treated with ICI therapy. Then, the underlying immune response landscapes of different subtypes were investigated with multidimensional data. RESULTS This study included genomic and clinical data for 12,647 patients. An eleven-gene mutation-based gene set was generated to divide patients into a high-risk group and a low-risk group in a training cohort (1572 patients with 9 types of cancers who were treated with ICI therapy). Validation was performed in a validation cohort (932 patients with 5 types of cancers who were treated with ICI therapy). Mutations in these 11 genes were associated with a better response to ICI therapy. In addition, the mutation-based gene set was demonstrated to be an independent prognostic factor after ICI therapy. We further explored the role of the immune context in determining the benefits of immunotherapy in 10,143 patients with 33 types of cancers and found distinct immune landscapes for the high- and low-risk groups. CONCLUSIONS The mutation-based gene set developed in this study can be used to reliably predict survival benefit across cancers in patients receiving ICI therapy. The close interplay between the extrinsic and intrinsic immune landscapes in the identified patient subgroups and the subgroups' differing responses to ICI therapy could guide immunotherapy treatment decisions for cancer patients.
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Affiliation(s)
- Junyu Long
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Dongxu Wang
- Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Anqiang Wang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, Beijing, China
| | - Peipei Chen
- Department of Clinical Nutrition and Department of Health Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Yu Lin
- Shenzhen Withsum Technology Limited, Shenzhen, China
| | - Jin Bian
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Mingjun Zheng
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
| | - Haohai Zhang
- Liver Center and The Transplant Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Yongchang Zheng
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
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Lee KK, Rishishwar L, Ban D, Nagar SD, Mariño-Ramírez L, McDonald JF, Jordan IK. Association of genetic ancestry and molecular signatures with cancer survival disparities: a pan-cancer analysis. Cancer Res 2022; 82:1222-1233. [DOI: 10.1158/0008-5472.can-21-2105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/20/2021] [Accepted: 01/18/2022] [Indexed: 11/16/2022]
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Cao Y, Qin S, Luo S, Li Z, Cheng Y, Fan Y, Sun Y, Yin X, Yuan X, Li W, Liu T, Hsu CH, Lin X, Kim SB, Kojima T, Zhang J, Lee SH, Bai Y, Muro K, Doi T, Bai C, Gu K, Pan HM, Bai L, Yang JW, Cui Y, Lu W, Chen J. Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia. ESMO Open 2021; 7:100341. [PMID: 34973513 DOI: 10.1016/j.esmoop.2021.100341] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND In the randomized phase III KEYNOTE-181 study, pembrolizumab prolonged overall survival (OS) compared with chemotherapy as second-line therapy in patients with advanced esophageal cancer and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10. We report a post hoc subgroup analysis of patients with esophageal squamous cell carcinoma (ESCC) enrolled in KEYNOTE-181 in Asia, including patients from the KEYNOTE-181 China extension study. PATIENTS AND METHODS Three hundred and forty Asian patients with advanced/metastatic ESCC were enrolled in KEYNOTE-181, including the China cohort. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200 mg every 3 weeks for ≤2 years or investigator's choice of paclitaxel, docetaxel, or irinotecan. OS, progression-free survival, response, and safety were analyzed without formal comparisons. OS was evaluated based on PD-L1 CPS expression level. RESULTS In Asian patients with ESCC, median OS was 10.0 months with pembrolizumab and 6.5 months with chemotherapy [hazard ratio (HR), 0.63; 95% CI 0.50-0.80; nominal P < 0.0001]. Median progression-free survival was 2.3 months with pembrolizumab and 3.1 months with chemotherapy (HR, 0.79; 95% CI 0.63-0.99; nominal P = 0.020). Objective response rate was 17.1% with pembrolizumab and 7.1% with chemotherapy; median duration of response was 10.5 months and 7.7 months, respectively. In patients with PD-L1 CPS <1 tumors (pembrolizumab versus chemotherapy), the HR was 0.99 (95% CI 0.56-1.72); the HR (95% CI) for death was better for patients with PD-L1 CPS cut-offs >1 [CPS ≥1, 0.57 (0.44-0.75); CPS ≥5, 0.56 (0.41-0.76); CPS ≥10, 0.53 (0.37-0.75)]. Treatment-related adverse events were reported in 71.8% of patients in the pembrolizumab group and 89.8% in the chemotherapy group; grade 3-5 events were reported in 20.0% and 44.6%, respectively. CONCLUSIONS Pembrolizumab monotherapy demonstrated promising efficacy in Asian patients with ESCC, with fewer treatment-related adverse events than chemotherapy. PD-L1 CPS ≥1 is an appropriate cut-off and a predictive marker of pembrolizumab efficacy in Asian patients with ESCC.
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Affiliation(s)
- Y Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
| | - S Qin
- PLA Cancer Centre of Nanjing Bayi Hospital, Nanjing, China
| | - S Luo
- The Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Z Li
- Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Y Cheng
- Jilin Cancer Hospital, Jilin, China
| | - Y Fan
- Cancer Hospital of University of Chinese Academy of Sciences, Institute of Cancer and Basic Medicine of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Y Sun
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, and The Affiliated Hospital of Anhui Medical University, Hefei, China
| | - X Yin
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - X Yuan
- Tongji Hospital, Wuhan, China
| | - W Li
- Hubei Cancer Hospital, Wuhan, China
| | - T Liu
- Zhongshan Hospital, Fudan University, Shanghai, China
| | - C-H Hsu
- National Taiwan University Hospital, Taipei, Taiwan
| | - X Lin
- Fujian Medical University Union Hospital, Fuzhou, China
| | - S-B Kim
- Asan Medical Center, Seoul, South Korea
| | - T Kojima
- National Cancer Center Hospital East, Kashiwa, Japan
| | - J Zhang
- Ruijin Hospital, Shanghai, China
| | - S-H Lee
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Y Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | - K Muro
- Aichi Cancer Center Hospital, Nagoya, Japan
| | - T Doi
- National Cancer Center Hospital East, Kashiwa, Japan
| | - C Bai
- Peking Union Medical College Hospital, Beijing, China
| | - K Gu
- The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - H-M Pan
- Sir Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - L Bai
- Chinese PLA General Hospital, Beijing, China
| | - J-W Yang
- Fujian Province Cancer Hospital, Fuzhou, China
| | - Y Cui
- MSD China, Shanghai, China
| | - W Lu
- MSD China, Shanghai, China
| | - J Chen
- Jiangsu Cancer Hospital, Nanjing, China
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Shi X, Li R, Zhai J, Chen AM, Huang K, Zheng Z, Chen Z, Dong X, Liu X, Lu D, Feng S, Diao D, Ren P, Liu Z, Morahan G, Cai K. The first comprehensive database of germline pathogenic variants in East Asian cancer patients. Database (Oxford) 2021; 2021:6487783. [PMID: 34964846 PMCID: PMC8730286 DOI: 10.1093/database/baab075] [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: 07/27/2021] [Revised: 09/29/2021] [Accepted: 10/26/2021] [Indexed: 11/27/2022]
Abstract
Pathogenic germline variants in cancer-associated genes are risk factors for cancer
predisposition. However, systematic mining and summarizing of cancer pathogenic or
likely pathogenic variants has not been performed for people of East Asian descent. This
study aimed to investigate publicly available data to identify germline variants in East
Asian cancer cohorts and compare them to variants in Caucasian cancer cohorts. Based on
the data we retrieved, we built a comprehensive database, named COGVIC (Catalog of
Germline Variants in Cancer). A total of 233 variants in the East Asian population were
identified. The majority (87%) of genes with cancer-associated variants were not shared
between the East Asian and Caucasian cohorts. This included pathogenic variants in
BRCA2. Our study summarized the prevalence of germline variants in
East Asian cancer cohorts and provides an easy-to-use online tool to explore germline
mutations related to cancer susceptibility.
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Affiliation(s)
- Xiaoshun Shi
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China.,Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, 6 Verdun St, Nedlands WA 6009, Australia
| | - Ruidong Li
- Genetics, Genomics, and Bioinformatics Program, University of California, 900 University Ave, Riverside, CA 92507, USA
| | - Jianxue Zhai
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
| | - Allen Menglin Chen
- Guangzhou Mendel Genomics and Medical Technology Co., Ltd., 6/F, Bldg D, 188 Kaiyuan Ave, Guangzhou 510535, P. R. China
| | - Kailing Huang
- Guangzhou Mendel Genomics and Medical Technology Co., Ltd., 6/F, Bldg D, 188 Kaiyuan Ave, Guangzhou 510535, P. R. China
| | - Zhouxia Zheng
- Guangzhou Mendel Genomics and Medical Technology Co., Ltd., 6/F, Bldg D, 188 Kaiyuan Ave, Guangzhou 510535, P. R. China
| | - Zhuona Chen
- Guangzhou Mendel Genomics and Medical Technology Co., Ltd., 6/F, Bldg D, 188 Kaiyuan Ave, Guangzhou 510535, P. R. China
| | - Xiaoyin Dong
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
| | - Xiguang Liu
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
| | - Di Lu
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
| | - Siyang Feng
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
| | - Dingwei Diao
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
| | - Pengfei Ren
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
| | - Zhaoguo Liu
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
| | - Grant Morahan
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, 6 Verdun St, Nedlands WA 6009, Australia
| | - Kaican Cai
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guang Zhou Avenue North, Guangzhou 510515, P. R. China
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Zhang S, Zeng X, Lin S, Liang M, Huang H. Identification of seven-gene marker to predict the survival of patients with lung adenocarcinoma using integrated multi-omics data analysis. J Clin Lab Anal 2021; 36:e24190. [PMID: 34951053 PMCID: PMC8841135 DOI: 10.1002/jcla.24190] [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: 11/01/2021] [Revised: 12/04/2021] [Accepted: 12/10/2021] [Indexed: 12/28/2022] Open
Abstract
Background The mechanism of cancer occurrence and development could be understood with multi‐omics data analysis. Discovering genetic markers is highly necessary for predicting clinical outcome of lung adenocarcinoma (LUAD). Methods Clinical follow‐up information, copy number variation (CNV) data, single nucleotide polymorphism (SNP), and RNA‐Seq were acquired from The Cancer Genome Atlas (TCGA). To obtain robust biomarkers, prognostic‐related genes, genes with SNP variation, and copy number differential genes in the training set were selected and further subjected to feature selection using random forests. Finally, a gene‐based prediction model for LUAD was validated in validation datasets. Results The study filtered 2071 prognostic‐related genes and 230 genomic variants, 1878 copy deletions, and 438 significant mutations. 218 candidate genes were screened through integrating genomic variation genes and prognosis‐related genes. 7 characteristic genes (RHOV, CSMD3, FBN2, MAGEL2, SMIM4, BCKDHB, and GANC) were identified by random forest feature selection, and many genes were found to be tumor progression‐related. A 7‐gene signature constructed by Cox regression analysis was an independent prognostic factor for LUAD patients, and at the same time a risk factor in the test set, external validation set, and training set. Noticeably, the 5‐year AUC of survival in the validation set and training set was all ˃ 0.67. Similar results were obtained from multi‐omics validation datasets. Conclusions The study builds a novel 7‐gene signature as a prognostic marker for the survival prediction of patients with LUAD. The current findings provided a set of new prognostic and diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Surong Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, China
| | - Xueni Zeng
- Department of Infectious Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, China.,Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, China
| | - Shaona Lin
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, China
| | - Minchao Liang
- Department of Medicine, Shenzhen Haplox Biotechnology Co., Ltd, Shenzhen City, China
| | - Huaxing Huang
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, China
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Mai Z, Liu Q, Wang X, Xie J, Yuan J, Zhong J, Fang S, Xie X, Yang H, Wen J, Fu J. Integration of Tumor Heterogeneity for Recurrence Prediction in Patients with Esophageal Squamous Cell Cancer. Cancers (Basel) 2021; 13:cancers13236084. [PMID: 34885197 PMCID: PMC8656931 DOI: 10.3390/cancers13236084] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/20/2021] [Accepted: 11/26/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary This manuscript reports a deep sequencing study comprehensively analyzing the clinical impact of mutations considering the abundance of mutations. We built an eight-gene mutation predictor considering intratumoral heterogeneity to predict post-surgery recurrence in ESCC patients. Unlike previous studies that simply treated mutations as binary variables (mutant and wild type), we quantified mutations by the fraction of cancer cells carrying the mutations, and our results showed that the cancer cell fraction of mutations was more informative than the mutation status of genes in recurrence prediction. The predictor was further validated as a powerful recurrence indicator in our validation set and the TCGA-ESCC cohort. With the popularization of targeted deep sequencing in clinical work, our study will help clinicians make accurate predictions of recurrence for patients and will provide a new perspective in the clinical transformation of genomic findings. Abstract Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignancies in China. The prognostic value of mutations, especially those in minor tumor clones, has not been systematically investigated. We conducted targeted deep sequencing to analyze the mutation status and the cancer cell fraction (CCF) of mutations in 201 ESCC patients. Our analysis showed that the prognostic effect of mutations was relevant to the CCF, and it should be considered in prognosis prediction. EP300 was a promising biomarker for overall survival, impairing prognosis in a CCF dose-dependent manner. We constructed a CCF-based predictor using a smooth clipped absolute deviation Cox model in the training set of 143 patients. The 3-year disease-free survival rates were 6.3% (95% CI: 1.6–23.9%), 29.8% (20.9–42.6%) and 70.5% (56.6–87.7%) in high-, intermediate- and low-risk patients, respectively, in the training set. The prognostic accuracy was verified in a validation set of 58 patients and the TCGA-ESCC cohort. The eight-gene model predicted prognosis independent of clinicopathological factors and the combination of our model and pathological staging markedly improved the prognostic accuracy of pathological staging alone. Our study describes a novel recurrence predictor for ESCC patients and provides a new perspective for the clinical translation of genomic findings.
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Affiliation(s)
- Zihang Mai
- Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; (Z.M.); (Q.L.); (X.W.); (J.Y.); (J.Z.); (S.F.); (H.Y.)
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
| | - Qianwen Liu
- Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; (Z.M.); (Q.L.); (X.W.); (J.Y.); (J.Z.); (S.F.); (H.Y.)
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
| | - Xinye Wang
- Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; (Z.M.); (Q.L.); (X.W.); (J.Y.); (J.Z.); (S.F.); (H.Y.)
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
| | - Jiaxin Xie
- School of Statistics, Renmin University of China, Beijing 100872, China;
| | - Jianye Yuan
- Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; (Z.M.); (Q.L.); (X.W.); (J.Y.); (J.Z.); (S.F.); (H.Y.)
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
| | - Jian Zhong
- Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; (Z.M.); (Q.L.); (X.W.); (J.Y.); (J.Z.); (S.F.); (H.Y.)
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
| | - Shuogui Fang
- Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; (Z.M.); (Q.L.); (X.W.); (J.Y.); (J.Z.); (S.F.); (H.Y.)
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
| | - Xiuying Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
| | - Hong Yang
- Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; (Z.M.); (Q.L.); (X.W.); (J.Y.); (J.Z.); (S.F.); (H.Y.)
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
| | - Jing Wen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
- Correspondence: (J.W.); (J.F.)
| | - Jianhua Fu
- Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; (Z.M.); (Q.L.); (X.W.); (J.Y.); (J.Z.); (S.F.); (H.Y.)
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
- Guangdong Esophageal Cancer Institute, Guangzhou 510060, China
- Correspondence: (J.W.); (J.F.)
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Moody S, Senkin S, Islam SMA, Wang J, Nasrollahzadeh D, Cortez Cardoso Penha R, Fitzgerald S, Bergstrom EN, Atkins J, He Y, Khandekar A, Smith-Byrne K, Carreira C, Gaborieau V, Latimer C, Thomas E, Abnizova I, Bucciarelli PE, Jones D, Teague JW, Abedi-Ardekani B, Serra S, Scoazec JY, Saffar H, Azmoudeh-Ardalan F, Sotoudeh M, Nikmanesh A, Poustchi H, Niavarani A, Gharavi S, Eden M, Richman P, Campos LS, Fitzgerald RC, Ribeiro LF, Soares-Lima SC, Dzamalala C, Mmbaga BT, Shibata T, Menya D, Goldstein AM, Hu N, Malekzadeh R, Fazel A, McCormack V, McKay J, Perdomo S, Scelo G, Chanudet E, Humphreys L, Alexandrov LB, Brennan P, Stratton MR. Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence. Nat Genet 2021; 53:1553-1563. [PMID: 34663923 DOI: 10.1038/s41588-021-00928-6] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 07/28/2021] [Indexed: 12/28/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.
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Affiliation(s)
- Sarah Moody
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Sergey Senkin
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - S M Ashiqul Islam
- Moores Cancer Centre, UC San Diego Health, La Jolla, CA, USA
- Department of Cellular and Molecular Medicine, University of California, La Jolla, CA, USA
- Department of Bioengineering, University of California, La Jolla, CA, USA
| | - Jingwei Wang
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Dariush Nasrollahzadeh
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | | | - Stephen Fitzgerald
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Erik N Bergstrom
- Moores Cancer Centre, UC San Diego Health, La Jolla, CA, USA
- Department of Cellular and Molecular Medicine, University of California, La Jolla, CA, USA
- Department of Bioengineering, University of California, La Jolla, CA, USA
| | - Joshua Atkins
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Yudou He
- Moores Cancer Centre, UC San Diego Health, La Jolla, CA, USA
- Department of Cellular and Molecular Medicine, University of California, La Jolla, CA, USA
- Department of Bioengineering, University of California, La Jolla, CA, USA
| | - Azhar Khandekar
- Moores Cancer Centre, UC San Diego Health, La Jolla, CA, USA
- Department of Cellular and Molecular Medicine, University of California, La Jolla, CA, USA
- Department of Bioengineering, University of California, La Jolla, CA, USA
| | - Karl Smith-Byrne
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Christine Carreira
- Evidence Synthesis and Classification Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Valerie Gaborieau
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Calli Latimer
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Emily Thomas
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Irina Abnizova
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Pauline E Bucciarelli
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - David Jones
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Jon W Teague
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Behnoush Abedi-Ardekani
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | | | - Jean-Yves Scoazec
- Department Laboratory Medicine and Pathology, Gustave Roussy, Paris, France
| | - Hiva Saffar
- Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Farid Azmoudeh-Ardalan
- Liver Transplantation Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Sotoudeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | - Arash Nikmanesh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | - Hossein Poustchi
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | - Ahmadreza Niavarani
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | - Samad Gharavi
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | - Michael Eden
- Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
| | - Paul Richman
- Histopathology Department, Hemel Hempstead General Hospital, Hemel Hempstead, UK
| | - Lia S Campos
- West Suffolk NHS Foundation Trust, Bury St Edmunds, UK
| | | | | | | | | | - Blandina Theophil Mmbaga
- Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical Centre & Kilimanjaro Christian Medical University College, Moshi, Tanzania
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, National Cancer Centre Research Institute, Tokyo, Japan
| | | | - Alisa M Goldstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA
| | - Nan Hu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA
| | - Reza Malekzadeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | - Abdolreza Fazel
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Valerie McCormack
- Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - James McKay
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Sandra Perdomo
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Ghislaine Scelo
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Estelle Chanudet
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Laura Humphreys
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
| | - Ludmil B Alexandrov
- Moores Cancer Centre, UC San Diego Health, La Jolla, CA, USA
- Department of Cellular and Molecular Medicine, University of California, La Jolla, CA, USA
- Department of Bioengineering, University of California, La Jolla, CA, USA
| | - Paul Brennan
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Michael R Stratton
- Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
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DaSilva LL, Aguiar PN, de Lima Lopes G. Immunotherapy for Advanced Esophageal Squamous Cell Carcinoma-Renewed Enthusiasm and a Lingering Challenge. JAMA Oncol 2021; 7:1613-1614. [PMID: 34519775 DOI: 10.1001/jamaoncol.2021.4410] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
- Laercio Lopes DaSilva
- Department of Medicine, MetroWest Medical Center/Tufts University School of Medicine, Framingham, Massachusetts
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Zhang X, Xiao R, Lu B, Wu H, Jiang C, Li P, Huang J. Kinase DYRK2 acts as a regulator of autophagy and an indicator of favorable prognosis in gastric carcinoma. Colloids Surf B Biointerfaces 2021; 209:112182. [PMID: 34749023 DOI: 10.1016/j.colsurfb.2021.112182] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/20/2021] [Accepted: 10/23/2021] [Indexed: 01/22/2023]
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide; therefore, new and more specific molecules for GC are needed. Here, we found that dual specificity tyrosine phosphorylation regulated kinase 2 (DYRK2) may be a specific marker for GC. Immunohistochemistry (IHC) and statistical and bioinformatics analyses were conducted to detect DYRK2 expression in stomach tissues. The role of DYRK2 in GC was analyzed with a nude mouse model and CCK-8, wound healing and Transwell assays. Western blotting and immunofluorescence experiments were also performed to elucidate the relationship between DYRK2 expression and both epithelial-mesenchymal transition (EMT) and autophagy progression. We found that DYRK2 expression in GC tissues was lower than that in benign or normal tissues, and patients with high DYRK2 expression had a good prognosis. The in vitro results showed that DYRK2 expression inhibited the tumorigenic activities of GC, including proliferation, migration, and invasion. By analyzing the expression of EMT markers after altering DYRK2 expression, we observed that DYRK2 inhibits the occurrence of EMT. The nude mouse model revealed that DYRK2 inhibits tumor growth. Finally, we used Western blotting and immunofluorescence assays and found that DYRK2 promotes autophagy. Based on these data, DYRK2 may be a good reference indicator for the clinical diagnosis of GC.
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Affiliation(s)
- Xiaojing Zhang
- Department of Clinical Biobank & Institute of Oncology, Nantong University Affiliated Hospital, Nantong 226001, China
| | - Runze Xiao
- Clinical Medicine, Xuzhou Medical University, Xuzhou 221000, China
| | - Bing Lu
- Department of Clinical Biobank & Institute of Oncology, Nantong University Affiliated Hospital, Nantong 226001, China
| | - Han Wu
- Department of General Surgery, Nantong University Affiliated Hospital, Nantong 226001, China
| | - Chunyi Jiang
- Department of Pathology, Nantong University Affiliated Hospital, Nantong 226001, China
| | - Peng Li
- Department of General Surgery, Nantong University Affiliated Hospital, Nantong 226001, China
| | - Jianfei Huang
- Department of Clinical Biobank & Institute of Oncology, Nantong University Affiliated Hospital, Nantong 226001, China.
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Munari FF, Dos Santos W, Evangelista AF, Carvalho AC, Pastrez PA, Bugatti D, Wohnrath DR, Scapulatempo-Neto C, Guimarães DP, Longatto-Filho A, Reis RM. Profile of esophageal squamous cell carcinoma mutations in Brazilian patients. Sci Rep 2021; 11:20596. [PMID: 34663841 PMCID: PMC8523676 DOI: 10.1038/s41598-021-00208-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 10/08/2021] [Indexed: 12/24/2022] Open
Abstract
Esophageal cancer is an aggressive tumor that has a high rate of incidence and mortality worldwide. It is the 10th most frequent type in Brazil, being squamous cell carcinoma (ESCC) the predominant subtype. There is currently an incessant search to identify the frequently altered genes associated with esophageal squamous cell carcinoma biology that could be druggable. This study aimed to analyze the somatic mutation profile of a large panel of cancer-related genes in Brazilian ESCC. In a series of 46 ESCC diagnoses at Barretos Cancer Hospital, DNA isolated from paired fresh-frozen and blood tissue, a panel of 150 cancer-related genes was analyzed by next-generation sequencing. The genes with the highest frequency of mutations were TP53 (39/46, 84.8%), followed by NOTCH1 (7/46, 15.2%), NFE2L2 (5/46, 10.8%), RB1 (3/46, 6.5%), PTEN (3/46, 6.5%), CDKN2A (3/46, 6.5%), PTCH1 (2/46, 4.3%) and PIK3CA (2/46, 4.3%). There was no significant association between molecular and patients' clinicopathological features. Applying an evolutionary action score of p53 (EAp53), we observed that 14 (35.9%) TP53 mutations were classified as high-risk, yet no association with overall survival was observed. Concluding, this the largest mutation profile of Brazilian ESCC patients, which helps in the elucidation of the major cancer-related genes in this population.
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Affiliation(s)
- Fernanda Franco Munari
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Wellington Dos Santos
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Adriane Feijó Evangelista
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Ana Carolina Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Paula Aguiar Pastrez
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil
| | - Diego Bugatti
- Department of Upper Digestive, Barretos Cancer Hospital, Barretos, Brazil
| | - Durval R Wohnrath
- Department of Upper Digestive, Barretos Cancer Hospital, Barretos, Brazil
| | - Cristovam Scapulatempo-Neto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil.,Department of Pathology, Barretos Cancer Hospital, Barretos, Brazil
| | - Denise Peixoto Guimarães
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil.,Department of Endoscopy, Barretos Cancer Hospital, Barretos, Brazil
| | - Adhemar Longatto-Filho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil.,Medical Laboratory of Medical Investigation (LIM) 14, Department of Pathology, Medical School, University of São Paulo, São Paulo, Brazil.,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos, São Paulo, 14784 400, Brazil. .,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal. .,ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal.
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45
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Jin X, Liu L, Wu J, Jin X, Yu G, Jia L, Wang F, Shi M, Lu H, Liu J, Liu D, Yang J, Li H, Ni Y, Luo Q, Jia W, Wang W, Chen W. A multi-omics study delineates new molecular features and therapeutic targets for esophageal squamous cell carcinoma. Clin Transl Med 2021; 11:e538. [PMID: 34586744 PMCID: PMC8473482 DOI: 10.1002/ctm2.538] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/16/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with inferior prognosis. Here, we conducted comprehensive transcriptomic, proteomic, phosphoproteomic, and metabolomic characterization of human, treatment-naive ESCC and paired normal adjacent tissues (cohort 1, n = 24) in an effort to identify new molecular vulnerabilities for ESCC and potential therapeutic targets. Integrative analysis revealed a small group of genes that were related to the active posttranscriptional and posttranslational regulation of ESCC. By using proteomic, phosphoproteomic, and metabolomic data, networks of ESCC-related signaling and metabolic pathways that were closely linked to cancer etiology were unraveled. Notably, integrative analysis of proteomic and phosphoproteomic data pinpointed that certain pathways involved in RNA transcription, processing, and metabolism were stimulated in ESCC. Importantly, proteins with close linkage to ESCC prognosis were identified. By enrolling an ESCC patient cohort 2 (n = 41), three top-ranked prognostic proteins X-prolyl aminopeptidase 3 (XPNPEP3), bromodomain PHD finger transcription factor (BPTF), and fibrillarin (FBL) were verified to have increased expression in ESCC. Among these prognostic proteins, only FBL, a well-known nucleolar methyltransferase, was essential for ESCC cell growth in vitro and in vivo. Furthermore, a validation study using an ESCC patient cohort 3 (n = 100) demonstrated that high FBL expression predicted unfavorable patient survival. Finally, common cancer/testis antigens and established cancer drivers and kinases, all of which could direct therapeutic decisions, were characterized. Collectively, our multi-omics analyses delineated new molecular features associated with ESCC pathobiology involving epigenetic, posttranscriptional, posttranslational, and metabolic characteristics, and unveiled new molecular vulnerabilities with therapeutic potential for ESCC.
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Affiliation(s)
- Xing Jin
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lei Liu
- Department of Thoracic SurgeryThe Affiliated Tumor Hospital of Nantong UniversityNantongChina
| | - Jia Wu
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Xiaoxia Jin
- Department of PathologyThe Affiliated Tumor Hospital of Nantong UniversityNantongChina
| | - Guanzhen Yu
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lijun Jia
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Fengying Wang
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Minxin Shi
- Department of Thoracic SurgeryThe Affiliated Tumor Hospital of Nantong UniversityNantongChina
| | - Haimin Lu
- Department of Thoracic SurgeryThe Affiliated Tumor Hospital of Nantong UniversityNantongChina
| | - Jibin Liu
- Department of Thoracic SurgeryThe Affiliated Tumor Hospital of Nantong UniversityNantongChina
| | - Dan Liu
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Jing Yang
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Hua Li
- Bio‐ID CenterSchool of Biomedical EngineeringShanghai Jiao Tong UniversityShanghaiChina
| | - Yan Ni
- The Children's HospitalNational Clinical Research Center for Child HealthZhejiang University School of MedicineHangzhouChina
| | - Qin Luo
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Wei Jia
- Hong Kong Traditional Chinese Medicine Phenome Research CenterSchool of Chinese MedicineHong Kong Baptist UniversityKowloon TongHong KongChina
| | - Wei Wang
- Department of Thoracic SurgeryThe Affiliated Tumor Hospital of Nantong UniversityNantongChina
| | - Wen‐Lian Chen
- Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
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46
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Erkizan HV, Sukhadia S, Natarajan TG, Marino G, Notario V, Lichy JH, Wadleigh RG. Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma. Sci Rep 2021; 11:14814. [PMID: 34285259 PMCID: PMC8292420 DOI: 10.1038/s41598-021-94064-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 06/24/2021] [Indexed: 12/13/2022] Open
Abstract
Esophageal cancer has a strikingly low survival rate mainly due to the lack of diagnostic markers for early detection and effective therapies. In the U.S., 75% of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) are of African descent. African American ESCC (AA ESCC) is particularly aggressive, and its biological underpinnings remain poorly understood. We sought to identify the genomic abnormalities by conducting whole exome sequencing of 10 pairs of matched AA esophageal squamous cell tumor and control tissues. Genomic analysis revealed diverse somatic mutations, copy number alterations (SCNAs), and potential cancer driver genes. Exome variants created two subgroups carrying either a high or low tumor mutation burden. Somatic mutational analysis based on the Catalog of Somatic Mutations in Cancer (COSMIC) detected SBS16 as the prominent signature in the high mutation rate group suggesting increased DNA damage. SBS26 was also detected, suggesting possible defects in mismatch repair and microsatellite instability. We found SCNAs in multiple chromosome segments, encoding MYC on 8q24.21, PIK3CA and SOX2 on 3q26, CCND1, SHANK2, CTTN on 11q13.3, and KRAS on 12p12. Amplifications of EGFRvIII and EGFRvIVa mutants were observed in two patients, representing a novel finding in ESCC that has potential clinical relevance. This present exome sequencing, which to our knowledge, represents the first comprehensive exome analysis exclusively in AA ESCC, and highlights novel mutated loci that might explain the aggressive nature of AA ESCC and lead to the development of diagnostic and prognostic markers as well as therapeutic targets.
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Affiliation(s)
- Hayriye Verda Erkizan
- Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA.
| | | | | | - Gustavo Marino
- Hepatology and Gastroenterology, Veterans Affairs Medical Center, Washington, DC, USA
| | - Vicente Notario
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Jack H Lichy
- Pathology and Laboratory Service, Veterans Affairs Medical Center, Washington, DC, USA
| | - Robert G Wadleigh
- Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA.,Hematology and Medical Oncology, Veterans Affairs Medical Center, Washington, DC, USA
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47
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Yang CS, Chen XL. Research on esophageal cancer: With personal perspectives from studies in China and Kenya. Int J Cancer 2021; 149:264-276. [PMID: 33270917 PMCID: PMC8141013 DOI: 10.1002/ijc.33421] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022]
Abstract
The most common form of esophageal cancer (EC), esophageal squamous cell carcinoma (ESCC), is prevalent in many unindustrialized societies, among people with lower socioeconomic status and those who frequently use tobacco and alcohol. In some areas, ESCC mortality ranked top among all cancer. In this review, we begin with discussions of the extensive research on EC in Linxian in northern China that started 60 years ago and the recent studies in Kenya from our personal perspectives. Based on the results obtained from these studies and information from the literature, we summarize our current understanding about the risk factors for ESCC including lifestyle factors (smoking, alcohol, consumption of food and beverages at high temperature and other unhealthy habits), poor diet and nutritional insufficiencies and genetic susceptibility. Elimination or minimization of these environmental risk factors, as well as early detection and treatment of precancerous lesions, would be effective means for the prevention of ESCC. Current knowledge of molecular alterations in ESCC (gene mutations, hypermethylation and amplification or overexpression), as well as treatment of ESCC and the potential of targeted therapy, are also discussed. Finally, we propose effective approaches for the prevention of ESCC by adapting a healthy lifestyle, including a healthy diet that would also prevent other diseases. Community outreach, public education and international collaboration are important for achieving this public health goal.
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Affiliation(s)
- Chung S. Yang
- Department of Chemical BiologyErnest Mario School of Pharmacy, Rutgers, The State University of New JerseyPiscatawayNew JerseyUSA
| | - Xiaoxin Luke Chen
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central UniversityDurhamNorth CarolinaUSA
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48
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Zhang Y, Mi K, Li Z, Qiang L, Lv M, Wu Y, Yuan L, Jin S. Identification of Prognostic miRNAs Associated With Immune Cell Tumor Infiltration Predictive of Clinical Outcomes in Patients With Non-Small Cell Lung Cancer. Front Oncol 2021; 11:705869. [PMID: 34277450 PMCID: PMC8281680 DOI: 10.3389/fonc.2021.705869] [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: 05/06/2021] [Accepted: 06/07/2021] [Indexed: 12/28/2022] Open
Abstract
Background A detailed means of prognostic stratification in patients with non-small cell lung cancer (NSCLC) is urgently needed to support individualized treatment plans. Recently, microRNAs (miRNAs) have been used as biomarkers due to their previously reported prognostic roles in cancer. This study aimed to construct an immune-related miRNA signature that effectively predicts NSCLC patient prognosis. Methods The miRNAs and mRNA expression and mutation data of NSCLC was obtained from The Cancer Genome Atlas (TCGA). Immune-associated miRNAs were identified using immune scores calculated by the ESTIMATE algorithm. LASSO-penalized multivariate survival models were using for development of a tumor immune-related miRNA signature (TIM-Sig), which was evaluated in several public cohorts from the Gene Expression Omnibus (GEO) and the CellMiner database. The miRTarBase was used for constructing the miRNA-target interactions. Results The TIM-Sig, including 10 immune-related miRNAs, was constructed and successfully predicted overall survival (OS) in the validation cohorts. TIM-Sig score negatively correlated with CD8+ T cell infiltration, IFN-γ expression, CYT activity, and tumor mutation burden. The correlation between TIM-Sig score and genomic mutation and cancer chemotherapeutics was also evaluated. A miRNA-target network of 10 miRNAs in TIM-Sig was constructed. Further analysis revealed that these target genes showed prognostic value in both lung squamous cell carcinoma and adenocarcinoma. Conclusions We concluded that the immune-related miRNAs demonstrated a potential value in clinical prognosis.
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Affiliation(s)
- Yuepeng Zhang
- Department of Respiratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kai Mi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Zhiheng Li
- Department of Medical Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lixia Qiang
- Department of Respiratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Meiyu Lv
- Department of Respiratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yushan Wu
- Department of Respiratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ligong Yuan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shoude Jin
- Department of Respiratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
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49
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Hatano Y, Ideta T, Hirata A, Hatano K, Tomita H, Okada H, Shimizu M, Tanaka T, Hara A. Virus-Driven Carcinogenesis. Cancers (Basel) 2021; 13:2625. [PMID: 34071792 PMCID: PMC8198641 DOI: 10.3390/cancers13112625] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer arises from the accumulation of genetic and epigenetic alterations. Even in the era of precision oncology, carcinogens contributing to neoplastic process are still an important focus of research. Comprehensive genomic analyses have revealed various combinations of base substitutions, referred to as the mutational signatures, in cancer. Each mutational signature is believed to arise from specific DNA damage and repair processes, including carcinogens. However, as a type of carcinogen, tumor viruses increase the cancer risk by alternative mechanisms, including insertional mutagenesis, viral oncogenes, and immunosuppression. In this review, we summarize virus-driven carcinogenesis to provide a framework for the control of malignant cell proliferation. We first provide a brief overview of oncogenic viruses and describe their implication in virus-related tumors. Next, we describe tumor viruses (HPV, Human papilloma virus; HBV, Hepatitis B virus; HCV, Hepatitis C virus; EBV, Epstein-Barr virus; Kaposi sarcoma herpesvirus; MCV, Merkel cell polyoma virus; HTLV-1, Human T-cell lymphotropic virus, type-1) and tumor virus-related cancers. Lastly, we introduce emerging tumor virus candidates, human cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and adeno-associated virus-2 (AAV-2). We expect this review to be a hub in a complex network of data for virus-associated carcinogenesis.
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Affiliation(s)
- Yuichiro Hatano
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
| | - Takayasu Ideta
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (T.I.); (M.S.)
- Department of Laboratory Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akihiro Hirata
- Laboratory of Veterinary Pathology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1194, Japan;
| | - Kayoko Hatano
- Department of Obstetrics and Gynecology, Gifu University Hospital, Gifu 501-1194, Japan;
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan;
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (T.I.); (M.S.)
| | - Takuji Tanaka
- Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu 500-8513, Japan;
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
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50
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Zeng B, Huang P, Du P, Sun X, Huang X, Fang X, Li L. Comprehensive Study of Germline Mutations and Double-Hit Events in Esophageal Squamous Cell Cancer. Front Oncol 2021; 11:637431. [PMID: 33889545 PMCID: PMC8056176 DOI: 10.3389/fonc.2021.637431] [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: 12/03/2020] [Accepted: 02/10/2021] [Indexed: 01/12/2023] Open
Abstract
Esophageal squamous cell cancer (ESCC) is the eighth most common cancer around the world. Several reports have focused on somatic mutations and common germline mutations in ESCC. However, the contributions of pathogenic germline alterations in cancer susceptibility genes (CSGs), highly frequently mutated CSGs, and pathogenically mutated CSG-related pathways in ESCC remain unclear. We obtained data on 571 ESCC cases from public databases and East Asian from the 1000 Genomes Project database and the China Metabolic Analytics Project database to characterize pathogenic mutations. We detected 157 mutations in 75 CSGs, accounting for 25.0% (143/571) of ESCC cases. Six genes had more than five mutations: TP53 (n = 15 mutations), GJB2 (n = 8), BRCA2 (n = 6), RECQL4 (n = 6), MUTYH (n = 6), and PMS2 (n = 5). Our results identified significant differences in pathogenic germline mutations of TP53, BRCA2, and RECQL4 between the ESCC and control cohorts. Moreover, we identified 84 double-hit events (16 germline/somatic double-hit events and 68 somatic/somatic double-hit events) occurring in 18 tumor suppressor genes from 83 patients. Patients who had ESCC with germline/somatic double-hit events were diagnosed at younger ages than patients with the somatic/somatic double-hit events, though the correlation was not significant. Fanconi anemia was the most enriched pathway of pathogenically mutated CSGs, and it appeared to be a primary pathway for ESCC predisposition. The results of this study identified the underlying roles that pathogenic germline mutations in CSGs play in ESCC pathogenesis, increased our awareness about the genetic basis of ESCC, and provided suggestions for using highly mutated CSGs and double-hit features in the early discovery, prevention, and genetic counseling of ESCC.
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Affiliation(s)
- Bing Zeng
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China
- BGI-Shenzhen, Shenzhen, China
| | | | - Peina Du
- BGI Genomics, BGI-Shenzhen, Shenzhen, China
| | | | | | - Xiaodong Fang
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China
- BGI-Shenzhen, Shenzhen, China
- China National GeneBank, BGI-Shenzhen, Shenzhen, China
| | - Lin Li
- BGI-Shenzhen, Shenzhen, China
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