Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer
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Published:2022-12-09
Issue:12
Volume:5
Page:e2245836
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ISSN:2574-3805
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Container-title:JAMA Network Open
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language:en
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Short-container-title:JAMA Netw Open
Author:
Liu Ze-Xian1, Zhang Xiao-Long1, Zhao Qi1, Chen Yungchang2, Sheng Hui1, He Cai-Yun3, Sun Yu-Ting4, Lai Ming-Yu4, Wu Min-Qing5, Zuo Zhi-Xiang1, Wang Wei2, Zhou Zhi-Wei6, Wang Feng-Hua4, Li Yu-Hong4, Xu Rui-Hua147, Qiu Miao-Zhen14
Affiliation:
1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China 2. Department of Medical Oncology, The First People’s Hospital of Foshan, Chancheng District, Foshan, People’s Republic of China 3. Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China 4. 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, People’s Republic of China 5. Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China 6. Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China 7. Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, People’s Republic of China
Abstract
ImportanceThe E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown.ObjectiveTo assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC.Design, Setting, and ParticipantsThis cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020.Main Outcomes and MeasuresIncidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC.ResultsAmong 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC.Conclusions and RelevanceThis study provided a genetic landscape for HDGC. The study’s findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.
Publisher
American Medical Association (AMA)
Cited by
3 articles.
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