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      BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese.

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          Esophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole-exome sequencing (WES) included 186 familial ESCC patients from high-risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate-risk Hong Kong Chinese. A WES approach identified BRCA2 loss-of-function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10-10 ). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild-type somatic allelic loss via loss of heterozygosity. Gene-based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10-5 ), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.

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          Author and article information

          Int. J. Cancer
          International journal of cancer
          February 15 2020
          : 146
          : 4
          [1 ] Department of Clinical Oncology, University of Hong Kong, Hong Kong, People's Republic of China.
          [2 ] Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, State Key Laboratory for Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
          [3 ] Department of Surgery, University of Hong Kong, Hong Kong, People's Republic of China.
          [4 ] Hereditary Breast Cancer Family Registry Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, People's Republic of China.
          [5 ] Division of Anatomical Pathology, Queen Mary Hospital, Hong Kong, People's Republic of China.
          [6 ] Department of Gastroenterology, Shanghai University of Medicine and Health Sciences, Affiliated Zhoupu Hospital, Shanghai, People's Republic of China.

          Chinese,loss-of-function mutations,esophageal cancer susceptibility gene,BRCA2,synthetic lethality


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