BRCA2 mutations associated with oesophageal squamous cell carcinoma risk in Chinese
Researchers from Hong Kong, Zhengzhou and Shanghai applied next-generation sequencing to a large sample of Chinese OSCC patients (n=2,459), aiming to identify cancer predisposition gene(s) for OSCC susceptibility. The study comprehensively sequenced BRCA2 and is the first to report the association between germline BRCA2 loss-of-function (LOF) mutations and OSCC risk in Chinese. [Int J Cancer 2019, doi: 10.1002/ijc.32619]
In the study, BRCA2 LOF mutations were detected in 3.23 percent (1:31) of 186 familial OSCC cases in Henan, China, during the discovery phase, and in 0.8 percent (1:125) and 1.16 percent (1:86) of the larger OSCC population in the high-risk Henan and moderate-risk Hong Kong validation cohorts.
Oesophageal cancer (OC) is prevalent worldwide with 456,000 new cases annually, approximately half of which occur in China. [Int J Cancer 2015;136:E359-E386] In Hong Kong and mainland China, the major histological OC subtype is squamous cell carcinoma (SCC), which is associated with a 90 percent mortality rate, while adenocarcinoma is more common in Western countries. [Cancer Discov 2012;2:899-905]
“OC exhibits striking geographical variations, with a more than 21-fold difference between high-risk and low-risk regions,” wrote the researchers. The high-risk region of Northern China has an incidence of >100/100,000 compared with <10/100,000 in countries such as Finland and Switzerland. [Eur J Cancer Prev 2017;26:107-118]
“Our study is the first to utilize a genetically-enriched cohort of patients with familial OSCC from the high OC risk province of Henan, located near the Tai-Hang Mountain region in Northern China, to identify high penetrance of OSCC predisposition genes using a comprehensive unbiased exome sequencing strategy,” the investigators explained.
Between 2001 and 2014, OSCC samples were collected from high OC risk Linxian and Anyang counties of Henan province from the Linzhou Centre Hospital and Yaocun Oesophageal Cancer Hospital, and were confirmed by histopathology. Blood samples of OSCC cases from a moderate OC risk population were collected from Queen Mary Hospital in Hong Kong and used for validation.
“With a combined Henan and Hong Kong sample size of 4,517 Chinese individuals, this study comprehensively sequenced 598 genes and is the first to report the significantly higher prevalence of BRCA2 LOF mutations in Chinese OSCC patients compared with controls [odds ratio, 9.71; p=6.80x10-5],” reported the investigators.
Although BRCA2 is of great relevance to familial OSCC in Henan, a substantial fraction of familial clustering and high incidence of OSCC cases remained unexplained. “The missing heredity component may be located at non-coding regulatory regions or other susceptibility loci may act in a gene-environmental interaction or gene-lifestyle dependent manner,” suggested the researchers. “Synergistic interaction between alcohol consumption, smoking and two functional variants in [alcohol dehydrogenase] ALDH2 and ADH1B polymorphisms increase OSCC risk.” A previous Japanese genome-wide association study suggested that alcohol/acetaldehyde metabolism plays an important aetiologic role in OSCC pathogenesis in moderate-risk regions. [Gastroenterology 2009;137:1768-1775]
“Our data has an important potential implication on therapeutic options … PARP1 inhibitors may warrant further consideration for OSCC patients with BRCA2 deficiency,” concluded the researchers.