Abstract
Besides CDH1, few hereditary gastric cancer predisposition genes have been previously reported. In this study, we discovered two germline ATM mutations (p.Y1203fs and p.N1223S) in a Chinese family with a history of gastric cancer by screening 83 cancer susceptibility genes. Using a published exome sequencing dataset, we found deleterious germline mutations of ATM in 2.7% of 335 gastric cancer patients of different ethnic origins. The frequency of deleterious ATM mutations in gastric cancer patients is significantly higher than that in general population (p=0.0000435), suggesting an association of ATM mutations with gastric cancer predisposition. We also observed biallelic inactivation of ATM in tumors of two gastric cancer patients. Further evaluation of ATM mutations in hereditary gastric cancer will facilitate genetic testing and risk assessment.
Highlights
Gastric cancer is the third most common cause of cancer mortality worldwide, accounting for 723,000 deaths in 2012 [1]
Germline mutations in CDH1 genes contribute to about 40% of hereditary diffuse gastric cancer (HDGC) cases [6], and
Germline mutations in MAP3K6 were found to be associated with familial gastric cancer [10]
Summary
Gastric cancer is the third most common cause of cancer mortality worldwide, accounting for 723,000 deaths in 2012 [1]. Familial aggregation of gastric cancer is common in about 10% of the cases [2]. Environmental risk factors, such as chronic infections by Helicobacter pylori and Epstein-Barr virus, partly explain the familial clustering of gastric cancer [3, 4], genetic susceptibility has a role in the disease [5]. Germline mutations in CDH1 genes contribute to about 40% of hereditary diffuse gastric cancer (HDGC) cases [6], and. Lynch syndrome families with inherited mutations in the mismatch repair genes are at an increased risk for gastric cancer [7,8,9]. Germline mutations in MAP3K6 were found to be associated with familial gastric cancer [10]. For most gastric cancer cases, whether genetic events contribute to cancer susceptibility remains unknown
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