Abstract
Gastric cancer is among the leading causes of cancer-related deaths worldwide. While heritable forms of gastric cancer are relatively rare, identifying the genes responsible for such cases can inform diagnosis and treatment for both hereditary and sporadic cases of gastric cancer. Mutations in the E-cadherin gene, CDH1, account for 40% of the most common form of familial gastric cancer (FGC), hereditary diffuse gastric cancer (HDGC). The genes responsible for the remaining forms of FGC are currently unknown. Here we examined a large family from Maritime Canada with FGC without CDH1 mutations, and identified a germline coding variant (p.P946L) in mitogen-activated protein kinase kinase kinase 6 (MAP3K6). Based on conservation, predicted pathogenicity and a known role of the gene in cancer predisposition, MAP3K6 was considered a strong candidate and was investigated further. Screening of an additional 115 unrelated individuals with non-CDH1 FGC identified the p.P946L MAP3K6 variant, as well as four additional coding variants in MAP3K6 (p.F849Sfs*142, p.P958T, p.D200Y and p.V207G). A somatic second-hit variant (p.H506Y) was present in DNA obtained from one of the tumor specimens, and evidence of DNA hypermethylation within the MAP3K6 gene was observed in DNA from the tumor of another affected individual. These findings, together with previous evidence from mouse models that MAP3K6 acts as a tumor suppressor, and studies showing the presence of somatic mutations in MAP3K6 in non-hereditary gastric cancers and gastric cancer cell lines, point towards MAP3K6 variants as a predisposing factor for FGC.
Highlights
Gastric cancer is the second leading cause of cancer-related death worldwide with 738,000 deaths per year [1]
1% to 3% are caused by a hereditary syndrome, as opposed to environmental factors such as shared dietary practices [5]
The most well established familial form of gastric cancer is hereditary diffuse gastric cancer (HDGC [MIM 137215]), where approximately 40% of cases are attributed to germline mutations in the E-cadherin encoding gene, CDH1 [6,7,8,9]
Summary
Gastric cancer is the second leading cause of cancer-related death worldwide with 738,000 deaths per year [1]. Primary treatment consists of surgical resection of the tumor and may be followed by chemotherapy and/or radiotherapy. The 5-year survival rates after surgical resection are high if the disease is detected early (71% for stage 1A), they drop off quickly when the diagnosis is made at later stages (46% stage IIA, 20% stage IIIA, 4% stage IV) (National Cancer Institute’s SEER database, October 2013). Because early symptoms of gastric cancer closely resemble other diseases, detection often does not occur until advanced stages have already been reached [2]
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