Germline Mutations in MAP3K6 Are Associated with Familial Gastric Cancer

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.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…Germline mutations in MAP3K6 gene have been described in families with FGC, although the role of these mutations is yet to be proven [44]. In CDH1-negative HDGC families, multiplexed targeted sequencing of cancer associated genes led recently to the identification of new germline mutations in several genes, such as CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2 [35].…”

Gastric carcinoma in canines and humans, a review

“…Recently, novel germline mutations in non‐CHD1 hereditary gastric cancer have been identified. Multiple genetic mutations in the mitogen‐activated protein kinase kinase kinase (MAP3K6) were described in patients with familial gastric cancer from different families . Also candidate mutations in BRCA2, STK11, SDHB, PRSS1, ATM, MSR1 and PALB2 were identified in individual CDH1‐negative HDGC family members .…”

MicroRNAs in hereditary diffuse gastric cancer

“…The presence of mutations has been observed in diverse genes, listed as follows: Mutations reported in RHOA (10,11) are associated with the initial stages of cancer and its progression to metastasis; CTNNA1 mutated in HDGC acts as a tumor-suppressor gene (12) and changes in MAP3K6 generate an alteration in inflammation pathways and apoptosis. In addition, it has been found that these are predisposed to develop GC (13) and that changes in the INSR gene (14) exert an effect on the insulin signaling pathway, giving rise to changes in the pattern of glycosylation of the E-cadherin protein, destabilization of cellular membranes and the appearance of a mesenchymal phenotype. Contrary to previously described, the roles of the mutations in the genes FBXO24, DOT1L (14) and TGF-β (15) have not yet been studied (Table I).…”