1. Germline mutations in MAP3K6 are associated with familial gastric cancer
- Author
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Daniel Gaston, Lynette S. Penney, Sarah Blowers, Samantha Hansford, Hugo Pinheiro, Mark E. Samuels, Wenda L. Greer, Weei-Yuarn Huang, Carla Oliveira, Jacek Majewski, Gabriela Soares, David G. Huntsman, Karen Bedard, Christine Macgillivray, Andrew C. Orr, Pardeep Kaurah, Scott Whitehouse, Christopher R. McMaster, Marissa A. LeBlanc, Mark Ludman, Andrea L. Rideout, Haiyan Jiang, Conrad V. Fernandez, Sarah Dyack, Mathew Nightingale, and Patricia Steele
- Subjects
Male ,Cancer Research ,Heredity ,Genetic Linkage ,DNA Mutational Analysis ,medicine.disease_cause ,Germline ,CDH1 ,Database and Informatics Methods ,0302 clinical medicine ,Genotype ,Genetics (clinical) ,Genetics ,0303 health sciences ,Mutation ,Heterozygosity ,biology ,Nonsense Mutation ,Genomics ,Germline Mutation ,Cadherins ,MAP Kinase Kinase Kinases ,Pedigree ,3. Good health ,Genetic Mapping ,Mutant Genotypes ,030220 oncology & carcinogenesis ,DNA methylation ,Female ,Hereditary diffuse gastric cancer ,Research Article ,Missense Mutation ,lcsh:QH426-470 ,Bioinformatics ,Variant Genotypes ,Genetic Predisposition ,Research and Analysis Methods ,Polymorphism, Single Nucleotide ,Human Genomics ,03 medical and health sciences ,Germline mutation ,Genetic Disorders ,Antigens, CD ,Stomach Neoplasms ,Cancer Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Germ-Line Mutation ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Biology and Life Sciences ,Cancer ,Human Genetics ,medicine.disease ,lcsh:Genetics ,Genetics of Disease ,biology.protein ,Somatic Mutation - 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., Author Summary The underlying genetic mutations involved in 60% of inherited gastric cancer cases remain unknown. Here we present a large, extended pedigree with familial gastric cancer and an association in part of the family with a mutation in MAP3K6. The conservation, predicted pathogenicity of the variant, tissue distribution, and known function of MAP3K6 made this a strong candidate that warranted further investigation. Examination of an additional 115 unrelated probands identified additional mutations in MAP3K6, including a truncating mutation.
- Published
- 2014