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Germline mutations in MAP3K6 are associated with familial gastric cancer
- Source :
- PLoS Genetics, Vol 10, Iss 10, p e1004669 (2014), Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos), Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação, instacron:RCAAP, PLoS Genetics
- Publication Year :
- 2014
- Publisher :
- Public Library of Science (PLoS), 2014.
-
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.<br />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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 10
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....3b6fdf9003a9cd76822df1e8a01991b4