title: 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.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaston
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Hansford
authors.affiliation: Expression Regulation in Cancer Group, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto & Medical Faculty of the University of Porto, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Mathew
authors.initials: M
authors.lastname: Nightingale
authors.affiliation: Expression Regulation in Cancer Group, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto & Medical Faculty of the University of Porto, Porto, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Pinheiro
authors.affiliation: Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Macgillivray
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Pardeep
authors.initials: P
authors.lastname: Kaurah
authors.affiliation: Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Rideout
authors.affiliation: Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Steele
authors.affiliation: Center of Medical Genetics Jacinto de Magalhães, Porto Hospital Center, Porto, Portugal.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Soares
authors.affiliation: Division of Anatomical Pathology, Department of Pathology, Queen Elizabeth II Health Science Center and Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Weei-Yuarn
authors.initials: WY
authors.lastname: Huang
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Whitehouse
authors.affiliation: Queen's Family Health Team, Kingston, Ontario, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Blowers
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: LeBlanc
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Wenda
authors.initials: W
authors.lastname: Greer
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Centre de Recherche du CHU Ste-Justine and Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Orr
authors.affiliation: Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Conrad V
authors.initials: CV
authors.lastname: Fernandez
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada; Oncogenetics Service, Institute of Medical Genetics, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Ludman
authors.affiliation: Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dyack
authors.affiliation: Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada; Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Lynette S
authors.initials: LS
authors.lastname: Penney
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McMaster
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Bedard
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D020930:MAP Kinase Kinase Kinases; C116394:MAP kinase kinase kinase 6