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Germline mutations in MAP3K6 are associated with familial gastric cancer

2014-10Journal article Open access
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dc.contributor.authorGaston, D.
dc.contributor.authorHansford, S.
dc.contributor.authorOliveira, C.
dc.contributor.authorNightingale, M.
dc.contributor.authorPinheiro, H.
dc.contributor.authorMacgillivray, C.
dc.contributor.authorKaurah, P.
dc.contributor.authorRideout, A.
dc.contributor.authorSteele, P.
dc.contributor.authorSoares, G.
dc.contributor.authorHuang, W.
dc.contributor.authorWhitehouse, S.
dc.contributor.authorBlowers, S.
dc.contributor.authorLeBlanc, M.
dc.contributor.authorJiang, H.
dc.contributor.authorGreer, W.
dc.contributor.authorSamuels, M.
dc.contributor.authorOrr, A.
dc.contributor.authorFernandez, C.
dc.contributor.authorMajewski, J.
dc.contributor.authorLudman, M.
dc.contributor.authorDyack, S.
dc.contributor.authorPenney, L.
dc.contributor.authorMcMaster, C.
dc.contributor.authorHuntsman, D.
dc.contributor.authorBedard, K.
dc.date.accessioned2015-10-27T11:19:51Z
dc.date.available2015-10-27T11:19:51Z
dc.date.issued2014-10
dc.description.abstractGastric 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.pt_PT
dc.description.sponsorshipThe following agencies provided funding for this project: Genome Canada, Genome Atlantic, Nova Scotia Health Research Foundation, Nova Scotia Research and Innovation Trust, Dalhousie Faculty of Medicine, Dalhousie Department of Ophthalmology, Health Canada, The Centre for Drug Research and Development, Capital District Health Authority, IWK Health Centre Foundation, Capital Health Research Fund, and The COMPETE/FEDER Portuguese Foundation for Science and Technology (FCT), Projects Ref. FCT PTDC/SAU-GMG/110785/2009 and Post-doc grant SFRH/BPD/79499/2011 to HP “financiados no âmbito do Programa Operacional Temático Factores de Competitividade (COMPETE) e comparticipado pelo fundo Comunitário Europeu FEDER.” MES is supported by the CHU Ste-Justine Centre de Recherche. The authors would like to acknowledge the contribution of: the Genome Quebec High Throughput Sequencing Platform; and Sónia Sousa and José Carlos Machado from the IPATIMUP Diagnostics Unit, Porto, Portugal. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.pt_PT
dc.identifier10.1371/journal.pgen.1004669
dc.identifier.citationPLoS Genet. 2014;10(10): e1004669pt_PT
dc.identifier.doi10.1371/journal.pgen.1004669
dc.identifier.doi10.1371/journal.pgen.1004669
dc.identifier.issn1553-7390
dc.identifier.urihttp://hdl.handle.net/10400.16/1870
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPublic Library of Sciencept_PT
dc.relationNew E-cadherin RNAs: the dark side of a tumour suppressor gene
dc.relationCDH1 LOCUS, THE NEXT JEKYLL AND HYDE IN CANCER
dc.relation.publisherversionhttp://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004669pt_PT
dc.titleGermline mutations in MAP3K6 are associated with familial gastric cancerpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleNew E-cadherin RNAs: the dark side of a tumour suppressor gene
oaire.awardTitleCDH1 LOCUS, THE NEXT JEKYLL AND HYDE IN CANCER
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-GMG%2F110785%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/FARH/SFRH%2FBPD%2F79499%2F2011/PT
oaire.citation.conferencePlaceUnited States of Americapt_PT
oaire.citation.titlePLoS geneticspt_PT
oaire.citation.volume10(10)pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStreamFARH
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationd6e0dbc8-27d2-44b4-8fd9-945f9519ed50
relation.isProjectOfPublication6fe6ee55-1f23-471c-a600-d93f3f014fde
relation.isProjectOfPublication.latestForDiscovery6fe6ee55-1f23-471c-a600-d93f3f014fde

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