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Point mutations in Exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant

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dc.contributor.authorLi, J.
dc.contributor.authorWoods, S.
dc.contributor.authorHealey, S.
dc.contributor.authorBeesley, J.
dc.contributor.authorChen, X.
dc.contributor.authorLee, J.
dc.contributor.authorSivakumaran, H.
dc.contributor.authorWayte, N.
dc.contributor.authorNones, K.
dc.contributor.authorWaterfall, J.
dc.contributor.authorPearson, J.
dc.contributor.authorPatch, A.
dc.contributor.authorSenz, J.
dc.contributor.authorFerreira, M.
dc.contributor.authorKaurah, P.
dc.contributor.authorMacKenzie, R.
dc.contributor.authorHeravi-Moussavi, A.
dc.contributor.authorHansford, S.
dc.contributor.authorLannagan, T.
dc.contributor.authorSpurdle, A.
dc.contributor.authoret al.
dc.date.issued2016
dc.description.abstractGastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.
dc.description.statementofresponsibilityJun Li, Susan L. Woods ... Tamsin R.M. Lannagan ... Nicola Poplawski, Kerry Phillips … Jacqueline Armstrong … Graeme K. Suthers … Daniel L. Worthley … et al.
dc.identifier.citationAmerican Journal of Human Genetics, 2016; 98(5):830-842
dc.identifier.doi10.1016/j.ajhg.2016.03.001
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.orcidWoods, S. [0000-0002-8955-2017]
dc.identifier.orcidLannagan, T. [0000-0002-8206-8898]
dc.identifier.orcidPoplawski, N. [0000-0002-9372-3325]
dc.identifier.orcidWorthley, D. [0000-0003-0374-9124]
dc.identifier.urihttp://hdl.handle.net/2440/100179
dc.language.isoen
dc.publisherElsevier
dc.relation.grantNHMRC
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1045237
dc.rights© 2016 by The American Society of Human Genetics. All rights reserved
dc.source.urihttps://doi.org/10.1016/j.ajhg.2016.03.001
dc.subjectGastric Mucosa
dc.subjectHumans
dc.subjectAdenomatous Polyps
dc.subjectAdenomatous Polyposis Coli
dc.subjectAdenocarcinoma
dc.subjectStomach Neoplasms
dc.subjectAdenomatous Polyposis Coli Protein
dc.subjectPedigree
dc.subjectAllelic Imbalance
dc.subjectLoss of Heterozygosity
dc.subjectPoint Mutation
dc.subjectExons
dc.subjectFemale
dc.subjectMale
dc.subjectPromoter Regions, Genetic
dc.subjectDNA Copy Number Variations
dc.subjectGenetic Linkage
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectExome
dc.titlePoint mutations in Exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant
dc.typeJournal article
pubs.publication-statusPublished

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