Investigating the potential role of genetic and epigenetic variation of DNA methyltransferase genes in hyperplastic polyposis syndrome

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Drini M, Wong NC, Scott HS, Craig JM, Dobrovic A, Hewitt CA, Dow C, Young JP, Jenkins MA, Saffery R, Macrae FA (2011) Investigating the potential role of genetic and epigenetic variation of DNA methyltransferase genes in hyperplastic polyposis syndrome. PloS one 6:e16831


BACKGROUND: Hyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC). At least half of CRCs arising in HPS show a CpG island methylator phenotype (CIMP), potentially linked to aberrant DNA methyltransferase (DNMT) activity. CIMP is associated with methylation of tumor suppressor genes including regulators of DNA mismatch repair (such as MLH1, MGMT), and negative regulators of Wnt signaling (such as WIF1). In this study, we investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, in the aetiology of HPS. METHODS: We utilized high resolution melting (HRM) analysis to screen 45 cases with HPS for novel sequence variants in DNMT1, DNMT3A, DNMT3B, and DNMT3L. 21 polyps from 13 patients were screened for BRAF and KRAS mutations, with assessment of promoter methylation in the DNMT1, DNMT3A, DNMT3B, DNMT3L MLH1, MGMT, and WIF1 gene promoters. RESULTS: No pathologic germline mutations were observed in any DNA-methyltransferase gene. However, the T allele of rs62106244 (intron 10 of DNMT1 gene) was over-represented in cases with HPS (p<0.01) compared="" with="" population="" controls.="" the="" dnmt1,="" dnmt3a="" and="" dnmt3b="" promoters="" were="" unmethylated="" in="" all="" instances.="" interestingly,="" the="" dnmt3l="" promoter="" showed="" low="" levels="" of="" methylation="" in="" polyps="" and="" normal="" colonic="" mucosa="" relative="" to="" matched="" disease="" free="" cells="" with="" methylation="" level="" negatively="" correlated="" to="" expression="" level="" in="" normal="" colonic="" tissue.="" dnmt3l="" promoter="" hypomethylation="" was="" more="" often="" found="" in="" polyps="" harbouring="" kras="" mutations="" (p="0.0053)." braf="" mutations="" were="" common="" (11="" out="" of="" 21="" polyps),="" whilst="" kras="" mutations="" were="" identified="" in="" 4="" of="" 21="" polyps.="" conclusions:="" genetic="" or="" epigenetic="" alterations="" in="" dnmt="" genes="" do="" not="" appear="" to="" be="" associated="" with="" hps,="" but="" further="" investigation="" of="" genetic="" variation="" at="" rs62106244="" is="" justified="" given="" the="" high="" frequency="" of="" the="" minor="" allele="" in="" this="" case="">

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