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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.  DNMT3 L 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 series.

Investigating the Potential Role of Genetic and Epigenetic Variation of DNA Methyltransferase Genes in Hyperplastic Polyposis Syndrome