Widespread monoallelic methylation of colorectal cancer associated tumour suppressor genes, including multiple Wnt pathway inhibitors, in Hyperplastic Polyposis Syndrome.

Hyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC). The majority of CRCs arising in HPS show a CpG island methylator phenotype (CIMP) that encompasses several common tumor suppressor genes, including regulators of DNA mismatch repair, and negative regulators of Wnt signaling. However, little is currently known about the CIMP status of premalignant polyp tissue in HPS or the temporal changes in CIMP profile associated with transition to malignancy. Using genomescale DNA methylation analysis of HPS polyp and disease-free tissue, we identified widespread coordinated DNA methylation changes, common to all HPS polyps examined. The majority of consistent changes involve low-intermediate (10-50%) methylation and include several tumour suppressor genes, including multiple negative regulators of Wnt signalling (SFRP-1, -2, -4, -5) and cell cycle regulation (eg. RASSF1). We also confirmed selective methylation of the RUNX1, CHFR, CDKN2A, and MLH-1 promoters previously described in HPS, but found no evidence for methylation of DNA mismatch repair genes MGMT or MSH-2 in premalignant polyps. Consistent and widespread methylation of the WT-1 tumour suppressor gene also appears to be a common feature of HPS. Interestingly, where tested the majority of methylation identified was localised to a single allele within the polyp tissue. These findings reveal that premalignant HPS is associated with coordinated, widespread intermediate levels of gene promoter methylation in several TS genes implicated in CRC, primarily restricted to one of two alleles. Transition to malignancy appears to be associated with widespread elevation of methylation at these sites. These findings warrant a further investigation of the potential for future development of novel methylation-based molecular assays for the prediction of HPS cases likely to transition to malignancy. DNA was extracted from eleven HPS and four control colon samples.