Genotypic and phenotypic studies in hyperplastic polyposis syndrome

Deposited with the permission of the author. © 2010 Dr. Musa DriniHyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps and colorectal cancer (CRC) risk, and is related to a third pathway to human CRC known as “serrated neoplasia pathway”. Several genetic aberrations have been linked to HPS, including frequent BRAF and KRAS mutations and aberrant methyation known as CIMP. At least half of CRCs arising in HPS also show a CpG island methylator phenotype (CIMP). CIMP usually involves a wide panel of tumor suppressor genes including regulators of DNA mismatch repair (such as MLH1, MGMT), and negative regulators of Wnt signaling (such as WIF1). DNA methylation is one of many epigenetic factors that are important for cellular differentiation, gene regulation and genomic imprinting. The aberrant DNA methylation found in CIMP phenotype may be a consequence of dysfunctional machinery involved in establishing and maintaining normal DNA methylation. DNA methyltransferases DNMTs (DNMT1, -3A, -3B and -3L) are a family of proteins responsible for transfer of methyl groups specifically to cytosine in CpG dinucleotides of DNA. Given the role of DNMT’s in DNA methylation, we investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, together with variation in BRAF and KRAS genes, in the molecular pathogenesis of HPS. A candidate gene approach identified no novel sequence variants that showed significant association with HPS. However, the T allele of rs62106244 (intron 10 of DNMT1 gene) was over-represented in cases with HPS (p