Abstract
BackgroundHyperplastic 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.MethodsWe 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.ResultsNo 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.ConclusionsGenetic 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.
Highlights
Hyperplastic Polyposis Syndrome (HPS) is a colorectal cancer (CRC) predisposition associated with the development of multiple serrated polyps, and is defined by the World Health Organization as:(1) at least five serrated polyps proximal to the sigmoid colon with two or more of these being .10 mm; or (2) any number of serrated polyps proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis; or (3) .20 serrated polyps of any size, but distributed throughout the colon
Given the observation that even apparently normal mucosa in patients with HPS is highly methylated [6], we investigated the potential for mutation or epigenetic disruption of DNMT1 (CCDS12228.1), DNMT3A (CCDS1718.1), DNMT3B (CCDS13204.1) and DNMT3L (CCDS13705.1) in the development of HPS
In order to ascertain whether the previously reported methylation disruption associated with HPS may be due to genetic variability in DNA methyltransferase (DNMT), we screened a total of 92 DNMT exons for novel mutations by High Resolution Melting (HRM) analysis in lymphoblast cell lines (LCLs) genomic DNA from HPS subjects
Summary
Hyperplastic Polyposis Syndrome (HPS) is a colorectal cancer (CRC) predisposition associated with the development of multiple serrated polyps, and is defined by the World Health Organization as:(1) at least five serrated polyps proximal to the sigmoid colon with two or more of these being .10 mm; or (2) any number of serrated polyps proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis; or (3) .20 serrated polyps of any size, but distributed throughout the colon. Hyperplastic Polyposis Syndrome (HPS) is a colorectal cancer (CRC) predisposition associated with the development of multiple serrated polyps, and is defined by the World Health Organization as:. HPS is the genetic disease model for the serrated neoplasia pathway of CRC development [2,3,4] This new distinct pathway of CRC is characterized by activating mutation of the BRAF proto-oncogene ( V600E) and widespread and concordant gene promoter hypermethylation (CpG Island methylation Phenotype or CIMP) [5,6,7,8], and is responsible for silencing of many genes by CpG island methylation in specific cancer subtypes [9]. Hyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC). We investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, in the aetiology of HPS
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