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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34068 | GEO | 2014/12/01

SECONDARY ACCESSION(S): PRJNA149987

REPOSITORIES: GEO

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Project description:Background: Alternative polyadenylation (APA) is emerging as a widespread mechanism of gene regulation. The usage of APA sites allows a single gene to encode multiple mRNA transcripts with different 3'-untranslated region (3'UTR) lengths. Many disease processes reflect the importance of the regulation of APA site switching. The objective of this study was to explore the profiling of tandem APA sites in nasal polyps compared with nasal uncinate process mucosa. Methods: Sequencing of APA sites (SAPAS) based on second-generation sequencing technology was undertaken to investigate the use of tandem APA sites and identify gene expression patterns in samples from the nasal polyps and nasal uncinate process mucosa of two patients with chronic rhinosinusitis with nasal polyps. The findings of the SAPAS analysis were validated via quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Results: First, the results showed a switching of 3'UTR lengths in nasal polyps compared with nasal uncinate process mucosa. From the two patients, 105 overlapping genes in the nasal polyps were switched to distal poly(A) sites, and 90 such genes were switched to proximal poly(A) sites. Several Gene Ontology terms were enriched in the list of genes with switched APA sites, including transcription regulation, cell cycle, apoptosis, and metabolism. Second, we detected genes that showed differential expression with at least a 3-fold difference between nasal polyp tissue and nasal uncinate process mucosa. Between the two sample types, 627 genes exhibited differential expression. The qRT-PCR results confirmed our SAPAS results. Conclusion: APA site-switching events of 3'UTRs are prevalent in nasal polyp tissue, and the regulation of gene expression mediated by APA may play an important role in the formation and persistence of nasal polyps. Our results may provide new insights into the possible pathophysiologic processes involved in nasal polyps. Investigate the use of tandem APA sites of 3'ends of mRNAs using second-generation sequencing technology.

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

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