title: Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer.
abstract: DNA methylation is a hallmark in a subset of right-sided colorectal cancers. Methylation-based screening may improve prevention and survival rate for this type of cancer, which is often clinically asymptomatic in the early stages. We aimed to discover prognostic or diagnostic biomarkers for colon cancer by comparing DNA methylation profiles of right-sided colon tumours and paired normal colon mucosa using an 8.5 k CpG island microarray. We identified a diagnostic CpG-rich region, located in the first intron of the protein-tyrosine phosphatase gamma gene (PTPRG) gene, with altered methylation already in the adenoma stage, that is, before the carcinoma transition. Validation of this region in an additional cohort of 103 sporadic colorectal tumours and 58 paired normal mucosa tissue samples showed 94% sensitivity and 96% specificity. Interestingly, comparable results were obtained when screening a cohort of Lynch syndrome-associated cancers. Functional studies showed that PTPRG intron 1 methylation did not directly affect PTPRG expression, however, the methylated region overlapped with a binding site of the insulator protein CTCF. Chromatin immunoprecipitation (ChIP) showed that methylation of the locus was associated with absence of CTCF binding. Methylation-associated changes in CTCF binding to PTPRG intron 1 could have implications on tumour gene expression by enhancer blocking, chromosome loop formation or abrogation of its insulator function. The high sensitivity and specificity for the PTPRG intron 1 methylation in both sporadic and hereditary colon cancers support biomarker potential for early detection of colon cancer.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Eddy H J
authors.initials: EH
authors.lastname: van Roon
authors.forename: Noël F C C
authors.initials: NF
authors.lastname: de Miranda
authors.forename: Merlijn P
authors.initials: MP
authors.lastname: van Nieuwenhuizen
authors.forename: Emile J
authors.initials: EJ
authors.lastname: de Meijer
authors.forename: Marjo
authors.initials: M
authors.lastname: van Puijenbroek
authors.forename: Pearlly S
authors.initials: PS
authors.lastname: Yan
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
mesh_terms: D000076246:CCCTC-Binding Factor; D047369:Chromatin Immunoprecipitation; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006801:Humans; D007438:Introns; D011401:Promoter Regions, Genetic; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D012680:Sensitivity and Specificity
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004273:DNA, Neoplasm; D012097:Repressor Proteins; C516850:PTPRG protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5