Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer

Eddy H J Van Roon, Noël F C C De Miranda, Merlijn P. Van Nieuwenhuizen, Emile J. De Meijer, Marjo Van Puijenbroek, Pearlly S. Yan, Hui-ming Huang, Tom Van Wezel, Hans Morreau, Judith M. Boer

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)307-312
Number of pages6
JournalEuropean Journal of Human Genetics
Volume19
Issue number3
DOIs
StatePublished - Mar 2011
Externally publishedYes

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Hereditary Nonpolyposis Colorectal Neoplasms
Introns
Methylation
Colorectal Neoplasms
Colonic Neoplasms
Neoplasms
DNA Methylation
Colon
Mucous Membrane
Sensitivity and Specificity
CpG Islands
Protein Tyrosine Phosphatases
Chromatin Immunoprecipitation
Tumor Biomarkers
Early Detection of Cancer
Adenoma
Genes
Chromosomes
Biomarkers
Binding Sites

Keywords

  • colorectal cancer
  • CTCF
  • DNA methylation
  • Lynch syndrome
  • PTPRG

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Van Roon, E. H. J., De Miranda, N. F. C. C., Van Nieuwenhuizen, M. P., De Meijer, E. J., Van Puijenbroek, M., Yan, P. S., ... Boer, J. M. (2011). Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer. European Journal of Human Genetics, 19(3), 307-312. https://doi.org/10.1038/ejhg.2010.187

Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer. / Van Roon, Eddy H J; De Miranda, Noël F C C; Van Nieuwenhuizen, Merlijn P.; De Meijer, Emile J.; Van Puijenbroek, Marjo; Yan, Pearlly S.; Huang, Hui-ming; Van Wezel, Tom; Morreau, Hans; Boer, Judith M.

In: European Journal of Human Genetics, Vol. 19, No. 3, 03.2011, p. 307-312.

Research output: Contribution to journalArticle

Van Roon, EHJ, De Miranda, NFCC, Van Nieuwenhuizen, MP, De Meijer, EJ, Van Puijenbroek, M, Yan, PS, Huang, H, Van Wezel, T, Morreau, H & Boer, JM 2011, 'Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer', European Journal of Human Genetics, vol. 19, no. 3, pp. 307-312. https://doi.org/10.1038/ejhg.2010.187
Van Roon EHJ, De Miranda NFCC, Van Nieuwenhuizen MP, De Meijer EJ, Van Puijenbroek M, Yan PS et al. Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer. European Journal of Human Genetics. 2011 Mar;19(3):307-312. https://doi.org/10.1038/ejhg.2010.187
Van Roon, Eddy H J ; De Miranda, Noël F C C ; Van Nieuwenhuizen, Merlijn P. ; De Meijer, Emile J. ; Van Puijenbroek, Marjo ; Yan, Pearlly S. ; Huang, Hui-ming ; Van Wezel, Tom ; Morreau, Hans ; Boer, Judith M. / Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer. In: European Journal of Human Genetics. 2011 ; Vol. 19, No. 3. pp. 307-312.
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