Novel candidate colorectal cancer biomarkers identified by methylation microarray-based scanning

Yuriko Mori, Alexandru V. Olaru, Yulan Cheng, Rachana Agarwal, Jian Yang, Delgermaa Luvsanjav, Wayne Yu, Florin M. Selaru, Susan Hutfless, Mark Lazarev, John H. Kwon, Steven R. Brant, Michael R. Marohn, David F. Hutcheon, Mark D. Duncan, Ajay Goel, Stephen J. Meltzer

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

DNA hypermethylation is a common epigenetic abnormality in colorectal cancers (CRCs) and a promising class of CRC screening biomarkers. We conducted a genome-wide search for novel neoplasia-specific hypermethylation events in the colon. We applied methylation microarray analysis to identify loci hypermethylated in 17 primary CRCs relative to eight non-neoplastic colonic mucosae (NCs) from neoplasia-free subjects. These CRC-associated hypermethylation events were then individually evaluated for their ability to discriminate neoplastic from non-neoplastic cases, based on real-time quantitative methylation-specific PCR (qMSP) assays in 113 colonic tissues: 51 CRCs, nine adenomas, 19 NCs from CRC patients (CRC-NCs), and 34 NCs from neoplasia-free subjects (control NCs). A strict microarray data filtering identified 169 candidate CRC-associated hypermethylation events. Fourteen of these 169 loci were evaluated using qMSP assays. Ten of these 14 methylation events significantly distinguished CRCs from age-matched control NCs (P < 0.05 by receiver operator characteristic curve analysis); methylation of visual system homeobox 2 (VSX2) achieved the highest discriminative accuracy (83.3% sensitivity and 92.3% specificity, P < 1 × 10-6), followed by BEN domain containing 4 (BEND4), neuronal pentraxin I (NPTX1), ALX homeobox 3 (ALX3), miR-34b, glucagon-like peptide 1 receptor (GLP1R), BTG4, homer homolog 2 (HOMER2), zinc finger protein 583 (ZNF583), and gap junction protein, gamma 1 (GJC1). Adenomas were significantly discriminated from control NCs by hypermethylation of VSX2, BEND4, NPTX1, miR-34b, GLP1R, and HOMER2 (P < 0.05). CRC-NCs were significantly distinguished from control NCs by methylation of ALX3 (P < 1 × 10-4). In conclusion, systematic methylome-wide analysis has identified ten novel methylation events in neoplastic and non-neoplastic colonic mucosae from CRC patients. These potential biomarkers significantly discriminate CRC patients from controls. Thus, they merit further evaluation in stool- and circulating DNA-based CRC detection studies.

Original languageEnglish (US)
Pages (from-to)465-478
Number of pages14
JournalEndocrine-Related Cancer
Volume18
Issue number4
DOIs
StatePublished - Aug 1 2011

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

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    Mori, Y., Olaru, A. V., Cheng, Y., Agarwal, R., Yang, J., Luvsanjav, D., Yu, W., Selaru, F. M., Hutfless, S., Lazarev, M., Kwon, J. H., Brant, S. R., Marohn, M. R., Hutcheon, D. F., Duncan, M. D., Goel, A., & Meltzer, S. J. (2011). Novel candidate colorectal cancer biomarkers identified by methylation microarray-based scanning. Endocrine-Related Cancer, 18(4), 465-478. https://doi.org/10.1530/ERC-11-0083