Genome-scale discovery of DNA-methylation biomarkers for blood-based detection of colorectal cancer

There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA methylation biomarkers for blood-based detection of colorectal cancer. We used DNA methylation data from 7...

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Bibliographic Details
Published in:	PloS one Vol. 7; no. 11; p. e50266
Main Authors:	Lange, Christopher P E, Campan, Mihaela, Hinoue, Toshinori, Schmitz, Roderick F, van der Meulen-de Jong, Andrea E, Slingerland, Hilde, Kok, Peter J M J, van Dijk, Cornelis M, Weisenberger, Daniel J, Shen, Hui, Tollenaar, Robertus A E M, Laird, Peter W
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 28-11-2012 Public Library of Science (PLoS)
Subjects:	Adult Aged Biological markers Biology Biomarkers Biomarkers, Tumor - metabolism Blood Blood tests Breast cancer Cancer Cancer diagnosis Cancer genetics Cancer research Cancer therapies Carcinoembryonic antigen Case-Control Studies Cell Line, Tumor Colon Colonoscopy Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - blood Colorectal Neoplasms - diagnosis Colorectal Neoplasms - genetics CpG Islands Deoxyribonucleic acid Disease DNA DNA - genetics DNA Methylation Endoscopy Epigenetics Female Gastroenterology Gastrointestinal diseases Genetic aspects Genetic Markers - genetics Genome, Human Genomes Genomics Health aspects Hepatology Hospitals Humans Inflammatory bowel disease Male Medical prognosis Medical research Medicine Methylation Middle Aged Optimization Plasma Studies Surgery Surveillance Tumors Los Angeles California Netherlands California United States > US
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Summary:	There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA methylation biomarkers for blood-based detection of colorectal cancer. We used DNA methylation data from 711 colorectal tumors, 53 matched adjacent-normal colonic tissue samples, 286 healthy blood samples and 4,201 tumor samples of 15 different cancer types. DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively. We first performed a multistep marker selection to identify candidate markers with high methylation across all colorectal tumors while harboring low methylation in healthy samples and other cancer types. We then used pre-therapeutic plasma and serum samples from 107 colorectal cancer patients and 98 controls without colorectal cancer, confirmed by colonoscopy, to verify candidate markers. We selected two markers for further evaluation: methylated THBD (THBD-M) and methylated C9orf50 (C9orf50-M). When tested on clinical plasma and serum samples these markers outperformed carcinoembryonic antigen (CEA) serum measurement and resulted in a high sensitive and specific test performance for early colorectal cancer detection. Our systematic marker discovery and verification study for blood-based DNA methylation markers resulted in two novel colorectal cancer biomarkers, THBD-M and C9orf50-M. THBD-M in particular showed promising performance in clinical samples, justifying its further optimization and clinical testing.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors would like to declare that P.W. Laird holds the following issued patents on the MethyLight technology (“Process for High Throughput DNA Methylation Analysis”; U.S. Patent # 6,331,393; Date Filed: May 14, 1999; Date of Issue: December 18, 2001. “Process for High Throughput DNA Methylation Analysis”; U.S. Patent # 7,112,404; Date Filed: December 10, 2001; Date of Issue: September 26, 2006. “Process for High Throughput DNA Methylation Analysis”; Date Filed: December 10, 2001; Date of Issue: June 30, 2009), which have been licensed to Epigenomics AG. In addition, P.W. Laird, D.J. Weisenberger, and M. Campan are named as inventors on the following pending patent application for the Digital MethyLight technology (“DNA Methylation Analysis by Digital Bisulfite Genomic Sequencing and Digital MethyLight”; Pub App No: 20080254474; Date Filed: April 14, 2008). D.J. Weisenberger is a consultant for Zymo Research. There are no further patents, products in development or marketed products to declare. This does not alter the authors‚ adherence to all the PLOS ONE policies on sharing data and materials. Conceived and designed the experiments: CPEL MC DJW PWL. Performed the experiments: CPEL MC TH HS. Analyzed the data: CPEL MC TH HS PWL. Contributed reagents/materials/analysis tools: CPEL RFS AEMJ HS PJMJK CMD RAEMT PWL. Wrote the paper: CPEL.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0050266