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DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

Abstract

There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at ‘type A’ (ESR1, GATA5, HIC1, HPP1, SFRP1) and ‘type C’ markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. ‘Type A’ genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. ‘Type C’ methylation is more specific for neoplasia. The last five ‘type C’ markers comprise a CIMP panel. The mean ‘type A’ and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most ‘type A’ genes showed direct correlations between methylation and age (ESR1, ρ=0.66, P<0.0001), with higher methylation distally (ESR1, P<0.0001). On multivariate analysis, ‘type A’ methylation was inversely associated with colorectal adenomas (odds ratio=0.23, P<0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio=5.1, P=0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.

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Abbreviations

CIMP:

CpG island methylator phenotype

CIN:

chromosomal instability

CRC:

colorectal cancer

PMR:

percent of methylated reference

PSP:

proximal serrated polyp

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Acknowledgements

We thank the gastroenterologists and gastroenterology nurses who helped to collect samples. This study was funded by a National Health and Medical Research Council project grant (442965), a Gastroenterological Society of Australia post-graduate medical scholarship (DLW), the Royal Australasian College of Physicians Cottrell Fellowship (DLW), a Royal Brisbane and Women's Hospital Foundation Research Grant (VLW, DLW, BAL) and a Queensland Smart State PhD award (DLW).

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Correspondence to D L Worthley.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Worthley, D., Whitehall, V., Buttenshaw, R. et al. DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer. Oncogene 29, 1653–1662 (2010). https://doi.org/10.1038/onc.2009.449

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