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Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters

Oncogene volume 28, pages 899–909 (2009)Cite this article

Abstract

Silencing of gene expression by aberrant cytosine methylation is a prominent feature of human tumors, including colorectal cancers. Epigenetic changes of this type play undisputed roles in cell transformation when they involve genes that safeguard genome stability, and they can also be detected in precancerous lesions and seemingly normal peritumoral tissues. We explored physiological conditions associated with aberrant promoter methylation involving two DNA-repair genes in normal colorectal mucosa. Samples of cecal, transverse colon, sigmoid and rectal mucosa collected from 100 healthy individuals undergoing screening colonoscopy were analysed for hMLH1 and MGMT promoter methylation with a quantitative PCR assay. Positivity in at least one colon segment was common in both sexes, with methylation involving 0.1–18.8% of the alleles (median=0.49%). Samples from males showed no consistent patterns for either promoter, but there were striking age- and colon segment-specific differences in the female subgroup. Here, the prevalence of hMLH1 and MGMT methylation increased significantly with age, particularly in the right colon, where there was also an age-related increase in the percentage of alleles showing hMLH1 methylation. Concomitant methylation of both promoters was also significantly more common in the right colon of women. These findings paralleled immunohistochemical patterns of hMLH1 and MGMT protein loss in an independent series of 231 colorectal cancers and were consistent with current epigenetic profiles of colorectal cancer subsets. They suggest the intriguing possibility that the epigenetic signatures of cancers may have early-stage, normal-tissue counterparts that reflect potentially important aspects of the initial carcinogenetic process.

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Abbreviations

CIMP:

CpG island methylator phenotype

COBRA:

combined bisulfite restriction analysis

MSI:

microsatellite instability

qMSP:

quantitative methylation-specific PCR

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Acknowledgements

We thank Josef Jiricny at the Institute of Molecular Cancer Research of the University of Zurich and our colleagues at the Department of Biomedicine of the University of Basel for helpful discussions and support throughout the project. We are also grateful to Patric Urfer and Christophe Kunz for critical reading of the manuscript, Ritva Haider for technical assistance, and Marian E Kent for editorial assistance. The study was supported by the Swiss National Science Foundation (to GM), the Krebsliga Zentralschweiz (to GM), the Krebsliga Beider Basel (to PS), Julius-Müller Stiftung, Zürich (to KT) and the Hanne-Liebermann Stiftung, Zürich (to KT).

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  1. M Menigatti and K Truninger: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedicine, University of Basel, Basel, Switzerland

    M Menigatti & P Schär

  2. SRO Hospital Langenthal, Langenthal, Switzerland

    K Truninger

  3. Department of Pathology, Cantonal Hospital Lucerne, Lucerne, Switzerland

    J-O Gebbers

  4. Clinic of Internal Medicine, Cantonal Hospital Altdorf, Altdorf, Switzerland

    U Marbet

  5. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

    G Marra

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  1. M Menigatti
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Correspondence to G Marra.

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

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Menigatti, M., Truninger, K., Gebbers, JO. et al. Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters. Oncogene 28, 899–909 (2009). https://doi.org/10.1038/onc.2008.444

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