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Carcinogenesis Advance Access published online on March 13, 2008
Carcinogenesis, doi:10.1093/carcin/bgn074
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer

Stefan de Vogel1,2, Brenda WC Bongaerts1, Kim AD Wouters2, Arnold DM Kester3, Leo J Schouten1, Anton FPM de Goeij2, Adriaan P de Bruïne2, R Alexandra Goldbohm4, Piet A van den Brandt1, Manon van Engeland2 and Matty P Weijenberg1

1 Department of Epidemiology, GROW - School for Oncology and Developmental Biology
2 Department of Pathology, Maastricht University, Maastricht, the Netherlands
3 Department of Statistics, Maastricht University, Maastricht, the Netherlands
4 TNO Quality of Life, Department of Prevention and Health, Leiden, the Netherlands

Correspondence: Stefan de Vogel, Dept. of Epidemiology, Maastricht University, PO Box 616, 6200 MD, Maastricht, Fax: +31-43-3884128, E-mail: stefan.devogel{at}epid.unimaas.nl

Intake of dietary factors that serve as methyl group donors may influence promoter hypermethylation in colorectal carcinogenesis. We investigated whether dietary folate, vitamins B2 and B6, methionine and alcohol were associated with MLH1 hypermethylation, and the related molecular phenotypes of MLH1 protein expression, microsatellite instability (MSI) and BRAF mutations in patients with colorectal carcinomas.

Within the Netherlands Cohort Study on diet and cancer (n=120,852), 648 cases (367 men and 281 women) and 4,059 subcohort members were available for data analyses from a follow-up period between 2.3 and 7.3 years after baseline. Gender-specific adjusted incidence rate ratios (RR) were calculated over categories of dietary intake in case-cohort analyses.

The intakes of folate, vitamin B2, methionine and alcohol were not associated with risk of tumors showing MLH1 hypermethylation, those lacking MLH1 protein expression, or with MSI. Among men, we observed strong positive associations between folate and BRAF-mutated tumors (RR=3.04, for the highest versus lowest tertile of intake, Ptrend=0.03), and between vitamin B6 and tumors showing MLH1 hypermethylation (highest vs. lowest tertile: RR=3.23, Ptrend=0.03). Among women, the relative risks of tumors with BRAF mutations or MLH1 hypermethylation were also increased in the highest tertiles of folate and vitamin B6 intake respectively, but these did not reach statistical significance.

The positive associations between folate intake and tumors harboring BRAF mutations and between vitamin B6 intake and those showing MLH1 hypermethylation were most pronounced among men, and may suggest that these vitamins enhance CRC risk through genetic as well as epigenetic aberrations.

Key Words: Methyl donors • promoter hypermethylation • MLH1 • CRC

Received January 25, 2008; revised March 3, 2008; accepted March 6, 2008.


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