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Carcinogenesis Advance Access published online on May 21, 2008
Carcinogenesis, doi:10.1093/carcin/bgn121
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Haplotypes of DNMT1 and DNMT3B are associated with mutagen sensitivity induced by benzo[a]pyrene diol epoxide among smokers

Shuguang Leng1, Christine A. Stidley2, Amanda Bernauer1, Maria A. Picchi1, Xin Sheng3, Melissa A. Frasco3, David Van Den Berg3, Frank D. Gilliland3, Richard E. Crowell2,4 and Steven A. Belinsky1,*

1 Lung Cancer Program, 2425 Ridgecrest Dr. SE, Lovelace Respiratory Research Institute, Albuquerque, NM 87108
2 Department of Internal Medicine, University of New Mexico, 2500 Lomas Boulevard, Albuquerque, NM 87131
3 Keck School of Medicine, 1540 Alcazar Street, University of Southern California, Los Angeles, CA 90033
4 New Mexico VA Health Care System, 1501 San Pedro SE, Albuquerque, NM 87108

*To whom correspondence should be addressed. Tel: +1 505 348 9465; Fax: +1 505 348 8567; Email: sbelinsk{at}LRRI.org

The mutagen sensitivity assay is an in vitro measure of DNA repair capacity used to evaluate intrinsic susceptibility for cancer. The high heritability of mutagen sensitivity to different mutagens validates the use of this phenotype to predict cancer susceptibility. However, genetic determinants of mutagen sensitivity have not been fully characterized. Recently, several studies found that three major cytosine DNA methyltransferases (DNMTs), especially DNMT1, have a direct role in the DNA damage response, independent of their methyltransferase activity. This study evaluated the hypothesis that sequence variants in DNMT1, DNMT3A, and DNMT3B are associated with mutagen sensitivity induced by the tobacco carcinogen benzo[a]pyrene diolepoxide (BPDE) in 278 cancer-free smokers. Single nucleotide polymorphisms (SNPs) (n = 134) dispersed over the entire gene and regulatory regions of these DNMTs were genotyped by the Illumina Golden Gate Assay. DNA sequence variation in the DNMT1 and DNMT3B loci was globally associated with breaks per cell (P < 0.04 for both). No global association between DNMT3A and breaks per cell was seen (P = 0.09). Two haplotypes in block1 of DNMT1 (H284) and 3B (H70) were associated with 16% and 24% increase in breaks per cell, respectively. Subjects with three or four adverse haplotypes of both DNMT1 and 3B had a 50% elevation in mean level of breaks per cell compared to persons without adverse alleles (P = 0.004). The association between sequence variants of DNMT1 and 3B, and mutagen sensitivity induced by BPDE supports the involvement of these DNMTs in protecting the cell from DNA damage.

Key Words: DNA methyltransferase • mutagen sensitivity • single nucleotide polymorphism • genetic association study • haplotype

Received March 12, 2008; revised May 8, 2008; accepted May 8, 2008.


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