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Polymorphisms in Nucleotide Excision Repair Genes, Polycyclic Aromatic Hydrocarbon-DNA Adducts, and Breast Cancer Risk

Departments of ¹ Epidemiology and ² Environmental Health Sciences, Mailman School of Public Health and ³ Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University; ⁴ Global Epidemiology, Pfizer, Inc.; ⁵ Department of Community and Preventive Medicine, Mt. Sinai School of Medicine, New York, New York and ⁶ Department of Epidemiology, University of North Carolina, School of Public Health, Chapel Hill, North Carolina

Requests for reprints: Katherine D. Crew, Columbia University, 161 Fort Washington Avenue, New York, NY 10032. Phone: 212-305-1732: Fax: 212-305-0178. E-mail: kd59{at}columbia.edu

Genes involved in the nucleotide excision repair (NER) pathway, which removes bulky DNA adducts, are potential low-penetrance cancer susceptibility genes. We recently reported an association between detectable polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer risk. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in NER genes modified the association between PAH-DNA adducts and breast cancer risk. We examined polymorphisms in ERCC1 (3'-untranslated region 8092C/A), XPA (5'-untranslated region –4G/A), XPD (Asp³¹²Asn in exon 10), XPF (Arg⁴¹⁵Gln in exon 8), and XPG (Asp¹¹⁰⁴His in exon 15) in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele in XPD was associated with a 25% increase in the odds ratio [OR, 1.25; 95% confidence interval (95% CI), 1.04-1.50] for breast cancer. The increase associated with homozygosity of the variant alleles for XPD and ERCC1 was stronger among those with detectable PAH-DNA adduct levels (OR, 1.83; 95% CI, 1.22-2.76 and OR, 1.92; 95% CI, 1.14-3.25 for detectable versus nondetectable adducts and homozygous wild-type genotype for XPD and ERCC1, respectively). We found no association between XPA, XPF, and XPG genotypes, PAH-DNA adducts, and breast cancer risk. When we combined genotypes for these NER pathway genes, there was a significant trend for increasing breast cancer risk with increasing number of putative high-risk alleles. Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in NER pathway genes and detectable PAH-DNA adducts. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2033–41)

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