Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-DNA adducts, and breast cancer risk.
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 (Asp(312)Asn in exon 10), XPF (Arg(415)Gln in exon 8), and XPG (Asp(1104)His 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.
Crew
Katherine D
KD
Department of Epidemiology, Mailman School of Public Health, Columbia University, 161 Fort Washington Avenue, New York, NY 10032, USA. kd59@columbia.edu
Gammon
Marilie D
MD
Terry
Mary Beth
MB
Zhang
Fang Fang
FF
Zablotska
Lydia B
LB
Agrawal
Meenakshi
M
Shen
Jing
J
Long
Chang-Min
CM
Eng
Sybil M
SM
Sagiv
Sharon K
SK
Teitelbaum
Susan L
SL
Neugut
Alfred I
AI
Santella
Regina M
RM
D000328:Adult; D000368:Aged; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D018736:DNA Adducts / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D009518:New York; D016017:Odds Ratio; D011084:Polycyclic Aromatic Hydrocarbons; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
D018736:DNA Adducts; D004268:DNA-Binding Proteins; D011084:Polycyclic Aromatic Hydrocarbons; D051760:Xeroderma Pigmentosum Group A Protein; C095911:polycyclic aromatic hydrocarbons-DNA adduct; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human