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Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-DNA adducts, and breast cancer

Katherine D Crew1, Marilie D Gammon, Mary Beth Terry

  • 1Department of Epidemiology, Mailman School of Public Health, Columbia University, 161 Fort Washington Avenue, New York, NY 10032, USA. kd59@columbia.edu

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
|October 13, 2007
PubMed

Insights

Genetic variations in nucleotide excision repair (NER) genes may increase breast cancer risk, especially when combined with polycyclic aromatic hydrocarbon (PAH)-DNA adducts. This suggests a gene-environment interaction influencing cancer susceptibility.

Area of Science:

  • Genetics
  • Environmental Health
  • Cancer Epidemiology

Background:

  • Nucleotide excision repair (NER) pathway genes are implicated in removing DNA damage, acting as potential low-penetrance cancer susceptibility genes.
  • Previous research indicated a link between polycyclic aromatic hydrocarbon (PAH)-DNA adducts and increased breast cancer risk.
  • The role of genetic polymorphisms within NER genes in modifying this association remains to be fully elucidated.

Purpose of the Study:

  • To investigate whether polymorphisms in key NER genes (ERCC1, XPA, XPD, XPF, XPG) modify the association between PAH-DNA adducts and breast cancer risk.
  • To assess the combined effect of multiple NER gene polymorphisms on breast cancer risk in the context of PAH-DNA adduct exposure.

Main Methods:

  • A population-based breast cancer case-control study was conducted on Long Island, New York, involving 1,053 cases and 1,102 controls.
  • Genotyping was performed for polymorphisms in ERCC1, XPA, XPD, XPF, and XPG.
  • PAH-DNA adduct levels were measured, and their association with breast cancer risk was analyzed in relation to NER gene genotypes.

Main Results:

  • Carriage of at least one variant allele in the XPD gene was associated with a 25% increased odds of breast cancer.
  • The risk increase associated with homozygous variant genotypes in XPD and ERCC1 was significantly amplified in individuals with detectable PAH-DNA adducts.
  • No significant associations were observed for XPA, XPF, and XPG genotypes with breast cancer risk or PAH-DNA adduct levels. A trend of increasing breast cancer risk was observed with a higher number of high-risk NER alleles.

Conclusions:

  • Polymorphisms in NER pathway genes, particularly XPD and ERCC1, may elevate breast cancer risk, especially in the presence of detectable PAH-DNA adducts.
  • These findings suggest a gene-environment interaction where NER gene variations modify susceptibility to breast cancer induced by PAH exposure.
  • Further research into NER pathway gene polymorphisms could enhance our understanding of breast cancer etiology and identify high-risk individuals.

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