Polymorphisms in the DNA Repair Enzyme XPD are Associated with Increased Levels of PAH–DNA Adducts in a Case-Control Study of Breast Cancer

Abstract

We present findings on the associations between DNA adduct levels in breast tissue, risk of breast cancer, and polymorphisms in the DNA repair enzyme XPD. Breast cancer cases, benign breast disease (BBD) controls, and healthy controls were enrolled. Polycyclic aromatic hydrocarbons (PAH)-DNA adduct levels were measured by immunohistochemistry in breast tissue samples from cases and BBD controls. XPD polymorphisms at codons 312 and 751 was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis using white blood cell DNA. Neither of the polymorphisms were associated with case-control status, both in comparisons of cases and BBD controls, and cases and healthy controls. XPD polymorphisms at codons 312 and 751 were associated with higher levels of PAH-DNA in tumor tissue from breast cancer cases. Subjects with an Asp/Asn or Asn/Asn polymorphic genotype in codon 312 of XPD had elevated levels of PAH-DNA adducts compared to subjects with the Asp/Asp genotype (0.55 optical density (OD) v.s. 0.33 OD, p < 0.01). PAH-DNA adducts were associated with increasing copy number of the Gln allele for the codon 751 polymorphism (p for trend <0.01). Among subjects with the Asp/Asn or Asn/Asn genotype at codon 312, adduct levels were higher in tumor tissue compared to tissue from BBD controls (0.55 OD v.s. 0.36 OD, p = 0.003). Among subjects with the Gln/Gln genotype at codon 751 adduct levels were higher in tumor tissue compared to tissue from BBD controls (0.68 OD v.s. 0.40 OD, p = 0.01). The trend of increasing PAH-DNA adduct levels with either the Asn/Asn or Gln/Gln genotype was greater in tumor tissue than the trend in BBD control tissue.

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

“…In vitro studies (11)(12)(13) show that PAHs are metabolized in human breast epithelial tissue to form PAH-DNA adducts. Previous epidemiologic studies (14,15) noted that increased levels of aromatic DNA adducts in breast tissue were associated with breast cancer risk. Methods for measuring DNA adducts in humans have become more reliable in recent years, allowing detection of even background adduct levels in environmentally exposed individuals (16).…”

“…Methods for measuring DNA adducts in humans have become more reliable in recent years, allowing detection of even background adduct levels in environmentally exposed individuals (16). PAH-DNA adduct levels reflect both exposure to PAH and possibly modulation of exposure by genetic factors, which affect carcinogen metabolism and DNA repair (15,(17)(18)(19).…”

DNA Repair Capacity-Related to Genetic Polymorphisms of DNA Repair Genes and Aflatoxin B1-Related Hepatocellular Carcinoma Among Chinese Population

“…Recent studies have showed the polymorphisms at codon 312 and 751 of XPD are correlated with DNA-adducts levels, p53 gene mutation, and cancers risk (88,94,(98)(99)(100). In a hospital-based case-control study in Guangxi (39), we found that the variant XPD codon 751 genotypes (namely Lys/Gln and Gln/Gln) detected by TaqMan-MGB PCR was significantly different between controls (26.3% and 8.6% for Lys/Gln and Gln/Gln, respectively) and HCC cases (35.9% and 20.1% for Lys/Gln and Gln/Gln, respectively, P < 0.001).…”

A Critical Evaluation of DNA Adducts as Biological Markers for Human Exposure to Polycyclic Aromatic Compounds

“…Currently, however, genetic polymorphisms are promising, but still cannot completely identify individuals at higher cancer risk. Therefore, other factors that could affect adduct formation in vivo should be taken into account, like gender (Ryberg et al, 1994), body composition (Godschalk et al, 2002), diet (Palli et al, 2000) and DNA repair efficiency (Tang et al, 2002). Since the variation in adduct formation within or between individuals can be high, the question remains whether aromatic-DNA adduct levels in WBC can be applied to discriminate between individuals in various exposure or risk groups.…”