Xeroderma pigmentosum complementation group C genotypes/diplotypes play no independent or interaction role with polycyclic aromatic hydrocarbons-DNA adducts for breast cancer risk

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Abstract

Xeroderma pigmentosum complementation group C (XPC) is an important DNA nuclear excision repair (NER) gene that recognises the damage caused by a variety of bulky DNA adducts. We evaluated the association of two common non-synonymous polymorphisms in XPC (Ala499Val and Lys939Gln) with breast cancer risk in the Long Island Breast Cancer Study Project (LIBCSP), a population-based case–control study. Genotyping of 1067 cases and 1110 controls was performed by a high throughput assay with fluorescence polarisation. There were no overall associations between XPC polymorphisms and breast cancer risk. A diplotype CC–CC was significantly associated with increased breast cancer risk compared with diplotype CA–CA (OR = 1.4, 95%CI: 1.0–1.9), but was not significant when compared with all other diplotypes combined (OR = 1.22, 95%CI: 0.97–1.53). No modification effects were observed for XPC genotypes by cigarette smoking status, smoking pack-years or polycyclic aromatic hydrocarbons (PAH)-DNA adducts. The increase in breast cancer risk was slightly more pronounced among women with detectable PAH-DNA adducts and carrying the diplotype CC–CC (OR = 1.6, 95%CI: 1.1–2.2) compared to women with non-detectable PAH-DNA adducts carrying other diplotypes combined, but no statistically significant interaction was observed (Pinteraction = 0.69). These data suggest that XPCs have neither independent effects nor interactions with cigarette smoking and PAH-DNA adducts for breast cancer risk. Further studies with multiple genetic polymorphisms in NER pathway are warranted.

Introduction

DNA repair plays an important role in eliminating DNA damage and maintaining genetic integrity. Xeroderma pigmentosum complementation group C (XPC) is an important DNA damage recognition protein involved in global genome DNA repair (GGR), a subclass of nucleotide excision repair (NER). The XPC protein recognises a variety of bulky DNA adducts formed by exogenous carcinogens including those found in tobacco smoke (benzo[a]pyrene (B[a]P) and other polycyclic aromatic hydrocarbons (PAHs)), and endogenous carcinogens, all of which may play a role in the pathogenesis of breast cancer.1, 2, 3, 4, 5 It binds tightly with another protein, HR23B, to form a stable XPC-HR23B complex. Recent studies identified the XPC-HR23B complex as the first protein component that recognises and binds to the damaged sites. Interestingly, defects in XPC have been associated with many types of cancer.6, 7, 8 Transgenic mice studies also revealed predisposition to many types of cancer in XPC gene knockout mice.9, 10 These results suggest that the XPC protein plays an important role in the prevention of the DNA damage-mediated cancer occurrence. Recently, polymorphisms in XPC have been studied for associations with squamous cell carcinoma of the head and neck (SCCHN), lung, bladder, colorectal and breast cancer.11, 12 The heterozygous XPC genotype, Lys939Gln, but not the homozygous Gln939Gln genotype, was significantly associated with breast cancer susceptibility in Finnish11 and Chinese populations.13 But in Caucasians, African Americans or mixed population, no similar results were observed.12, 14 Overall, the relationship between XPC polymorphisms and breast cancer risk remains unclear.

Exposure to cigarette smoke and breast cancer risk has been investigated in numerous epidemiological studies with controversial outcomes. A recently published meta-analysis found that cigarette smoking had little or no independent effect on the risk of developing breast cancer.15 This is consistent with findings in the Long Island Breast Cancer Study Project (LIBCSP).16 However, several studies have suggested that cigarette smoking may increase breast cancer risk among women who have smoked for a long time or before their first full-term pregnancy.17, 18 An increasing number of studies are also indicating that a positive association between smoking and breast cancer risk may be stronger among or limited to women with certain genotypes.19 PAH have been shown to induce mammary tumours in laboratory-based studies.20 The major exposure sources include cigarette smoke, consumption of PAH-containing foods (such as grilled and smoked foods) and air pollutants (from industrial manufacturing, fires and motor vehicle traffic). PAH-DNA adducts have been associated with a modest increase in breast cancer risk in several epidemiologic studies,21, 22, 23, 24, 25 although no apparent dose–response and substantial variations associated with sources of PAH, such as cigarette smoking or consumption of grilled and smoked foods, were observed.21, 22 A previous study indicated that workers with lower DNA repair capacity (carrying XPC-PAT+/+ genotype) had significantly increased anti-B[a]P diol epoxide-DNA adduct levels, which was significantly related with PAH exposure.26XPC polymorphisms (Arg492His, Ala499Val and Lys939Gln) were shown to modify smoking-related risk of advanced colorectal adenoma, but not bladder or breast cancer.14 Whether XPC polymorphisms modify the risk of breast cancer by interaction with exogenous carcinogens (cigarette smoking and PAH-DNA adducts) is unknown.

In the present study, we describe the distribution of genotype for two non-conservative variants of XPC at codons 499 (Ala499Val) and 939 (Lys939Gln) in a large population-based case–control study, the LIBCSP, with the aim of evaluating associations between XPC genotypes and haplotypes/diplotypes and breast cancer risk, and the modifying effects of cigarette smoking and PAH-DNA adducts.

Section snippets

Study design

The study methods of the LIBCSP had been described in detail previously.27 In brief, case eligibility included adult female residents of Nassau and Suffolk counties on Long Island, NY, who were of any age or race, who spoke English, and were newly diagnosed with in situ or invasive breast cancer between 1st August 1996, and 31st July 1997. Potentially eligible controls were frequency matched to the age distribution of the cases and identified through random digit dialing for women under age 65

Results

The frequencies of the XPC polymorphisms (Ala499Val and Lys939Gln) did not deviate significantly from the Hardy–Weinberg equilibrium (P values were 0.45 and 0.18, respectively). For the codon 499 locus, the frequencies of the CC, CT and TT genotypes were 57.2%, 37.7% and 5.1%, respectively, among the control subjects (Table 1). The corresponding frequencies among the cases were 57.9%, 36.3% and 5.8%, respectively. The frequencies of the AA, AC, and CC genotypes for the codon 939 locus were

Discussion

Although some significant results were observed in several subgroups, the present study does not support the hypothesis that genotypes or haplotype/diplotype of XPC Ala499Val and Lys939Gln have an independent aetiological role in breast cancer nor do they interact with cigarette smoking or PHA-DNA adducts. This is consistent with a recent epidemiological study indicating no relationship between XPC polymorphisms and breast cancer risk in Caucasians, African Americans or mixed population,12, 14

Conflict of interest statement

None declared.

Acknowledgements

This work is funded by U01 CA/ES66572, P30ES09089 and P30ES10126 Grants from the National Cancer Institute and the National Institute of Environmental Health Sciences, and an award from the Breast Cancer Research Foundation and gifts from private citizens.

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