Xeroderma pigmentosum complementation group C genotypes/diplotypes play no independent or interaction role with polycyclic aromatic hydrocarbons-DNA adducts for breast cancer risk (original) (raw)
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Cancer Epidemiology, Biomarkers & Prevention
DNA repair is essential to an individual's ability to respond to damage caused by environmental carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to environmental exposures. XPD, a gene involved in nucleotide excision repair, may influence individual DNA repair capacity particularly of bulky adducts. Using a population-based breast cancer case-control study that was specifically conducted to examine markers of environmental exposures, such as polycyclic aromatic hydrocarbons (PAH), on Long Island, NY, we examined whether XPD genotype modified the associations among PAH-DNA adducts, cigarette smoking, and breast cancer risk. Specifically, we examined the XPD polymorphism at exon 23, position 751 in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele (Lys/Gln or Gln/Gln) was associated with a 20% increase in risk of breast cancer [odds ratio (OR), 1.21; 95% confidence ...
PAH–DNA Adducts, Cigarette Smoking, GST Polymorphisms, and Breast Cancer Risk
Environmental Health Perspectives, 2008
Background: Polycyclic aromatic hydrocarbons (PAHs) may increase breast cancer risk, and the association may be modified by inherited differences in deactivation of PAH intermediates by glutathione S-transferases (GSTs). Few breast cancer studies have investigated the joint effects of multiple GSTs and a PAH biomarker. oBjective: We estimated the breast cancer risk associated with multiple polymorphisms in the GST gene (GSTA1, GSTM1, GSTP1, and GSTT1) and the interaction with PAH-DNA adducts and cigarette smoking. Methods: We conducted unconditional logistic regression using data from a population-based sample of women (cases/controls, respectively): GST polymorphisms were genotyped using polymerase chain reaction and matrix-assisted laser desorption/ionization time-of-flight assays (n = 926 of 916), PAH-DNA adduct blood levels were measured by competitive enzyme-linked immunosorbent assay (n = 873 of 941), and smoking status was assessed by in-person questionnaires (n = 943 of 973). results: Odds ratios for joint effects on breast cancer risk among women with at least three variant alleles were 1.56 [95% confidence interval (CI), 1.13-2.16] for detectable PAH-DNA adducts and 0.93 (95% CI, 0.56-1.56) for no detectable adducts; corresponding odds ratios for three or more variants were 1.18 (95% CI, 0.82-1.69) for ever smokers and 1.44 (95% CI, 0.97-2.14) for never smokers. Neither interaction was statistically significant (p = 0.43 and 0.62, respectively). conclusion: We found little statistical evidence that PAHs interacted with GSTT1, GSTM1, GSTP1, and GSTA1 polymorphisms to further increase breast cancer risk.
Breast Cancer Research, 2005
The gene XRCC1 (X-ray repair crosscomplementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA.
Breast Cancer Research and Treatment, 2002
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 of the XRCC1 and XPD Genes and Breast Cancer Risk: A Case-Control Study
Pathology & Oncology Research, 2008
The purpose of this case control study was to evaluate the role of X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) genotypes as genetic indicators of susceptibility to breast cancer (BC). We analysed DNA samples from 114 breast cancer patients and 113 control subjects using polymerase chain reaction-restriction fragment length polymorphism. For the single nucleotide polymorphisms in XRCC1 exon 10 (Arg399Gln, G/A) and XPD exon 23 (Lys751Gln, A/C), no remarkable differences for genotype distribution and allele frequencies were observed between BC group and control group in the study. The genotype frequency for homozygote A/A in XPD exon 6 (Arg156Arg, C/A) were significantly different between BC and control groups (P<0.0001, odds ratio=2.14; 95% confidence interval 1.44-3.17). The data indicate a possible role for XPD (Arg156Arg, C/A) polymorphisms in BC susceptibility.
The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk
Carcinogenesis, 2002
The DNA repair protein xeroderma pigmentosum complementation group D (XPD) is involved in the nucleotide excision repair of DNA lesions induced by many tobacco and environmental carcinogens. In order to study the functional impact of the common polymorphisms in XPD exon 10 (G > A, Asp312Asn) and exon 23 (A > C, Lys751Gln), we have genotyped 185 Swedish lung cancer cases (97 smokers and 88 never-smokers) and 162 matched population controls (83 smokers and 79 never-smokers). Presence of one or two variant alleles was associated with increased risk for lung cancer among never-smokers only, in particular younger (<70 years) never-smokers [odds ratio (OR) ⍧ 2.6, 95% confidence interval (CI) ϭ 1.1-6.5 for exon 10; OR ⍧ 3.2, 95% CI ⍧ 1.3-8.0 for exon 23, adjusted for age, gender and environmental tobacco smoke]. Aromatic DNA adduct level (AL) in peripheral lymphocytes was found to be similar between cases and controls, but significantly increased by current or recent smoking. Overall, there was a significant trend for increasing AL with increasing number of variant alleles in exon 10 (P ⍧ 0.02) or in exon 23 (P ⍧ 0.001). In addition, subjects with the combined exon 10 AA and exon 23 CC genotype showed a significantly higher AL compared with all those with any of the other genotypes (P ϭ 0.02). We conclude that the XPD variant alleles may be associated with reduced repair of aromatic DNA adducts in general and increased lung cancer risk among never-smokers. Abbreviations: AL, adduct level; CI, confidence interval; ETS, environmental tobacco smoke; NER, nucleotide excision repair; OR, odds ratio; PAH, polycyclic aromatic hydrocarbons; XPD, xeroderma pigmentosum complementation group D.
XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects
DNA repair genes have an important role in protecting individuals from cancer-causing agents. Polymorphisms in several DNA repair genes have been identified and individuals with non-dramatic reductions in the capacity to repair DNA damage are observed in the population, but the impact of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. In 308 healthy Italian individuals belonging to the prospective European project EPIC, we have investigated the relationship between DNA damage, as measured by 32 P-DNA adduct levels, and three genetic polymorphisms in different repair genes: XRCC1-Arg399Gln (exon 10), XRCC3-Thr241Met (exon 7) and XPD-Lys751Gln (exon 23). DNA adduct levels were measured as relative adduct level (RAL) per 10 9 normal nucleotides by DNA 32 P-post-labelling assay in white blood cells from peripheral blood. Genotyping was performed by PCR-RFLP analysis. The XRCC3-241Met variant was significantly associated with higher DNA adduct levels, whereas XRCC1-399Gln and XPD-751Gln were associated with higher DNA adduct levels only in never-smokers. XRCC3-241Met homozygotes had an average DNA adduct level of 11.44 ⍨ 1.48 (⍨SE) compared with 7.69 ⍨ 0.88 in Thr/Met heterozygotes and 6.94 ⍨ 1.11 in Thr/Thr homozygotes (F ⍧ 3.206, P ⍧ 0.042). Never-smoking XRCC1-399Gln homozygotes had an average DNA adduct level of 15.60 ⍨ 5.42 compared with 6.16 ⍨ 0.97 in Gln/ Arg heterozygotes and 6.78 ⍨ 1.10 in Arg/Arg homozygotes (F ⍧ 5.237, P ⍧ 0.007). A significant odds ratio (3.81, 95% CI 1.02-14.16) to have DNA adduct levels above median value was observed for XPD-751Gln versus XPD-751Lys never-smoking homozygotes after adjustment for several confounders. These data show that all the analysed polymorphisms could result in deficient DNA repair and Abbreviations: BER, base excision repair; EPIC, European Prospective Investigation into Cancer and Nutrition; NER, nucleotide excision repair; OR, odds ratio; RAL, relative adduct level; SE, standard error; WBC, white blood cells; XPD, xeroderma pigmentosum-D gene; XRCC 1-3, X-ray repair cross complementing groups 1-3.
Clinical Breast Cancer, 2020
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Carcinogenesis, 2000
A number of polycyclic aromatic hydrocarbons (PAH) are widespread environmental contaminants that cause mammary cancer experimentally. We investigated whether exposure and susceptibility to PAH, as measured by PAH-DNA adducts in breast tissue, are associated with human breast cancer. We carried out a hospital-based case-control study using immunohistochemical methods to analyze PAH-DNA adducts in tumor and nontumor breast tissue from cases and benign breast tissue from controls. The subjects were white, African-American and Latina women without prior cancer or treatment, including 119 women with breast cancer and 108 with benign breast disease without atypia. PAH-DNA adducts measured in breast tumor tissue of 100 cases and in normal tissue from 105 controls were significantly associated with breast cancer (OR⍧4.43, 96% CI 1.09-18.01) after controlling for known breast cancer risk factors and current active and passive smoking, and dietary PAH. There was substantial interindividual (17-fold) variability in adducts overall, with 27% of cases and 13% of controls having elevated adducts. The odds ratio for elevated adducts in tumor tissue compared with control tissue was 2.56 (1.05-6.24), after controlling for potential confounders. Adduct levels in tumor tissue did not vary by stage or tumor size. Among 86 cases with paired tumor and nontumor tissue, adducts levels in these two tissues were highly correlated (r⍧0.56, P<0.001). However, the corresponding associations between case-control status and adducts measured in nontumor tissue from 90 cases and in normal tissue from 105 controls were positive but not statistically significant. Overall, neither active nor passive smoking, or dietary PAH were significantly associated with PAH-DNA adducts or breast cancer casecontrol status. These results suggest that genetic damage reflecting individual exposure and susceptibility to PAH may play a role in breast cancer; but more research is needed to determine whether the findings are relevant to causation or progression of breast cancer.
XPC polymorphisms and lung cancer risk
International Journal of Cancer, 2005
Polymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individual's susceptibility to smoking-related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (–449G→C, –371G→A, –27G→C, Val499Arg, PAT–/+, IVS11-5C→A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency-matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined –27CG+CC genotype was associated with a significantly increased risk for overall lung cancer compared to the –27GG genotype (adjusted OR = 1.97, 95% CI 1.22–3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the –371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined –371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09–4.00, p = 0.03). The PAT–/+, IVS11-5C→A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29–0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36–1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35–0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11-5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37–0.85, p = 0.007 and Bonferroni-corrected p = 0.049), whereas haplotype 5 (1122111) containing the –27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41–5.87, p = 0.004 and Bonferroni-corrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer. © 2005 Wiley-Liss, Inc.