XPC Polymorphisms Research Articles

A comprehensive haplotype analysis of the XPC genomic sequence reveals a cluster of genetic variants associated with sensitivity to tobacco-smoke mutagens.

The impact of single-nucleotide polymorphisms (SNPs) of the DNA repair gene XPC on DNA repair capacity (DRC) and genotoxicity has not been comprehensively determined. We constructed a comprehensive haplotype map encompassing all common XPC SNPs and evaluated the effect of Bayesian-inferred haplotypes on DNA damage associated with tobacco smoking, using chromosome aberrations (CA) as a biomarker. We also used the mutagen-sensitivity assay, in which mutagen-induced CA in cultured lymphocytes are determined, to evaluate the haplotype effects on DRC. We hypothesized that if certain XPC haplotypes have functional effects, a correlation between these haplotypes and baseline and/or mutagen-induced CA would exist. Using HapMap and single nucleotide polymorphism (dbSNP) databases, we identified 92 SNPs, of which 35 had minor allele frequencies >or= 0.05. Bayesian inference and subsequent phylogenetic analysis identified 21 unique haplotypes, which segregated into six distinct phylogenetically grouped haplotypes (PGHs A-F). A SNP tagging approach used identified 11 tagSNPs representing these 35 SNPs (r(2) = 0.80). We utilized these tagSNPs to genotype a population of smokers matched to nonsmokers (n = 123). Haplotypes for each individual were reconstituted and PGH designations were assigned. Relationships between XPC haplotypes and baseline and/or mutagen-induced CA were then evaluated. We observed significant interaction among smoking and PGH-C (p = 0.046) for baseline CA where baseline CA was 3.5 times higher in smokers compared to nonsmokers. Significant interactions among smoking and PGH-D (p = 0.023) and PGH-F (p = 0.007) for mutagen-induced CA frequencies were also observed. These data indicate that certain XPC haplotypes significantly alter CA and DRC in smokers and, thus, can contribute to cancer risk.

Modulation of nucleotide excision repair in human lymphocytes by genetic and dietary factors

Gene-environment interactions determine inter-individual variations in nucleotide excision repair (NER) capacity. Oxidative stress was previously found to inhibit NER, thus supplementation with dietary antioxidants could prevent this inhibition, especially in genetically susceptible subjects. To study the effects of genetic polymorphisms in NER-related genes and dietary intake of antioxidants on an individual's NER capacity, lymphocytes of 168 subjects were isolated before and after a 4-week blueberry and apple juice intervention. Twelve genetic polymorphisms in NER genes XPA, XPC, ERCC1, ERCC2, ERCC5, ERCC6 and RAD23B were assessed by multiplex PCR with single base extension. Based on specific genotype combinations, a subset of individuals (n 36) was selected for phenotypical assessment of NER capacity, which was significantly affected by the total sum of low-activity alleles (P = 0.027). The single polymorphism XPA G23A was the strongest predictor of NER capacity (P = 0.002); carriers of low-activity alleles AA had about three times lower NER capacity than XPA GG carriers. NER capacity assessed before and after intervention correlated significantly (R(2) 0.69; P < 0.001), indicating that inter-individual differences in NER capacity are maintained over 4 weeks. Although the intervention increased plasma trolox equivalent antioxidant capacity from 791 (SE 6.61) to 805 (SE 7.90) microm (P = 0.032), on average it did not affect NER capacity. Nonetheless, carriers of twelve or more low-activity alleles seemed to benefit from the intervention (P = 0.013). Among these, carriers of the variant allele for RAD23B Ala249Val showed improved NER capacity upon intervention (P = 0.020). In conclusion, improved NER capacity upon dietary intervention was detected in individuals carrying multiple low-activity alleles. The XPA G23A polymorphism might be a predictor for NER capacity.

Correlation of DNA repair genetic polymorphisms and non muscle-invasive bladder cancer risk

Objective To investigate the relationship between non muscle-invasive bladder can-cer and polymorphisms of DNA repair genes among Han nationality in Shanghai. Methods From January 2006 to June 2008, 94 patients with non muscle-invasive bladder cancer and 304 controls were enrolled. Known single nucleotide polymorphism(SNP) in the XPC, XPG, XRCC1 genes were detec-ted by TaqMan real-time PCR. After adjusted for age, sex, and smoking, interaction effects of the genotypes and non muscle-invasive bladder cancer risk, genotypes and clinical and pathological features of bladder cancer were analyzed using unconditional Logistic regression. Results After adjusted for age, sex, and smoking, the XPC 939 Lys/Gln, XPC 939Gin/Gin genotype and XPG 1104 Asp/His, XPG 1104 His/His genotype were more frequent in patients with non muscle-invasive bladder cancer, adjusted OR=1.89, 95%CI 1.14-3. 23 and OR=1.07,95%CI 0.86-1.87, respectively. The XRCC1 Arg399Gln polymorphisms were not significantly associated with non muscle-invasive bladder cancer, adjusted OR= 1.15, 95% CI 0.55-2.40. There were no significant associations between tumor clinical and pathological features in patients who possessed either the XPC or XPG polymor-phisms (P>0.05). Conclusion XPC Lys939Gln and XPG Asp1104His may modulate non muscle-invasive bladder cancer risk among Han nationality in Shanghai. Key words: Polymorphism, single nucleotide; DNA repair; Bladder neoplasms; Disease susceptibility

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio=4.9, 95% confidence interval=1.64-14.54, adjusted P-value=0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median=184 months, compared with 240 months for TT homozygotes; hazard ratio=5.76, 95% confidence interval=1.30-25.55; P-value=0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value= 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.

Stroke Risk Profiles

The impact of risk factors can be summarized in a quantitative way to provide a multivariate assessment of an individual’s probability of a stroke in a specified time period, usually 10 years. Multivariable risk factor modeling really was begun in Framingham in the 1960s and evolved to the present. Specific risk profiles for a number of cardiovascular disease (CVD) outcomes can be found at www.framinghamheartstudy.org, including the stroke risk profile published in 19911 with a modification for antihypertensive medication interaction in women.2 The ability to synthesize and summarize in a quantitative manner the additive impact of an array of CVD risk factors provides a way to identify persons at substantial elevated risk even if they have multiple borderline or slightly elevated risk factor levels. These persons whose significantly increased probability of stroke …

Micronuclei and chromosomal aberrations, important markers of ageing: Possible association with XPC and XPD polymorphisms

Life expectancy in central-Eastern European countries is more than 10 years lower compared with Northern or Western countries which could be the result of complex factors including genetics, nutrition and life style. We conducted a molecular epidemiological study with the aim of investigating links between DNA instability, genetic polymorphisms in nucleotide excision repair genes and ageing. Two groups—151 young people (78 women and 73 men) aged 20–25, and 140 elderly subjects (101 women and 39 men), aged 65–70 have been investigated. Results show elevated levels of micronuclei and chromosome aberrations in elderly compared with young groups ( P < 0.001); women had more micronuclei than men ( P < 0.001). Micronucleus frequencies were influenced by age ( P < 0.001). In the group of elderly people those who were homozygous with C/ C or A/ A in XPC IVS11 had more aberrant cells compared with C/ A heterozygotes ( P = 0.04). When the dependent variable was break per cell, elderly people A/ A homozygous in XPC IVS11 had more breaks per cell compared with C/ A heterozygous or C/ C homozygous subjects ( P = 0.03). Significantly the most chromatid breaks were found in elderly people both Lys/ Lys homozygous in the XPD Lys751 Gln genotype and C/ C or A/ A homozygous in the XPC IVS11 genotype ( P < 0.05). A General Linear Model analysis shows a statistically significant effect of interactions between age, sex and genotype XPC IVS11 ( P = 0.001) and age, sex and genotype XPCin9 ( P = 0.007) on number of chromatid breaks. When we divided people into two subgroups (without mutant allele and with one or two mutant alleles) we found a significantly higher number of chromosome exchanges in people with one or two variant polymorphism XPCin9 ( P = 0.04), XPC IVS11 ( P = 0.004) or XPCex15 ( P = 0.001). Level of cells with micronuclei was influenced by polymorphisms XPD Lys751 Gln ( P = 0.03). However, we did not find any relationship between XPA polymorphism and studied cytogenetic biomarkers.

XPC polymorphisms play a role in tissue-specific carcinogenesis: a meta-analysis

XPC participates in the initial recognition of DNA damage during the DNA nucleotide excision repair process in global genomic repair. Polymorphisms in XPC gene have been analyzed in case-control studies to assess the cancer risk attributed to these variants, but results are conflicting. To clarify the impact of XPC polymorphisms in cancer risk, we performed a meta-analysis that included 33 published case-control studies. Polymorphisms analyzed were Lys939Gln and Ala499Val. The overall summary odds ratio (OR) for the associations of the 939Gln/Gln genotype with risk of cancer was 1.01 (95% confidence interval (95% CI): 0.94-1.09), but there were statistically significant associations for lung cancer, observed for the recessive genetic model (Lys/Lys+Lys/Gln vs Gln/Gln), (OR 1.30; 95% CI: 1.113-1.53), whereas for breast cancer a reduced but nonsignificant risk was observed for the same model (OR 0.87; 95% CI: 0.74-1.01). The results for Ala499Val showed a significant overall increase in cancer risk (OR 1.15; 95% CI: 1.02-1.31), and for bladder cancer in both the simple genetic model (Ala/Ala vs Val/Val) (OR 1.30; 95% CI: 1.04-1.61) and the recessive genetic model (Ala/Ala+Ala/Val vs Val/Val) (OR 1.32; 95% CI: 1.06-1.63). Our meta-analysis supports that polymorphisms in XPC may represent low-penetrance susceptibility gene variants for breast, bladder, head and neck, and lung cancer. XPC is a good candidate for large-scale epidemiological case-control studies that may lead to improvement in the management of highly prevalent cancers.

Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

XPC, a key protein in the nucleotide excision repair (NER) pathway, recognizes damaged DNA and initiates NER. Genetic variations in the XPC gene might be associated with altered DNA repair capacities (DRC). In this study, we genotyped three XPC polymorphisms, Ala499Val (C → T), PAT (−/+) and Lys939Gln (A → C), and measured the DNA damage/DRC by alkaline comet assay challenged by BPDE and gamma-radiation in 476 healthy subjects. We also evaluated the associations between DNA damage/DRC and genotypes of XPC polymorphisms. Compared with the XPC Lys939Gln homozygous wild type (AA) subjects, subjects with the variant alleles (AC and CC) had significantly higher DNA damages induced by BPDE (Median and 95% confidence interval [CI]: 3.16 (3.01–3.44) vs. 2.88 (2.51–3.05), P = 0.01), and gamma-radiation (4.18 (3.94–4.44) vs. 3.71 (3.49–4.04), P = 0.01). However, subjects with the variant alleles (CT and TT) of Ala499Val exhibited a 8.6% and 13.1% decrease in DNA damages induced by BPDE ( P = 0.05) and gamma-radiation ( P = 0.001), respectively. Significant correlations were found between genotypes and induced DNA damages in XPC Lys939Gln (For BPDE: R = 0.12, P = 0.01; for gamma-radiation: R = 0.094, P = 0.046) and Ala499Val (For BPDE: R = −0.11, P = 0.03; for gamma-radiation: R = −0.16, P = 0.0009). The haplotypes “T-A” (in the order of Ala499Val-PAT-Lys939Gln) was associated with the lowest DNA damages. Our results suggested that the DRC of host cells might be modulated by specific XPC polymorphisms.

Mutagen Sensitivity and Genetic Variants in Nucleotide Excision Repair Pathway: Genotype-Phenotype Correlation

The rationale behind gene-disease association studies is that genetic variants (polymorphisms) result in alterations in intermediate phenotypes. However, genotype-phenotype correlations have not been established for most polymorphisms. In this study, we correlated genotype data of genes involved in the nucleotide excision repair pathway with mutagen sensitivity phenotype, quantified by benzo(a)pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocytes in 422 healthy subjects recruited into a twin study that included 138 pairs of monozygotic twins, 51 pairs of dizygotic twins, and 44 siblings. Among a panel of single nucleotide polymorphisms examined, we found that BPDE sensitivity was modified by individual polymorphisms in XPC, RAD23B, and XPA genes. Specific haplotypes and diplotypes of XPC also modified BPDE sensitivity profiles. In addition, a more consistent and stronger correlation was observed between mutagen sensitivity phenotype and the combination of multiple polymorphisms in the nucleotide excision repair pathway. Specifically, when XPC-PAT, XPC Lys939Gln, XPA A23G, and RAD23B Val249Ala were analyzed together, we observed a significant dose-response relationship between increasing mutagen sensitivity with increasing number of adverse alleles: mutagen sensitivity for those carrying zero to two, three to five, and six or more adverse alleles were 0.64, 0.68, and 1.06, respectively (P for trend = 0.008), and the results remained significant after adjusting for multiple comparisons. Using individuals carrying zero to two adverse alleles as the reference group, the risks of being mutagen sensitive (mutagen sensitivity values greater than the median) were 1.05 (95% confidence interval, 0.68-1.64) and 4.48 (95% confidence interval, 1.21-16.61) for those carrying three to five and six or more adverse alleles, respectively. Analyses of the effects of genotype combinations yielded similar results. These findings underscore the importance of assessing the collective effects of a panel of polymorphisms in the same pathway in modulating mutagen sensitivity. As risk assessment for cancer risk is moving toward a multigenic pathway-based approach, future genotype-phenotype correlation studies should also investigate the combined effects of multiple genetic variants.

Moving toward individualized therapy based on NER polymorphisms that predict platinum sensitivity in ovarian cancer patients

Objective Platinum-based chemotherapy exerts its cytotoxic effect by forming DNA adducts and subsequently inhibiting DNA replication. Removing platinum DNA adducts requires the nucleotide excision repair (NER) pathway. The xeroderma pigmentosum (XP) complementation group of genes plays an essential role in the NER pathway. We hypothesized that genetic polymorphisms in XP genes may predict clinical response to platinum chemotherapeutic treatment and survival in women with gynecological cancers. Method We genotyped 146 cases of advanced epithelial ovarian cancer for XP gene polymorphisms using the PCR-RFLP method. Kaplan–Meier plots and the log-rank test were used to assess associations between survival and recurrence-free interval and the XP gene polymorphisms. Hazard ratio of response was estimated from an adjusted multivariate Cox proportional hazard model. Results Women with a heterozygous variant XPA allele had shorter median survival (21.5 months, P = 0.03) and shorter median time to recurrence (11.3 months, P = 0.05) than women with the homozygous wild-type allele (37.9 and 13.9 months, respectively). Women with a homozygous variant XPG allele had significantly shorter median survival (8.3 months, P = 0.006) compared with women with the homozygous XPG wild-type allele (24.6 months). Polymorphisms in XPC, XPD exon10, and XPD exon23 were associated with a decreased risk of recurrence and death, but were not statistically significant. Conclusions This study suggests that NER gene polymorphisms may correlate with recurrence and patient survival. A larger sample size is needed to assess platinum chemotherapy response with these polymorphisms. These findings may help identify subgroups of cancer patients likely to benefit from individualized treatment strategies. Our next study will examine NER gene polymorphisms in cervical cancer patients.

Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of Northern Spain

BackgroundPolymorphisms in DNA repair genes have been associated to repair DNA lesions, and might contribute to the individual susceptibility to develop different types of cancer. Nucleotide excision repair (NER), base excision repair (BER), and double-strand break repair (DSBR) are the main DNA repair pathways. We investigated the relationship between polymorphisms in two NER genes, XPC (poly (AT) insertion/deletion: PAT-/+) and XPD (Asp312Asn and Lys751Gln), the BER gene XRCC1 (Arg399Gln), and the DSBR gene XRCC3 (Thr241Met) and the risk of developing lung cancer.MethodsA hospital-based case-control study was designed with 516 lung cancer patients and 533 control subjects, matched on ethnicity, age, and gender. Genotypes were determined by PCR-RFLP and the results were analysed using multivariate unconditional logistic regression, adjusting for age, gender and pack-years.ResultsBorderline association was found for XPC and XPD NER genes polymorphisms, while no association was observed for polymorphisms in BER and DSBR genes. XPC PAT+/+ genotype was associated with no statistically significant increased risk among ever smokers (OR = 1.40; 95%CI = 0.94–2.08), squamous cell carcinoma (OR = 1.44; 95%CI = 0.85–2.44), and adenocarcinoma (OR = 1.72; 95%CI = 0.97–3.04). XPD variant genotypes (312Asn/Asn and 751Gln/Gln) presented a not statistically significant risk of developing lung cancer (OR = 1.52; 95%CI = 0.91–2.51; OR = 1.38; 95%CI = 0.85–2.25, respectively), especially among ever smokers (OR = 1.58; 95%CI = 0.96–2.60), heavy smokers (OR = 2.07; 95%CI = 0.74–5.75), and adenocarcinoma (OR = 1.88; 95%CI = 0.97–3.63). On the other hand, individuals homozygous for the XRCC1 399Gln allele presented no risk of developing lung cancer (OR = 0.87; 95%CI = 0.57–1.31) except for individuals carriers of 399Gln/Gln genotype and without family history of cancer (OR = 0.57; 95%CI = 0.33–0.98) and no association was found between XRCC3 Thr241Met polymorphism and lung cancer risk (OR = 0.92; 95%CI = 0.56–1.50), except for the 241Met/Met genotype and squamous cell carcinoma risk (OR = 0.47; 95%CI = 0.23–1.00).ConclusionIn conclusion, we analysed the association between XPC, XPD, XRCC1, and XRCC3 polymorphisms and the individual susceptibility to develop lung cancer in the Spanish population, specifically with a highly tobacco exposed population. We attempt to contribute to the discovery of which biomarkers of DNA repair capacity are useful for screening this high-risk population for primary preventing and early detection of lung cancer.

Polymorphisms in XPD, XPC and the risk of death in patients with urinary bladder neoplasms

We conducted a follow-up study on 311 patients with urinary bladder neoplasms to investigate the association of polymorphisms in DNA repair and cell growth regulatory genes with the clinical outcomes of this disease. We found that patients carrying the variant allele of XPD (K751Q) polymorphism were at lower risk of death (p = 0.04) than the non-carriers. Patients that were simultaneous carriers of variant alleles from XPD (K751Q) and XPC (K939Q) polymorphisms, showed lower risk of death than the other patients (p = 0.001). The variant allele carriers of MSH6 (G39E) polymorphism showed a higher risk for highly malignant disease (TaG3+T1) than the non-carriers (p = 0.03). The variant allele carriers of XRCC1 (R399Q) polymorphism showed lower risk for recurrence (TaG2; p = 0.05) and death (T2+; p = 0.03) after instillation and radiotherapy than the non-carriers. After radiotherapy, an inverse association of the variant allele of OGG1 (S326C) polymorphism was observed with the risk of death (T2+; p = 0.04). A significant low-risk for stage progression (p = 0.03) was observed in patients carrying the variant allele of H-ras (H27H) polymorphism. Our results are consistent with the notion that the XPD (K751Q) polymorphism either individually or in combination with the XPC (K939Q) polymorphism modulates the risk of death in patients with urinary bladder neoplasms.

Polymorphisms of DNA repair genes are risk factors for prostate cancer

DNA repair gene alterations have been shown to cause a reduction in DNA repair capacity. We hypothesised that DNA repair gene polymorphisms may be risk factors for prostate cancer (PC). To test this hypothesis, DNA samples from 165 cases of prostate cancer and healthy controls were analyzed by PCR-RFLP to determine the genotypic frequency of three DNA repair genes ( XRCC1, XPC and XRCC7). We found that the frequency of 939Gln variant at XPC Lys939Gln was significantly lower in PC cases (OR = 0.39, P = 0.016). Haplotype analysis of XRCC1 Arg194Trp (C/T) and Arg399Gln (G/A) revealed that the frequency of the T–A haplotype was significantly higher in PC patients. This is the first report on the studies of XPC and XRCC1 Arg194Trp polymorphisms in PC, and our present data suggest that XPC Lys939Gln and the T–A haplotype of XRCC1 Arg194Trp and Arg399Gln may be risk factors for PC in Japanese.

Polymorphisms in the DNA Repair GenesXPC, XPD, andXPGand Risk of Cutaneous Melanoma: a Case-Control Analysis

Sunlight causes DNA damage, including bulky lesions that are removed effectively by the nucleotide-excision repair (NER) pathway. There are at least eight core NER proteins participating in the pathway, and genetic variations in their genes may alter NER functions. We hypothesized that some NER variants are associated with risk of cutaneous melanoma. In a hospital-based case-control study of 602 non-Hispanic White patients with cutaneous melanoma and 603 age- and sex-matched cancer-free controls, we genotyped five common non-synonymous single-nucleotide polymorphisms identified to date and assessed their associations with risk of cutaneous melanoma. We found that a significantly increased risk of cutaneous melanoma was associated with XPD 751Lys/Gln [adjusted odds ratio (OR), 1.55 and 95% confidence interval (95% CI), 1.12-2.16] and XPD 751Gln/Gln (OR, 1.66; 95% CI, 1.03-2.68) genotypes compared with the XPD 751Lys/Lys genotype as well as XPD312Asp/Asn (OR, 1.54; 95% CI, 1.11-2.12) and XPD312Asn/Asn (OR, 1.75; 95% CI, 1.05-2.90) genotypes compared with the XPD 312Asp/Asp genotype. This increased risk was not observed in the other three XPC and XPG single-nucleotide polymorphisms. Moreover, the number of the observed XPD at-risk genotypes (i.e., 312Asn/Asn+Asn/Asp and 751Gln/Gln+Lys/Gln) was associated with cutaneous melanoma risk in a dose-response manner (OR, 1.47; 95% CI, 0.97-2.23 for one at-risk genotype; OR, 1.83; 95% CI, 1.29-2.61 for two at-risk genotypes; P(trend) < 0.001). However, we found no evidence of any interaction between XPD genotypes with XPC and XPG genotypes or the known risk factors. We concluded that genetic variants of the XPD gene might serve as biomarkers for susceptibility to cutaneous melanoma.

Comprehensive Analysis of 22XPCPolymorphisms and Bladder Cancer Risk

Two major risk factors for bladder cancer are smoking and occupational exposure to chemicals. The XPC protein is crucial in the recognition and initiation of the nucleotide excision repair pathway which repairs the DNA adducts formed by carcinogens found in cigarette smoke and chemicals. Polymorphisms in the XPC gene have been shown to influence an individual's DNA repair capacity, and hence, increase that individual's susceptibility to cancer. We undertook a case-control study of 547 bladder cancer cases and 579 cancer-free controls to investigate the association between 22 XPC polymorphisms and bladder cancer susceptibility, and investigated gene-environment interactions. We showed that the nonsynonymous polymorphism Ala(499)Val was in strong linkage disequilibrium with two polymorphisms in the 3'-untranslated region (Ex15-184 and Ex15-177) with Lewontin's D' >or= 0.99 and r2 >or= 0.82. Individuals homozygous for the minor allele of Ala(499)Val, Ex15-184, or Ex15-177 had an increased risk of bladder cancer compared with those homozygous for the common allele [adjusted odds ratio (95% confidence interval), 1.65 (1.05-2.59), 1.82 (1.12-2.97), and 1.82 (1.12-2.96), respectively]. The associations were somewhat stronger for smokers and those occupationally exposed to chemicals, although tests for gene-environment interactions were not significant.

Nucleotide Excision Repair Gene Polymorphisms and Risk of Advanced Colorectal Adenoma:XPCPolymorphisms Modify Smoking-Related Risk

Nucleotide excision repair enzymes remove bulky damage caused by environmental agents, including carcinogenic polycyclic aromatic hydrocarbons found in cigarette smoke, a risk factor for colorectal adenoma. Among participants randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we studied the risk of advanced colorectal adenoma in relation to cigarette smoking and selected single nucleotide polymorphisms (SNP) in the nucleotide excision repair pathway. Cases (n = 772) were subjects with left-sided advanced adenoma (>1 cm in size, high-grade dysplasia, or villous characteristics). Controls (n = 777) were screen-negative for left-sided polyps by sigmoidoscopy. DNA was extracted from blood samples and 15 common nonsynonymous SNPs in seven-nucleotide excision repair genes [XPC, RAD23B (hHR23B), CSB (ERCC6), XPD (ERCC2), CCNH, XPF (ERCC4), and XPG (ERCC5)] were genotyped. None of the studied SNPs were independently associated with advanced adenoma risk. Smoking was related to adenoma risk and XPC polymorphisms (R492H, A499V, K939Q) modified these effects (P(interaction) from 0.03-0.003). Although the three XPC variants were in linkage disequilibrium, a multivariate logistic regression tended to show independent protective effects for XPC 499V (P(trend) = 0.06), a finding supported by haplotype analysis (covariate-adjusted global permutation P = 0.03). Examining a spectrum of polymorphic variants in nucleotide excision repair genes, we found evidence that smoking-associated risks for advanced colorectal adenoma are modified by polymorphisms in XPC, particularly haplotypes containing XPC 499V.

XPC polymorphisms and lung cancer risk

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.

Polymorphisms in nucleotide excision repair genes XPC and XPD and clinical responses to platinum-based chemotherapy in advanced non-small cell lung cancer

Nucleotide excision repair has been shown to have great impact on the sensitivity of tumors to platinum-based chemotherapy. This study was to examine the association between genetic polymorphisms in XPC and XPD, two important components in nucleotide excision repair system, and clinical response to platinum-based chemotherapy in advanced non-small cell lung cancer. Patients (n = 151) treated with platinum-based chemotherapy were genotyped for the AT dinucleotide insertion or deletion in intron 9 of XPC or Lys751Gln polymorphism in XPD. Clinical response to chemotherapy was obtained after 2 to 3 cycles. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression model and adjusted for sex, age, clinical stage, and regime of chemotherapy. The overall response rate to the chemotherapy (CR + PR) was 35.1%, with 1 CR, 52 PR, 75 SD, and 23 PD. It was found that patients with the XPC LL genotype had significantly higher response rate than patients with the XPC SS genotype (adjusted OR = 3.19, 95% CI = 1.11 - 9.17; P = 0.031). However, no association was found between the XPD Lys751Gln polymorphism and response to the chemotherapy. In addition, these two polymorphisms seemed to have synergic effect, with the OR being 2.90 (95% CI = 1.07 - 7.86) for patients carrying the XPC LL and XPD Lys/Lys genotypes compared with those carrying the XPC SS or SL and XPD Lys/Lys genotypes. These results suggest that genetic polymorphisms in nucleotide excision repair might be associated with clinical response to platinum-based chemotherapy.

Combinations of polymorphisms in XPD, XPC and XPA in relation to risk of lung cancer

Inherited polymorphisms in DNA repair genes may contribute to genetic susceptibility to cancer. XPA, XPC and XPD all encode proteins that are part of the nucleotide excision repair pathway. In a nested case–cohort study, we have investigated the occurrence of lung cancer in relation to commonly occurring polymorphisms in XPA, XPC and XPD. Among 54,220 members of a Danish prospective cohort study, 265 lung cancer cases were identified and a sub-cohort comprising 272 individuals was used for comparison. We found that XPA A23G and XPC Lys939Gln polymorphisms may be risk factors for lung cancer and evidence that positive interactions between the polymorphisms in XPA/XPD and XPC/XPD may occur.

Poly (AT) Polymorphism in Intron 11 of the XPC DNA Repair Gene Enhances the Risk of Lung Cancer

Abstract Reduced DNA repair capacity due to inherited polymorphisms may increase the susceptibility to smoking-related cancers. In this report, we investigate the relationship between xeroderma pigmentosum complementary group C poly (AT) insertion/deletion polymorphism (XPC-PAT) of the XPC gene and lung cancer risk in a hospital-based case-control study of 359 newly diagnosed lung cancer patients and 375 control subjects matched on age, sex, and catchment area. The XPC genotype was determined by PCR-RFLP, and the results were analyzed using logistic regression, adjusting for relevant covariates. We found that the frequency of the PAT+/+ genotype was higher in the cases (20.6%) than in the controls (14.1%; P = 0.057) and that the PAT+/+ subjects were at significantly increased risk for lung cancer [adjusted odds ratio (OR), 1.60; 95% confidence interval (95% CI), 1.01-2.55]. Stratified analysis revealed that the risk was higher in former smokers (OR, 2.15; 95% CI, 1.07-4.31) and older people (OR, 2.76; 95% CI, 1.02-7.51), although this probably occurs due to 63.4% of cases older than 73 years being ex-smokers. When stratified by histologic type, the variant genotype was associated with statistically significant increased risk for squamous cell carcinoma (OR, 1.93; 95% CI, 1.06-3.51). In conclusion, our findings support the hypothesis that PAT and intron 11 C/A XPC polymorphisms are linked in the Spanish population and may contribute to the risk of developing lung cancer probably due to a higher frequency of deletion of exon 12 and reduced DNA repair capacity of the XPC protein.