XPC Lys939Gln Research Articles

XRCC1 Arg399Gln was associated with repair capacity for DNA damage induced by occupational chromium exposure

BackgroundOccupational chromium exposure may induce DNA damage and lead to lung cancer and other work-related diseases. DNA repair gene polymorphisms, which may alter the efficiency of DNA repair, thus may contribute to genetic susceptibility of DNA damage. The aim of this study was to test the hypothesis that the genetic variations of 9 major DNA repair genes could modulate the hexavalent chromium (Cr (VI))-induced DNA damage.FindingsThe median (P25-P75) of Olive tail moment was 0.93 (0.58–1.79) for individuals carrying GG genotype of XRCC1 Arg399Gln (G/A), 0.73 (0.46–1.35) for GA heterozygote and 0.50 (0.43–0.93) for AA genotype. Significant difference was found among the subjects with three different genotypes (P = 0.048) after adjusting the confounding factors. The median of Olive tail moment of the subjects carrying A allele (the genotypes of AA and GA) was 0.66 (0.44–1.31), which was significantly lower than that of subjects with GG genotype (P = 0.043). The A allele conferred a significantly reduced risk of DNA damage with the OR of 0.39 (95% CI: 0.15–0.99, P = 0.048). No significant association was found between the XRCC1Arg194Trp, ERCC1 C8092A, ERCC5 His1104Asp, ERCC6 Gly399Asp, GSTP1 Ile105Val, OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln and DNA damage.ConclusionThe polymorphism of Arg399Gln in XRCC1 was associated with the Cr (VI)- induced DNA damage. XRCC1 Arg399Gln may serve as a genetic biomarker of susceptibility for Cr (VI)- induced DNA damage.

Differences in nucleotide excision repair capacity between newly diagnosed colorectal cancer patients and healthy controls

Alteration of DNA integrity is a potential cause of cancer and it is assumed that reduced DNA repair capacity and accumulation of DNA damage may represent intermediate markers in carcinogenesis. In this case-control study, DNA damage and nucleotide excision repair capacity (NER-DRC) were assessed in association with sporadic colorectal cancer (CRC). Both parameters were quantified by comet assay in blood cells of 70 untreated incident patients and 70 age-matched healthy controls. mRNA expression and polymorphisms in relevant NER genes were concurrently analyzed. The aim of this study was to characterize incident CRC patients for NER-DRC and to clarify possible relations between investigated variables. Comet assay and mRNA expression analysis showed that CRC patients differ in repair capacity as compared to controls. Patients had a lower NER-DRC and simultaneously they exhibited higher endogenous DNA damage (for both P < 0.001). Accumulation of DNA damage and decreasing NER-DRC behaved as independent modulating parameters strongly associated with CRC. Expression levels of 6 out of 9 studied genes differed between groups (P ≤ 0.001), but none of them was related to DRC or to any of the studied NER polymorphisms. However, in patients only, XPC Ala499Val modulated expression levels of XPC, XPB and XPD gene, whereas XPC Lys939Gln was associated with XPA expression level in controls (for all P < 0.05). This study provides evidence on altered DRC and DNA damage levels in sporadic CRC and proposes the relevance of the NER pathway in this malignancy. Further, alterations in a complex multigene process like DNA repair may be better characterized by functional quantification of repair capacity than by quantification of individual genes transcripts or gene variants alone.

Interaction between Polymorphisms of DNA Repair Genes Significantly Modulated Bladder Cancer Risk

DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences.

DNA repair genes XPC, XPG polymorphisms: Relation to the risk of colorectal carcinoma and therapeutic outcome with oxaliplatin‐based adjuvant chemotherapy

Xeroderma pigmentosum complementation group C and G (XPC, XPG) play important roles in DNA damage repairing machinery. Genetic variations in the XPC and XPG may be associated with increased risk for colorectal carcinoma (CRC). In this study, we evaluated the relation between the XPC Lys939Gln, XPG Asp1104His polymorphisms, and CRC susceptibility in a population-based case-control study, which included 1,028 CRC cases and 1,085 controls. Compared with the corresponding wild genotypes, we found that individuals with at least one copy of the XPC Lys939Gln (AC or CC genotype) and XPG Asp1104His (GC or CC genotype) had an increased risk for CRC. In addition, the variant genotypes of the XPC Lys939Gln AC/CC (P = 0.027) or XPG Asp1104His GC/CC (P = 0.003) reduced the elevation of preoperative carcinoembryonic antigen (CEA) level. Moreover a significantly longer progression-free survival (PFS) after Oxaliplatin-based adjuvant chemotherapy was observed in patients with XPG Asp1104His wide-type GG genotype (n = 432, Log-rank test: P = 0.033). Cox proportional hazards analyses demonstrated that variant genotypes of XPG Asp1104His [hazard ratio (HR) = 1.692, 95% confidence interval (95%CI): 1.202-2.383, P = 0.003] as well as pathology grade (HR = 2.545, 95%CI: 2.139-3.030, P < 0.001), and lymph node metastases (HR = 1.851, 95%CI: 1.306-2.625, P < 0.001) were predictive of shorter PFS for the CRC patients with Oxaliplatin-based adjuvant chemotherapy. In conclusion, the current data suggested that XPC Lys939Gln and XPG Asp1104His polymorphisms might contribute to the identification of patients with increased risk for CRC.

Evaluating chromosomal damage in workers exposed to hexavalent chromium and the modulating role of polymorphisms of DNA repair genes

Welders have been chronically exposed to hexavalent chromium with potential consequences on chromosomal integrity. Our study is focused on the extent of any such chromosomal aberrations with respect to chromium levels in the blood of welders as well as on the tentative modulating role of polymorphisms in DNA repair genes XPD Lys751Gln, XPG Asn114His, XPC Lys939Gln, hOGG1 Ser326Cys and XRCC1 Arg399Gln on chromosomal damage. The study was conducted on 144 individuals consisting of 73 welders exposed to chromium for 10.2 ± 1.67 years and 71 control individuals without known exposures. Chromosomal aberrations, their chromatid-type and chromosome-type aberrations were detected by conventional cytogenetic analysis. XPD, XPG, XPC, hOGG1 and XRCC1 gene polymorphisms were assayed for by Taqman SNP genotyping assay ("Assay-by-Demand") using Real-Time allelic discrimination on AB 7500 equipment. Chromium concentration in the blood was determined by atomic absorption spectrophotometry. The level of chromium in the blood of welders ranged between 0.032 and 0.182 μmol l(-1) and was significantly higher than that in controls (0.07 ± 0.04 μmol l(-1) vs. 0.03 ± 0.007 μmol l(-1)). Parameters of chromosomal damage were similar in both the exposed and the control individuals (1.89% vs. 1.70% for total chromosomal aberrations, 0.97% vs. 0.88% for chromosome-type and 0.92% vs. 0.80% for chromatid-type, respectively). Chromatid-type of aberrations positively correlated with the level of chromium in the blood (r = 0.28; P = 0.02). Significantly higher total chromosomal aberrations were detected in individuals with homozygous variant polymorphism in XRCC1 Arg399Gln gene as compared to those with heterozygous and homozygous wild-type genotypes (2.20, 1.89 and 1.48%, respectively; P = 0.01). A similar tendency was found for chromatid-type aberrations (1.30% for homozygous variant genotype bearers, 0.94% for those with heterozygous genotype and 0.75% for carriers of homozygous wild-type genotype, respectively; P = 0.04). Although no apparent increase in chromosomal damage was recorded in chromium-exposed welders in comparison with controls, genetic make-up in DNA repair genes may increase susceptibility toward adverse effect of chromium.

DNA repair enzyme polymorphisms and oxidative stress in a Turkish population with gastric carcinoma

Although the developmental stages of gastric carcinoma are still not clear, the constantly generated reactive oxygen and nitrogen species (ROS/RNS) may contribute to the process of carcinogenesis by interacting with DNA. 8-oxoguanine DNA glycosylase-1 (OGG1) is an enzyme involved in base excision repair of 8-oxoguanine that is one of the premutagenic lesions generated by ROS in DNA. The bulky adducts, are recognized and repaired by nucleotid excision repair (NER) enzymes, including xeroderma pigmentosum C and D (XPC, XPD). Eligible 106 gastric cancer patients and 116 cancer-free individuals constituted the study and control groups, respectively. Association between OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln polymorphisms and the susceptibility tho cancer and the oxidative stress status were evaluated. DNA was extracted from peripheral blood cells and genotypes were determined by using PCR-RFLP. Serum nitric oxide, albumin concentrations, total antioxidant status and Helicobacter pylori IgG were determined. Serum albumin and nitric oxide of cancer patients were lower than that of the controls (P < 0.05). None of the evaluated polymorphisms or Helicobacter pylori IgG seropositivity associated with increased risk of gastric cancer, despite of the increased oxidative stress in cancer patients.

Ala499Val (C &gt; T) and Lys939Gln (A &gt; C) polymorphisms of the XPC gene: their correlation with the risk of primary gallbladder adenocarcinoma--a case-control study in China

Genetic variations in the gene XPC may be associated with increased risk for gallbladder cancer (GBC). In this study, we detected two non-synonymous polymorphisms in XPC (Ala499Val and Lys939Gln) in 334 cases of GBC and 329 subjects of hospital-based age- and sex frequency-matched controls in China using a polymerase chain reaction-restriction fragment length polymorphism assay. Allelic association analysis for the two single-nucleotide polymorphisms (SNPs) showed that the risk allele T of Ala499Val was significantly associated with GBC [odds ratio (OR)=1.40, 95% confidence interval (CI): 1.11-1.76, P=0.005), with a population attributive risk of 5.3%. Logistic regression analysis revealed that Ala499Val CT heterozygote (OR=1.56, 95% CI: 1.13-2.14, P=0.002) and TT homozygote (OR=1.93, 95% CI: 1.04-3.55, P=0.048) had a significantly increased risk compared with CC homozygotes. Genetic analysis suggested that either the SNPs directly exert an effect or the linked functional gene impact of the disease trait likely follows an additive or dominant model. Gene interaction analysis demonstrated that the effects of XPC diplotypes (defined as the number of risk genotypes at the two SNP loci) were highly dependent on gallstone. The data from this case-control study indicated that XPC exonic variants contributed to the risk of GBC in this Chinese population.

Nucleotide Excision Repair Gene Polymorphisms May Predict Acute Toxicity in Patients Treated with Chemoradiotherapy for Bladder Cancer

Platinum-based chemoradiotherapy (CRT) as bladder conservation therapy has shown promising results for muscle-invasive bladder cancer. However, treatment-related toxicity remains a major consideration in therapeutic planning. Some common polymorphisms in genes involved in DNA repair (encoding enzymes that repair DNA damaged by platinum agents and ionizing radiation) are reported to result in modulation of the repair capacity. We investigated associations between functional genetic polymorphisms involved in DNA repair and acute toxicity of CRT to determine the predictive value of these polymorphisms for toxicity. The study group comprised of 101 bladder cancer patients treated with platinum-based CRT, and seven polymorphisms in XPC (Lys939Gln, rs2228001), XPD (Lys751Gln, rs13181), XPG (Asp1104His, rs17655), XRCC1 (Arg399Gln, rs25487), XRCC3 (Thr241Met, rs861539), TP53 (Arg72Pro, rs1042522) and MDM2 (SNP309, T>G, rs2279744) were genotyped. More than two total variant alleles in nucleotide excision repair genes, including XPC, XPD and XPG, were significantly associated with grade 3 or 4 neutropenia (adjusted odds ratio [aOR]: 6.8; 95% CI: 2.0-26; p = 0.0026). There were no significant associations between any genotypes and grade 2 or greater nausea/vomiting or diarrhea. Any grade 3 or 4 hematological toxicity was significantly associated with the Gln/Gln or Lys/Gln + Gln/Gln genotypes of XPC compared with Lys/Lys (aOR: 10; 95% CI: 2.0-65; p = 0.0070 or aOR: 6.3; 95% CI: 1.9-29; p = 0.0069; respectively). These results suggest that nucleotide excision repair gene polymorphisms, especially in XPC, might potentially be predictive factors for acute toxicity of CRT for bladder cancer, helping individual patient selection for bladder conservation therapy. However, further studies with larger sample sizes are needed to draw final conclusions.

Oxidative Stress, Helicobacter pylori, and OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln Polymorphisms in a Turkish Population with Colorectal Carcinoma

The contribution of polymorphisms of DNA repair genes OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln in developing colorectal carcinoma is controversial. Whether the group 1A carcinogen Helicobacter pylori is a risk factor or not in these patients could not be clearly elucidated. One hundred ten colorectal cancer patients and 116 cancer-free individuals constituted the test and control groups, respectively. The association of OGG1 Ser326Cys, XPC Lys939Gln, and XPD Lys751Gln polymorphisms and the susceptibility to colorectal carcinoma with or without oxidative stress were evaluated. DNA was extracted from peripheral blood cells and genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. For serum nitric oxide and total antioxidant status assay, spectrophotometric analyses were used. Serum albumin measurements were performed using an autoanalyzer. H. pylori IgG was measured by ELISA. The serum albumin concentrations of cancer patients were significantly lower than those of the controls (p < 0.05). The carriers of the variant genotype of OGG1 (odds ratio: 0.963; 95% confidence interval: 0.446-2.079), XPC (0.789, 0.366-1.700), or XPD (0.532, 0.259-1.094) did not associate with the increased risk of cancer progression, despite the increased oxidative stress in cancer patients. Seropositivity of H. pylori IgG has been found to increase the risk of colorectal carcinoma by 2.2-fold.

Abstract 1864: The association between XPC polymorphism and cooking fume exposure in the risk of female lung adenocarcinoma: a case-control study

Abstract Purpose: Lung cancer is the leading cause of cancer death in Taiwanese women who mainly have no smoking history throughout their lives. Thus, the identification of etiologic factors leading to lung adenocarcinoma among female nonsmokers is important. The XPC located on chromosome 3p25, involving in nucleotide excision repair system (NER) that repairs the DNA damages to maintain the genome integrity. We evaluated the association between XPC polymorphism, codon 939 Lys/Gln, Cooking fume exposure and the risk of female lung adenocarcinoma. Methods: The polymorphism was determined in 1030 cases with lung adenocarcinoma and 1087 healthy hospital controls and assayed by TaqMan assay, Unconditional multiple logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI). Results: Patients with Gln/Gln and Gln/Lys alleles had 1.3 and 1.7 fold (95% CI = 1.0-1.8 and 1.1-2.6, respectively) evaluated risk of developing lung adenocarcinoma compared with patients with Lys/Lys alleles after the adjustment for age, father's ethnicity, schooling years, family history of lung cancer, history of tuberculosis, cooking fume, BMI, arsenic-exposed area, active cigarette smoking, and exposure to environmental tobacco smoke. Besides, the interactions between the genetic polymorphism and environmental factors including cooking fume exposure and when to started cooking were also tested. Among those with cooking fume exposure, patients combined Gln/Gln and Gln/Lys genotype showed a 3.4 fold (95%CI, 1.1-10.2) risk of developing lung adenocarcinoma compared to those with Lys/Lys genotype, while among those without cooking fume exposure, combined Gln/Gln and Gln/Lys genotype had a slightly 1.2 fold (95%CI, 0.9-1.5) risk of developing lung adenocarcinoma compared to those with Lys/Lys genotype. In addition, gene dosage and environmental effect showed that patients combined Gln/Gln and Gln/Lys genotype in the group who exposed to cooking fume had a 6.1 fold (95%CI, 2.8-13.3) risk compared to those with Lys/Lys genotype among group without cooking fume exposure. Furthermore, exposed for cooking fume was categorized into non-cooking, and cooking with or without fume extractor, gene-environment interaction analysis showed that combined Gln/Gln and Gln/Lys genotype among cooking without fume extractor, had a 4.7 fold (95%CI, 2.8-13.3) risk compared to those with Lys/Lys genotype among group without cooking fume exposure. Conclusions: Our findings suggested that the XPC Lys939Gln polymorphism may associated with a significantly increased risk of female lung adenocarcinoma, and showed the interaction between the genotype and the exposed of cooking fume. Further studies may be required to explain whether Gln allele may as a weak metabolic function for above carcinogens and consequently causes the accumulation of reactive carcinogen in lung. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1864.

Association of XPC and XPG polymorphisms with the risk of hepatocellular carcinoma

To investigate whether the polymorphism of DNA repair genes XPC (Ala499Val and Lys939Gln) and XPG (His1104Asp) is associated with the susceptibility to hepatocellular carcinoma (HCC). A hospital-based case-control study was conducted in 500 cases with HCC and 507 controls. Genotypes of XPC and XPG were determined by real-time polymerase chain reaction with the TaqMan MGB probe. Compared to the CC genotype, the CT genotype and the TT genotype of XPC Ala499Val were not associated with the susceptibility to HCC (adjusted OR = 1.34, 95% CI: 0.85-2.12; adjusted OR = 1.30, 95% CI: 0.68-2.51, respectively). Compared to the AA genotype, the AC genotype and the CC genotype of Lys939Gln were not associated with the susceptibility to HCC (adjusted OR = 1.20, 95% CI: 0.78-1.85; adjusted OR = 1.81, 95% CI: 0.88-3.73, respectively). Compared to the CC genotype, the CG genotype and the GG genotype of XPG His1104Asp were not associated with the susceptibility to HCC (adjusted OR = 0.85, 95% CI: 0.56-1.27; adjusted OR = 1.12, 95% CI: 0.67-1.87, respectively) However, the stratified analysis revealed that the females with the AC+CC genotype of XPC Lys939Gln had increased risk of HCC compared to those with AA genotype (OR = 2.17, 95% CI: 1.01-4.64). Our results suggest that XPC and XPG polymorphisms do not independently affect on the susceptibility to HCC, but the joint effect of C allele of XPC Lys939Gln and female may modify the risk of HCC.

Acute myeloid leukemia outcome: role of nucleotide excision repair polymorphisms in intermediate risk patients

In acute myeloid leukemia (AML), cytogenetics predicts treatment outcome for the favorable and poor subgroups but not for the intermediate subgroup. Polymorphisms within the nucleotide excision repair (NER) pathway may lead to interindividual differences in DNA repair capacity, influencing outcome. We studied the role of six polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, XPG Asp1104His, and CCNH Val270Ala) in overall and disease-free survival among 170 adult de novo patients with intermediate cytogenetics (diploid [n = 117]; non-diploid [n = 53]), treated with induction chemotherapy. Kaplan–Meier and Cox proportional hazards models were performed. Diploid patients with the XPD AC/CC genotype survived shorter than those with the wild-type genotype (median survival 22 vs. 40 months, p = 0.03). Diploid patients with XPC CT/TT genotype survived shorter than those with the wild-type genotype (median survival 15 vs. 30 months, p = 0.02). After adjusting for clinical and sociodemographic variables, patients carrying both XPD AC/CC and XPC CT/TT had a greater than two-fold increased risk of dying, compared to those with the wild-type genotypes (HR = 2.49; 95% CI: 1.06–5.85). No associations were observed for disease-free survival. This combined genotype may modulate treatment effect, decreasing overall survival. These findings could in the future help select treatments for patients with normal cytogenetics.

Genetic polymorphisms in DNA repair genes XPC, XPD, and XRCC4, and susceptibility to Helicobacter pylori infection‐related gastric antrum adenocarcinoma in Guangxi population, China

Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of gastric antrum adenocarcinoma (GAA) related to Helicobacter pylori infection. This study, including 361 GAAs and 616 controls without any evidence of tumors, was designed to evaluate the association between the polymorphisms of DNA repair genes XPC Ala499Val (RS#2228000) and Lys939Gln (RS#2228001), XPD Lys751Gln (RS#13181), and XRCC4 Ala247Ser (RS#3734091) and Ser298Asn (RS#1805377), and GAA risk for Guangxi population by means of TaqMan-PCR analysis. Increased risks of GAA were found for individuals with H. pylori positive [odds ratio (OR), 2.48; 95% confidence interval (CI), 1.84-3.33] or cagA positive (OR, 7.34; 95% CI, 5.46-9.87). No differences were observed among the studied groups with regard to the genotype distribution of XPC codons 499 and 939 and of XRCC4 codon 247; but XPD codon 751 genotypes with Gln [ORs (95% CI) were 2.67 (1.98-3.58) and 3.97 (2.64-5.99) for Lys/Gln and Gln/Gln, respectively] and XRCC4 codon 298 genotypes with Asn [ORs (95% CI) were 3.01 (2.21-4.10) and 4.78 (3.24-7.05) for Ser/Asn and Asn/Asn, respectively] increased the risk of GAA. Interestingly, there was an interactive effect between the risk genotypes of these two genes and cagA-positive status in the GAA risk (OR(interact) = 2.05 and 2.08, respectively). However, we did not find the gene-H. pylori-status interaction effects on the risk of GAA (P(interact) > 0.05). The results suggested that the polymorphisms of XPD codon 751 and XRCC4 codon 298 are associated with an increased risk of developing H. pylori-related GAA among Guangxi population.

XPC gene variants: a risk factor for recurrence of urothelial bladder carcinoma in patients on BCG immunotherapy

To investigate the association between two Xeroderma pigmentosum group C polymorphism (XPC Lys939Gln and insertion/deletion PAT -/+ in intron 9) and bladder cancer (BC) susceptibility. Genotyping was performed in 208 BC patients and 245 controls by PCR-RFLP method. XPC PAT +/+ genotype was associated with elevated risk of BC (p = 0.021, OR = 2.49). XPC Lys939Gln AC + CC genotype was significantly associated with risk in invasive stage of BC (p = 0.041, OR = 2.52). Haplotype analysis revealed that variant genotypes C of XPC Lys939Gln and + of PAT, C+ were significantly associated with risk of BC (p = 0.004, OR = 1.70). The CC genotype of Lys939Gln was associated with high risk for recurrence in BCG-treated patients (HR = 3.21, p = 0.036) thus, showing reduced recurrence-free survival (AC + CC/AA = 36/60 months; log rank p = 0.045). Polymorphisms and haplotypes in XPC appear to influence susceptibility to BC risk. The variant C allele at Lys939Gln may be responsible for early recurrence in BCG-treated patients.

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.

Population study of genetic polymorphisms and superficial bladder cancer risk in Han-Chinese smokers in Shanghai

We investigated the association between the polymorphisms of DNA repair genes, metabolic enzyme genes, and superficial bladder cancer to better understand the role of gene polymorphisms in bladder carcinogenesis for the Han-Chinese population in Shanghai. The SNPs in the XPC, XPG, XRCC1, NQO2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genes were genotyped using the TaqMan Probe-based polymerase chain reaction. The AC + CC genotypes of XPC Lys939Gln and the CC genotype of XPG His1104Asp were more frequent in patients of superficial bladder cancer at the initial diagnosis (adjusted OR [95% CI], 1.89 [1.21-3.24]; adjusted OR [95% CI], 1.07 [0.86-1.87], respectively). The risk for carriers of the XPC-33512C allele increased after stratifying by smoking habits (adjusted OR [95% CI], 1.95 [0.56-6.09]). There was a significant trend for an increased carcinogenesis risk with an increasing number of putative high-risk alleles. We found no significant associations between any of the ten polymorphisms and clinicopathological features of superficial bladder cancer. These results suggest that the polymorphism in XPC Lys939Gln may modulate superficial bladder cancer risk, and these effects may preferentially affect current smokers. The data also support the possibility of an increased risk for superficial bladder cancer in individuals with a higher number of genetic variations in DNA repair and metabolic enzyme genes.

Abstract A107: Polymorphisms in nucleotide excision repair pathway and acute myeloid leukemia outcome

Abstract A107 Acute myeloid leukemia (AML), the most common leukemia in adults is frequently associated with genetic abnormalities. Based on pre-treatment cytogenetics, AML patients are classified into favorable, intermediate and poor subgroups. Cytogenetics are good predictors of treatment outcome for the favorable and poor subgroups. However, for patients with intermediate cytogenetics, optimal treatment is uncertain. For these patients incorporating genetic markers to the existing prognostic factors might be helpful to identify subgroups of patients. Variants in genes within the nucleotide excision repair (NER) pathway may lead to inter-individual differences in DNA repair capacity which could eventually influence AML outcome. We studied the role of 5 polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, and CCNH Val270Ala) within this pathway on overall and disease-free survival among 170 adult de-novo AML patients with intermediate cytogenetics [diploid karyotypes (n = 117) and non-diploid karyotypes (n = 53)], treated with induction chemotherapy. Kaplan-Meier methods and Cox proportional hazards models were performed. After a median follow-up of 16 months, 56% of diploid patients died compared to 71% among the non-diploid group (Log Rank p= 0.03). Among patients with diploid karyotypes, after adjusting for clinical and socio-demographic characteristics (age, sex, ethnicity, WBC, performance status, and smoking), XPD Lys751Gln and XPC Ala499Val were found to be independently associated with overall survival. Patients with the XPD Lys751Gln/Gln751Gln genotype were twice more likely to have died than those with the wild genotype (HR: 1.97; 95% CI: 1.09 - 3.55). XPC Ala499Val/Val499Val patients had a 75% increased mortality compared to those with the wild genotype (HR: 1.75; 95% CI: 1.02 - 2.98). Patients carrying both (XPD Lys751Gln/Gln751Gln and XPC Ala499Val/Val499Val) had significantly shorter survival compared to those with the wild genotype (HR: 3.49; 95% CI: 1.58 - 7.68). 21% of the AML patients with diploid cytogenetics carried both risk variants. No significant associations were observed for disease-free survival in AML patients. Our results suggest that polymorphic variants in NER repair enzymes may modulate AML outcome in patients with diploid cytogenetics. Patients with the high risk genotype combination could have diminished DNA repair capacity, which in turn, could result in greater susceptibility to genotoxic effects of treatment decreasing overall survival. These findings could in the future be used in selecting treatment strategies for patients with normal cytogenetics. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A107.

Inter-individual variation in nucleotide excision repair in young adults: effects of age, adiposity, micronutrient supplementation and genotype

Nucleotide excision repair (NER) is responsible for repairing bulky helix-distorting DNA lesions and is essential for the maintenance of genomic integrity. Severe hereditary impairment of NER leads to cancers such as those in xeroderma pigmentosum, and more moderate reductions in NER capacity have been associated with an increased cancer risk. Diet is a proven modifier of cancer risk but few studies have investigated the potential relationships between diet and NER. In the present study, the plasmid-based host cell reactivation assay was used to measure the NER capacity in peripheral blood mononuclear cells from fifty-seven volunteers aged 18-30 years before and after 6 weeks of supplementation with micronutrients (selenium and vitamins A, C and E). As a control, nine individuals remained unsupplemented over the same period. Volunteers were genotyped for the following polymorphisms in NER genes: ERCC5 Asp1104His (rs17655); XPC Lys939Gln (rs2228001); ERCC2 Lys751Gnl (rs13181); XPC PAT (an 83 bp poly A/T insertion-deletion polymorphism in the XPC gene). NER capacity varied 11-fold between individuals and was inversely associated with age and endogenous DNA strand breaks. For the first time, we observed an inverse association between adiposity and NER. No single polymorphism was associated with the NER capacity, although significant gene-gene interactions were observed between XPC Lys939Gln and ERCC5 Asp1104His and XPC Lys939Gln and ERCC2 Lys751Gnl. While there was no detectable effect of micronutrient supplementation on NER capacity, there was evidence that the effect of fruit intake on the NER capacity may be modulated by the ERCC2 Lys751Gnl single nucleotide polymorphism.

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.