A novel single nucleotide polymorphism in ERCC6 gene is associated with oral cancer susceptibility in Taiwanese patients

The DNA repair gene ERCC6, an important caretaker of the overall genome stability, is thought to play a role in the development of human malignancy. However, the polymorphic variants of ERCC6, has never been reported about their association with oral cancer susceptibility. In this hospital-based case-control study, the association of ERCC6 codon 399, 1097 and 1413 polymorphisms with oral cancer risk in a Central Taiwanese population was first investigated. In total, 292 patients with oral cancer and 290 age- and gender-matched healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped. We found a significant different distribution in the frequency of the ERCC6 codon 399 genotypes, but not the ERCC6 codon 1097 or 1413 genotypes, between the oral cancer and control groups. Those who had homozygous A/A or heterozygous A/G at ERCC6 codon 399 showed a 1.82- and 1.22-fold (95% confidence interval=1.19-2.79 and 0.83-1.78, respectively) increased risk of oral cancer compared to those with G/G. As for ERCC6 codon 1097 or 1413, there was no difference in distribution between the oral cancer and control groups. Gene-environment interactions with smoking and betel quid chewing, but not alcohol drinking, were significant for ERCC6 polymorphisms. ERCC6 codon 399, G/A+A/A ever user groups exhibited an increased risk of 2.36 (95% CI=1.36-4.10) for smoking and 2.72 (95% CI=1.31-5.63) for betel quid chewing. Our results firstly suggest that the heterozygous and homozygous A allele of the ERCC6 codon 399 may be associated with the development of oral cancer and may be a novel useful marker for primary prevention and anticancer intervention.     

XPD基因多态性与非霍奇金淋巴瘤发病风险

目的探讨核苷酸剪切修复基因(XPD)单核苷酸多态性与非霍奇金淋巴瘤(NHL)发病风险的关系。方法以309例NHL患者和305例健康对照者为研究对象,采用PCR-RFLP技术检测XPDG23591A、A35931C位点的基因多态。结果初步分析XPD G23591A和A35931C基因多态性与总的NHL无显著相关。对NHL亚类分析显示,在滤泡性淋巴瘤(FL)、弥漫性大B细胞淋巴瘤(DLBCL)、其他B细胞NHL和T细胞NHL中,XPD23591位点GA+AA型频率分别为16.3%、18.0%、10.5%、18.4%,对照组为12.5%,OR值分别为1.43、1.58、0.89和1.50,差异无统计学意义(P>0.05);XPD35931位点AC+CC型频率分别为15.2%、15.8%、18.4%、12.5%,对照组为11.5%,OR值分别为1.41、1.48、1.75和1.12,差异亦无统计学意义(P>0.05)。结论山东地区汉族人群XPD G23591A、G23591A位点多态性与非霍奇金淋巴瘤发病无关。     

TP53 Arg72Pro and XPD Lys751Gln Gene Polymorphisms and Risk of Lung Cancer in Bangladeshi Patients

Background: Tumor suppressor gene (TP53) is considered as the most frequently mutated gene in almost all forms of human cancer. Moreover, genetic variations in the XPD gene affect the DNA repair capacity increasing cancer susceptibility. Polymorphisms within these genes can play a major role in determining individual lung cancer susceptibility. However, several studies have investigated this possibility; but reported conflicting results. Therefore, the objective of this study was to investigate the role of TP53 Arg72Pro and XPD Lys751Gln gene polymorphisms on lung cancer susceptibility in the Bangladeshi population. Materials and Methods: Study subjects comprised of 180 lung cancer patients and 200 healthy volunteers. Genetic polymorphism of TP53 was determined by multiplex PCR-based method, while XPD genotypes were analyzed using Polymerase Chain Reaction-based Restriction Fragment Length Polymorphism (PCR-RFLP) method. Lung cancer risk was estimated as odds ratio (OR) and 95% confidence interval (CI). Results: From the results, no significant association between TP53 Arg72Pro polymorphism and lung cancer risk was observed. Whereas, patients with homozygous mutant variants (Gln/Gln) of XPD at codon 751 were found significantly associated with lung cancer risk when compared to the control (OR=3.58; 95% CI=1.58-8.09; p=0.002). Lung cancer risk was found significantly higher with Gln/Gln variants of XPD among smokers (OR=4.03; 95% CI=1.11-14.63; p=0.026). Significant increased risk of lung cancer was found with Arg/Pro genotypes of TP53, Lys/Gln and Gln/Gln variants of XPD in individuals with family history of cancer (OR=3.44; 95% CI=1.36-8.72; p=0.011; OR=3.17; 95% CI=1.20-8.39; p=0.024; OR=16.35; 95% CI=0.92-289.5; p=0.007, respectively). Conclusion: The findings indicated that homozygous mutant variants (Gln/Gln) of XPD were associated with increased lung cancer risk, whereas TP53 Arg72Pro polymorphism was not associated with risk of lung cancer among Bangladeshi patients.     

Genetic polymorphism of XRCC1 and lung cancer risk among African-Americans and Caucasians.

Reduced DNA repair capacity may influence susceptibility to lung cancer. XRCC1 plays an important role in base excision repair and in rejoining DNA strand breaks. In the XRCC1 gene, two common polymorphisms induce amino acid changes in codon 194 and codon 399 and correlate with levels of genotoxic damage. We examined the relation between these two polymorphisms and susceptibility to lung cancer among 334 incident cases and 704 population controls of African-American and Caucasian ethnicity in Los Angeles County, California. African-American and Caucasian subjects smoking 20+ cigarettes/day and carrying at least one copy of the codon 194 variant allele were at somewhat decreased risk of lung cancer (African-Americans OR=0.2, 95% CI 0.1-0.9; Caucasians OR=0.5, 95% CI 0.2-1.1). Similarly, for the codon 399 polymorphism, there was some evidence of a decreased risk for the homozygous variant genotype among heavier smokers (African-Americans OR=0.3, 95% CI 0.0-2.9; Caucasians OR=0.4, 95% CI 0.2-1.0). These results suggest that genetic variation in XRCC1 might contribute to lung cancer and may interact with the amount smoked.     

Polymorphisms of DNA Repair Genes in Endometrial Cancer

Endometrial cancer belongs to the commonest malignancy in females. Its development may be associated with the high exposure of endometrium to exo- and endogenous estrogens. Estrogens produce DNA bulky adducts and oxidative base damages which are removed in nucleotide excision repair (NER) and base excision repair (BER) pathways. The reaction of endometrial cells to DNA damage may be crucial for their susceptibility to cancer transformation. This reaction is executed mainly by DNA repair, which can be modulated by the variability in the genes encoding DNA repair proteins. In this report we genotyped 4 polymorphisms of 3 DNA repair genes in 94 endometrial cancer patients and 114 age-matched cancer-free women using RFLP-PCR. The following polymorphisms were studied: p.Arg194Trp, p.Arg399Gln of the XRCC1 gene, p.Ser326Cys of the hOGG1 gene and p.Lys751Gln of the ERCC2 gene. We found an association between the ERCC2 751Gln variant and endometrial cancer occurrence (OR 3.95; 95?% CI 1.88-8.31). Gene-gene interaction between the ERCC2 751Gln and XRCC1 194Trp variants also increased the risk of endometrial cancer (OR 4.41; 95?% CI 2.01-9.67). The risk in the carriers of the ERCC2 751Gln variant was increased by a positive cancer history in first degree relatives (OR 4.97; 95?% CI 1.98-12.48). The risk of endometrial cancer was not alter by polymorphism p.Ser326Cys of the hOGG1 gene. The 751 Lys/Gln polymorphism of the ERCC2 gene may be linked with endometrial cancer occurrence and its effect can be potentiated by variants of the XRCC1 gene or first degree relatives positive cancer history.     

Single-nucleotide polymorphisms in DNA repair genes and association with breast cancer risk in the web study

Base excision repair (BER) and nucleotide excision repair (NER) pathways repair damaged DNA, and polymorphisms in these genes might affect breast cancer susceptibility. We evaluated associations between seven single-nucleotide polymorphisms in four DNA repair genes (ERCC4 rs1799801, XPC rs2227998, rs2228001, rs2228000, OGG1 rs1052133 and XRCC1 rs25487 and rs25486) and breast cancer risk, examining modification by smoking and alcohol consumption, using data from the Western New York Exposures and Breast Cancer Study. Women aged 35-79 years with incident breast cancer (n = 1170) and age- and race-matched controls (n = 2115) were enrolled. Genotyping was performed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). No significant associations were observed in premenopausal women. Among postmenopausal women, rs25487 and rs25486 (OR = 1.24; 95% CI 1.01-1.51 and OR = 1.23; 95% CI 1.01-1.49, respectively, for combined heterozygous and homozygous variant compared with reference) were associated with increased risk of breast cancer. Postmenopausal women carrying the variant allele of the synonymous XPC polymorphism (rs2227998) were also at borderline significantly increased risk (OR = 1.24; 95% CI 1.01-1.52, heterozygous variant compared with reference; OR = 1.22; 95% CI 1.01-1.48, for combined heterozygous and homozygous variant compared with reference). There was no evidence of genotype-smoking and genotype-alcohol consumption interactions for pre- and postmenopausal women. These results indicate that some of the variants in BER and NER genes may influence risk of postmenopausal breast cancer.     

Genetic variation in the nucleotide excision repair pathway and bladder cancer risk.

Nucleotide excision repair (NER) is critical for protecting against damage from carcinogens in tobacco smoke. We evaluated the influence of common genetic variation in the NER pathway on bladder cancer risk by analyzing 22 single nucleotide polymorphisms (SNP) in seven NER genes (XPC, RAD23B, ERCC1, ERCC2, ERCC4, ERCC5, and ERCC6). Our study population included 1,150 patients with transitional cell carcinoma of the urinary bladder and 1,149 control subjects from Spain. Odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, gender, region, and smoking status. Subjects with the variant genotypes for SNPs in four of the seven genes evaluated had small increases in bladder cancer risk compared to subjects with the homozygous wild-type genotypes: RAD23B IVS5-15A>G (OR, 1.3; 95% CI, 1.1-1.5; P = 0.01), ERCC2 R156R (OR, 1.3; 95% CI, 1.1-1.6; P = 0.006), ERCC1 IVS5+33A>C (OR, 1.2; 95% CI, 1.0-1.5; P = 0.06; P(trend) = 0.04), and ERCC5 M254V (OR, 1.4; 95% CI, 1.0-2.0; P = 0.04). A global test for pathway effects indicated that genetic variation in NER characterized by the 22 SNPs analyzed in this study significantly predicts bladder cancer risk (P = 0.04). Pairwise comparisons suggested that carrying variants in two genes could result in substantial increases in risk. Classification tree analyses suggested the presence of subgroups of individuals defined by smoking and NER genotypes that could have substantial increases in risk. In conclusion, these findings provide support for the influence of genetic variation in NER on bladder cancer risk. A detailed characterization of genetic variation in key NER genes is warranted and might ultimately help identify multiple susceptibility variants that could be responsible for substantial joint increases in risk.     

Polymorphisms in the DNA nucleotide excision repair genes and lung cancer risk in Xuan Wei, China

The lung cancer mortality rate in Xuan Wei County is among the highest in China and has been attributed to exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). Nucleotide excision repair (NER) plays a key role in reversing DNA damage from exposure to environmental carcinogens, such as PAHs, that form bulky DNA adducts. We studied single nucleotide polymorphisms (SNPs) and their corresponding haplotypes in 6 genes (ERCC1, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG, RAD23B and XPC) involved in NER in a population-based case-control study of lung cancer in Xuan Wei. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled. Three linked SNPs in ERCC2 were associated with lung cancer with similar ORs; e.g., persons with the Gln allele at codon 751 had a 60% reduction of lung cancer (OR = 0.40, 95% CI 0.18-0.89). Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19-0.85) compared to the most common haplotype. In addition, subjects with one or 2 copies of the Val allele at codon 249 of RAD23B had a 2-fold increased risk of lung cancer (OR = 1.91, 95% CI 1.12-3.24). In summary, our results suggest that genetic variants in genes involved in the NER pathway may play a role in lung cancer susceptibility in Xuan Wei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuan Wei and in other populations with substantial environmental exposure to PAHs.     

Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-DNA adducts, and breast cancer risk.

Genes involved in the nucleotide excision repair (NER) pathway, which removes bulky DNA adducts, are potential low-penetrance cancer susceptibility genes. We recently reported an association between detectable polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer risk. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in NER genes modified the association between PAH-DNA adducts and breast cancer risk. We examined polymorphisms in ERCC1 (3'-untranslated region 8092C/A), XPA (5'-untranslated region -4G/A), XPD (Asp(312)Asn in exon 10), XPF (Arg(415)Gln in exon 8), and XPG (Asp(1104)His in exon 15) in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele in XPD was associated with a 25% increase in the odds ratio [OR, 1.25; 95% confidence interval (95% CI), 1.04-1.50] for breast cancer. The increase associated with homozygosity of the variant alleles for XPD and ERCC1 was stronger among those with detectable PAH-DNA adduct levels (OR, 1.83; 95% CI, 1.22-2.76 and OR, 1.92; 95% CI, 1.14-3.25 for detectable versus nondetectable adducts and homozygous wild-type genotype for XPD and ERCC1, respectively). We found no association between XPA, XPF, and XPG genotypes, PAH-DNA adducts, and breast cancer risk. When we combined genotypes for these NER pathway genes, there was a significant trend for increasing breast cancer risk with increasing number of putative high-risk alleles. Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in NER pathway genes and detectable PAH-DNA adducts.     

A single nucleotide polymorphism in the human H-ras proto-oncogene determines the risk of urinary bladder cancer.

Acquired mutations and inherited polymorphisms in the H-ras gene may modulate the risk of urinary bladder cancer. In DNA isolated from bladder cancer tissue, we screened the coding sequence of H-ras, including the exon-intron-junctions, for exon 1 (n = 68 patients), exon 2 (n = 50), and exons 3 and 4 (n = 25). Acquired mutations at codons 12 and 13 (exon 1) and codon 61 (exon 2), which had been described earlier in bladder cancer tissue, were not found in any of the tumors, but we identified a frequent polymorphism at nucleotide 81T-->C (exon 1) in a wobble position. The clinical impact of this polymorphism was investigated in a case-control study in which 312 patients with histologically verified bladder cancer were compared with 254 hospital controls; 13.5% of the cases but only 7.1% of controls were homozygous for the 81C-variant of this polymorphism [odds ratio (OR), 2.04; 95% confidence interval (CI), 1.15-3.61; P = 0.014]. The homozygous 81C genotype was overrepresented, particularly in the patient groups with poorly differentiated tumors (n = 145, >or=G3; OR, 2.22; 95% CI, 1.15-4.27; P = 0.017), muscle-invasive tumors (n = 107, >or=T(2); OR, 2.65; 95% CI, 1.35-5.23; P = 0.005), and flat transitional cell carcinoma (n = 45; OR, 3.69; 95% CI, 1.60-8.51; P = 0.002). In general, 81CC occurred more frequently in advanced types of bladder cancer. We conclude that individuals harboring the homozygous 81C-genotype of the H-ras proto-oncogene are at an increased risk of bladder cancer.     

Differences in base excision repair capacity may modulate the effect of dietary antioxidant intake on prostate cancer risk: an example of polymorphisms in the XRCC1 gene.

We propose a hypothesis that differences in base excision repair capacity modulate the effect of dietary antioxidant intake on prostate cancer risk. As a preliminary test of this hypothesis, we conducted a pilot case-control study to evaluate prostate cancer risk in men with polymorphisms in the XRCC1 gene, a key player in base excision repair, across different strata of antioxidant intake. Seventy-seven prostate cancer patients and 183 community controls, for whom we have detailed dietary information, were frequency matched on age and race. We found a somewhat lower prostate cancer risk for men with one or two copies of the variant alleles at the XRCC1 codons 194 and 399 than for those who were homozygous for the common allele [codon 194: odds ratio (OR) = 0.8; 95% confidence interval (CI), 0.4-1.8 and codon 399: OR = 0.8; 95% CI, 0.5-1.3]. The variant at codon 280 was associated with a slightly increased prostate cancer risk (OR = 1.5; 95% CI, 0.7-3.6). Only the codon 399 polymorphism occurred frequently enough to investigate its joint effect with antioxidant intake. Prostate cancer risk was highest among men who were homozygous for the common allele at codon 399 and had low dietary intake of vitamin E (OR = 2.4; 95% CI, 1.0-5.6) or lycopene (OR = 2.0; 95% CI, 0.8-4.9), whereas low intake of these antioxidants in men without this genotype hardly increased prostate cancer risk. The polymorphism did not modulate risk associated with low intake of vitamin C, A, or beta-carotene. The data give some support for our hypothesis but should be regarded as preliminary, because it is limited by small sample size. We discuss what kind of data and what kind of studies are needed for future evaluation of this hypothesis.     

Association of ERCC1 polymorphisms and susceptibility to nasopharyngeal carcinoma

The normal function of excision repair cross complementing group 1 (ERCC1) is essential for maintaining genomic integrity and preventing cellular neoplastic transformation, and multiple studies have reported an association between ERCC1 polymorphisms and increased risk of cancers. To test whether the genetic variants of ERCC1 gene modify the risk of nasopharyngeal carcinoma (NPC), we compared the 8092 C > A and 19007 C > T single nucleotide polymorphisms (SNPs) and the haplotypes of ERCC1 between 267 patients with NPC and 304 healthy controls. Linkage disequilibrium was observed between the two SNPs loci (D' = 0.861). Significant differences of allele frequencies were found for ERCC1 8092C > A between the cases and controls. Individuals with 8092 C allele showed 1.411-fold (OR = 1.411, 95% CI, 1.076-1.850, P = 0.014) increased risk of developing NPC, and the CC haplotype was associated with a significantly increased risk of NPC (OR = 1.712; 95% CI, 1.211-2.421; P = 0.013). No interactions were found between 8092C > A polymorphism and genders, smoking status and alcohol consumption. These results suggested that the polymorphism of ERCC1 8092 C > A might be a contributing factor in the development of NPC in Chinese population.     

Glutathione S-transferases as risk factors in prostate cancer.

Glutathione S-transferases are enzymes involved in the metabolism of carcinogens and in the defence against reactive oxygen species. Genetic polymorphisms have been detected in glutathione S-transferases M1, T1 and P1, and some of these polymorphisms have been associated with an increased risk of cancer. In a case-control study (153 cases and 288 controls) the effect of these genetic polymorphisms on the risk of prostate cancer was investigated. Homozygote deletion of either GSTM1 or GSTT1 was not associated with a statistically significant increased risk, odds ratio (OR) 1.3; 95% confidence intervals (CI) 0.9-1.9 and 1.3; 0.8-2.2, respectively. Deletion of both GSTM1 and GSTT1 gave a near-significant increased risk (OR 1.7; 95% CI 0.9-3.4). Two allelic variants of GSTP1 (codon 105) have been reported. This polymorphism was not linked to an increased risk (OR 0.8; 95% CI 0.5-1.1). Smokers that lack either GSTM1 or GSTT1 activity had a slightly higher risk of prostatic cancer than smokers expressing the genes, OR 1.4 (95% CI 0.6-3.3) and 1.6 (0.6-3.9), respectively. Our results show that differences in enzymes involved in the metabolism of carcinogens slightly modify prostate cancer risk, especially in people exposed to carcinogens that are detoxified by these enzymes.     

Polymorphisms in XPC and ERCC2 genes, smoking and breast cancer risk

To evaluate the associations of breast cancer risk with polymorphisms in the XPC and XPD/ERCC2 DNA nucleotide excision repair genes, a case-control study nested within a prospective cohort of 14,274 women was conducted. Genotypes were characterized for 612 incident, invasive breast cancer cases and their 1:1 matched controls. The homozygous variant of a poly(AT) insertion/deletion polymorphism in intron 9 of the XPC gene (XPC-PAT+/+), was associated with breast cancer risk [odds ratio (OR) = 1.45, 95% confidence interval: 1.07-1.97], after adjustment for other breast cancer risk factors. The breast cancer risk associated with XPC-PAT+/+ did not differ by age at diagnosis. There was an indication of an interaction (p = 0.08) between the XPC-PAT+/+ genotype and cigarette smoking. Ever smokers with the XPC-PAT+/+ genotype were at elevated risk of breast cancer (OR = 1.56, CI: 0.95-2.58), but no differences were observed among never smokers. Analyses of the ERCC2 Lys751Gln polymorphism did not show an association with breast cancer risk, either overall or at younger ages. The results suggest that breast cancer risk is related to the XPC haplotype tagged by the XPC-PAT+/+ insertion-deletion polymorphism in intron 9. Further study of the XPC haplotypes and their interactions with smoking in relation to breast cancer risk is needed.     

A gain of function TGFB1 polymorphism may be associated with late stage prostate cancer.

Transforming growth factor beta (TGFbeta) is known to exert both positive and negative effects on different stages of tumor formation. Of the TGFbetaisoforms, TGFbeta1 is highly expressed in prostate cancer and leads to tumor promotion and metastasis. Increased expression of TGFbeta1 is associated with more aggressive tumors and poor prognosis. Several polymorphisms in TGFB1 have been identified, and two variants in strong linkage disequilibrium, C-509T and T+29C, show increased serum levels. Because of the potential role of TGFB1 variants in prostate cancer and progression, we hypothesized that these two TGFB1 variants would be associated with prostate cancer risk, particularly later, more aggressive stage tumors. To test this, we conducted a nested case-control study of 492 men diagnosed with prostate cancer from the Physicians Health Study and 492 age-matched controls. In this study, cases who were homozygous for the T allele at position -509 had a 2.4-fold increased risk of more advanced stage of prostate cancer [95% confidence interval (95% CI) 1.03-5.43; P = 0.04]. The T allele frequencies in cases and controls were 32.7% and 31.4%, respectively. The same polymorphism showed a 1.23 nonsignificant odds ratio (OR) for overall prostate cancer risk (95% CI 0.80-1.87). Cases who were homozygous for the C allele at position +29 did not show any significant increase in risk for either total prostate cancer (OR 1.19, 95% CI 0.82-1.74) or advanced stage prostate cancer (OR 1.33, 95% CI 0.66-2.68). The C allele frequency in cases and controls were 39.9% and 38.5%, respectively. Our data suggest that the TGFB1 C-509T variant that affects expression of TGFbeta1 may play a role in advanced stage prostate cancer.     

Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer.

Cigarette smoking may induce DNA damage. Lower DNA repair capacities have been associated with higher risk of lung cancer. Excision repair cross-complementing group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process, and low expression of ERCC1 mRNA levels has been associated with higher risk of cancers. We examined the association between two polymorphisms of ERCC1, 8092C > A (rs3212986) and 19007T > C (codon 118, rs11615), which are associated with altered ERCC1 mRNA stability and mRNA levels, in 1,752 Caucasian lung cancer patients and 1,358 controls. The results were analyzed using logistic regression models, adjusting for relevant covariates. The two polymorphisms were in Hardy-Weinberg disequilibrium and in linkage disequilibrium. There was no overall association between ERCC1 polymorphisms and lung cancer risk, with the adjusted odds ratios (AOR) of 1.26 [95% confidence interval (95% CI), 0.81-1.96] for the 8092C > A polymorphism (A/A versus C/C) and 0.93 (95% CI, 0.67-1.30) for the 19007T > C polymorphism (C/C versus T/T). Stratified analyses revealed that the AORs for the 8092C > A polymorphism (A/A versus C/C) decreased significantly as pack-years increased, with the AOR of 2.11 (95% CI, 1.03-4.31) in never smokers and 0.50 (95% CI, 0.25-1.01) in heavy smokers (>/=56 pack-years), respectively. Consistent results were found when gene-smoking interaction was incorporated by joint effects and interactions models that considered both discrete and continuous variables for cumulative smoking exposure. The same direction for the gene-smoking interaction was found for the 19007T > C polymorphism, although the interaction was not statistically significant. In conclusion, ERCC1 8092C > A polymorphism may modify the associations between cumulative cigarette smoking and lung cancer risk.     

Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma

BACKGROUND: Pancreatic cancer risk has been linked to chronic pancreatitis and periodontitis, suggesting a role for inflammation in disease etiology. Myeloperoxidase (MPO) and superoxide dismutase (SOD2) are enzymes that regulate reactive oxygen species and contain recognized single nucleotide polymorphisms (SNPs) that confer altered enzyme activity. METHODS: One hundred twenty-two patients with pancreatic cancer and 331 age- and sex-matched controls were analyzed for polymorphisms of the MPO - guanine 463 adenine (-G463A) and the SOD2 alanine (Ala)-to-valine (Val) polymorphism at codon 16 (Ala16Val) genes. Cases and controls were analyzed for associations between these polymorphisms, adjusting for sex, age, history of alcohol use and smoking history. RESULTS: The variant A allele of MPO -G463A was associated with a lower risk of pancreatic cancer (adjusted odds ratio [OR] for pancreatic cancer, 0.57; 95% confidence interval [95% CI], 0.4-0.9; P = .02). The SOD2 homozygous variant genotype (Val/Val) was associated with a greater risk of pancreatic cancer (adjusted OR, 1.96; 95% CI, 1.0-3.8; P = .04). Compared with individuals who carried both low-risk alleles (A/- and Ala/-), significantly more cases than controls carried both high-risk genotypes (G/G and Val/Val; adjusted OR, 4.31; 95% CI, 1.8-10; P = .001), or 1 high-risk genotype (adjusted OR, 1.96; 95% CI, 1.1-3.4; P = .01). CONCLUSIONS: Polymorphisms of the inflammatory pathway genes MPO -G463A and SOD2 Ala16Val are associated with elevated pancreatic cancer risk. Oxidative stress may play an important role in pancreatic cancer carcinogenesis.     

DNA repair gene XRCC1 polymorphisms, smoking, and bladder cancer risk.

Bladder cancer is the sixth most common cancer in the United States. The main identified risk factor is cigarette smoking, which is estimated to contribute to up to 50% of new cases in men and 20% in women. Besides containing other carcinogens, cigarette smoke is a rich source of reactive oxygen species (ROS) that can induce a variety of DNA damage, some of which is repaired by the base excision repair (BER) pathway. The XRCC1 gene protein plays an important role in BER by serving as a scaffold for other repair enzymes and by recognizing single-strand DNA breaks. Three polymorphisms that induce amino acid changes have been found in codon 194 (exon 6), codon 280 (exon 9), and codon 399 (exon 10) of this gene. We tested whether polymorphisms in XRCC1 were associated with bladder cancer risk and whether this association was modified by cigarette smoking. Therefore, we genotyped for the three polymorphisms in 235 bladder cancer cases and 213 controls who had been frequency matched to cases on age, sex, and ethnicity. We found no evidence of an association between the codon 280 variant and bladder cancer risk [odds ratio (OR), 1.2; 95% confidence interval (CI), 0.6-2.6]. We found some evidence of a protective effect for subjects that carried at least one copy of the codon 194 variant allele relative to those homozygous for the common allele (OR, 0.59; 95% CI, 0.3-1.0). The combined analysis with smoking history suggested a possible gene-exposure interaction; however, the results were not statistically significant. Similarly, for the codon 399 polymorphism, our data suggested a protective effect of the homozygous variant genotype relative to carriers of either one or two copies of the common allele (OR, 0.70; 95% CI, 0.4-1.3), and provided limited evidence, albeit not statistically significant, for a gene-smoking interaction.