Single nucleotide polymorphisms in the EXO1 gene and risk of colorectal cancer in a Japanese population

EXO1 is a member of the RAD2 nuclease family and functions in DNA replication, repair and recombination. We investigated the relationship of single nucleotide polymorphisms (SNPs) at exon 10 (T439M) and exon 13 (P757L) of the EXO1 gene with development, progression and metastasis of colorectal cancer. For T439M, the Thr/Met genotype [odds ratio (OR) = 2.03, 95% confidence interval (CI) 1.04-3.98] and Thr/Met and Met/Met genotypes combined (OR = 2.37, 95% CI 1.23-4.56) demonstrated significant association with the development of colorectal cancer after adjusting for age, gender and smoking status. For P757L, patients with the Leu/Leu genotype showed a reduced risk of colorectal cancer (adjusted OR = 0.398, 95% CI 0.183-0.866) when the Pro/Leu and Pro/Pro genotypes were combined and used as the reference. The Leu/Leu genotype also had a reduced risk (adjusted OR = 0.373, 95% CI 0.164-0.850) when the Pro/Leu genotype was used as the reference. Individuals who carried both putative risk genotypes (Thr/Met and Met/Met for T439M and Pro/Leu for P757L) showed an adjusted OR of 4.95 (95% CI 1.56-15.7) compared with those who carried both low risk genotypes. Analysis of microsatellite instability (MSI) revealed that tumors from individuals who carried both putative risk genotypes tended to have a higher frequency of MSI positives than those from patients who carried both low risk genotypes, although a significant correlation was not found between EXO1 genotype and MSI status. This is the first report to provide evidence for an association of EXO1 gene polymorphisms with colorectal cancer risk. The EXO1 genotypes were not associated with any clinicopathological characteristics in colorectal cancer patients.     

High serum selenium and reduced risk of advanced colorectal adenoma in a colorectal cancer early detection program.

BACKGROUND: Epidemiologic and animal studies suggest that selenium may reduce risk of colorectal cancer. However, the epidemiologic data is mainly from relatively small investigations, limiting their interpretation. Although substantial evidence suggests that smoking is a strong effect modifier for other antioxidative nutrients, little is known about smoking-selenium interactions in colorectal tumors. METHODS: We studied the association of serum selenium and advanced colorectal adenoma, a cancer precursor, in 758 cases and 767 sex- and race-matched controls, randomly selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma (> or = 1 cm or villous elements, or high-grade dysplasia) of the distal colon, and controls had a negative sigmoidoscopy. RESULTS: The multivariable odds ratio (OR) comparing participants in the highest quintile of serum selenium with those in the lowest quintile was 0.76 [95% confidence interval (95% CI), 0.53-1.10; P(trend) = 0.01]. The inverse association between serum selenium and advanced colorectal adenoma was significant among recent smokers (OR, 0.53; 95% CI, 0.27-1.01 for highest versus lowest tertile; P(trend) = 0.008). Serum selenium was unrelated to adenoma risk in nonsmokers and former smokers who quit smoking > or = 10 years ago. CONCLUSION: Selenium may reduce the risk of developing advanced colorectal adenoma, particularly among the high-risk group of recent smokers.     

Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility

Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene-gene and gene-environment interactions followed by linkage disequilibrium and haplotype analysis. Overall, we did not find an association between any single DNA repair gene SNP and bladder cancer risk. We did find a marginally significant elevated risk of the XPD codon 751 homozygote variant among never smokers [adjusted odds ratio (OR) 2.5, 95% confidence interval (CI) 1.0-6.2]. In addition, the XRCC1 194 variant allele was associated with a reduced bladder cancer risk among heavy smokers [adjusted OR 0.4, 95% CI 0.2-0.9)]. The best predictors of bladder cancer included the XPD codon 751 and 312 SNPs along with smoking. Interpretation of this multifactor model revealed that the relationship between the XPD SNPs and bladder cancer is mostly non-additive while the effect of smoking is mostly additive. Since the two XPD SNPs are in significant linkage disequilibrium (D' = 0.52, P = 0.0001), we estimated XPD haplotypes. Individuals with variant XPD haplotypes were more susceptible to bladder cancer [e.g. adjusted OR 2.5, 95% CI 1.7-3.6] and the effect was magnified when smoking was considered. These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and emphasize the need for a multifaceted statistical approach to identify gene-gene and gene-environment interactions.     

Genetic variation in base excision repair genes and the prevalence of advanced colorectal adenoma

Base excision repair (BER) corrects DNA damage caused by oxidative stress and low folate intake, which are putative risk factors for colorectal neoplasia. To examine the relationship between genetic variation in BER genes and colorectal adenoma risk, we conducted a case-control study of 767 cases of advanced colorectal adenoma and 773 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma, and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy, frequency-matched to cases on race and gender. Twenty single nucleotide polymorphisms were genotyped in four BER genes (APEX1, PARP1, POLB, and XRCC1), and conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association with colorectal adenoma. Two variants with possible functional significance were associated with risk. The APEX1 51H variant was associated with a borderline significant decreased risk of colorectal adenoma (OR, 0.66; 95% CI, 0.44-1.00), and the XRCC1 399Q variant was inversely associated with risk among Caucasians (OR, 0.80; 95% CI, 0.64-0.99). Homozygotes at two PARP1 loci (A284A and IVS13+118G>A) were also associated with a decreased risk of colorectal adenoma compared with wild-type carriers (OR, 0.70; 95% CI, 0.49-0.98 for both), which was restricted to advanced adenomas displaying histologically aggressive characteristics (OR, 0.51; 95% CI, 0.33-0.78, P = 0.002 for PARP1 A284A). This study suggests that polymorphisms in APEX1, XRCC1, and PARP1 may be associated with advanced colorectal adenoma.     

XRCC1, XRCC3, and XPD polymorphisms as modifiers of the effect of smoking and alcohol on colorectal adenoma risk.

Using a sigmoidoscopy-based case-control study (753 cases, 799 controls) in Los Angeles County, we investigated the potential modifier role in the effect of alcohol and smoking of single-nucleotide polymorphisms (SNP) in three DNA repair genes, XRCC1 (Arg194Trp and Arg399Gln), XRCC3 (Thr241Met), and XPD (Lys751Gln). We have previously reported an inverse association between the XRCC1 codon 399 SNP and adenoma risk among these subjects. We now report that subjects with the XPD Gln/Gln genotype were inversely associated with adenoma risk [odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-1.0] when compared with subjects with the Lys/Lys and Lys/Gln genotypes combined. This association differed between different ethnic groups (gene x race heterogeneity likelihood ratio test, P = 0.009), with a stronger inverse association among Latinos (OR, 0.1; 95% CI, 0.01-0.5) than among non-Latinos (OR, 0.9; 95% CI, 0.-1.3). We found no evidence of an XRCC3 x smoking or alcohol interaction or an XRCC1 x alcohol interaction. Instead, our data supported an XRCC1 x smoking interaction (P = 0.048). Whereas XPD did not modify the effect of smoking, our data suggested an XPD x alcohol interaction. Analyses ignoring XPD showed no association between alcohol intake and adenoma prevalence; however, among carriers of the codon 751 Gln/Gln genotype, we found a significant positive association (OR, 2.5; 95% CI, 1.2-5.2 for ever drinkers; test of interaction P = 0.04). Our data suggest that the effects of smoking and alcohol may vary depending on the genetic background of proteins that participate in the base excision repair and nucleotide excision repair pathways.     

Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer

DNA repair and cell cycle control play an important role in the repair of DNA damage caused by cigarette smoking. Given this role, functionally relevant single nucleotide polymorphisms (SNPs) in genes in these pathways may well affect the risk of smoking-related lung cancer. We examined the relationship between 240 SNPs in DNA repair and cell cycle control pathway genes and lung cancer risk in a case-control study of white current and ex-cigarette smokers (722 cases and 929 controls). Additive, dominant, and recessive genetic models were evaluated for each SNP. A genetic risk summary score was also constructed. Odds ratios (OR) for lung cancer risk and 95% confidence intervals (95% CI) were estimated using logistic regression models. Thirty-eight SNPs were associated with lung cancer risk in our study population at P?相似文献   

Colorectal adenoma risk is modified by the interplay between polymorphisms in arachidonic acid pathway genes and fish consumption

Associations between polymorphisms in genes (SNPs) involved in the arachidonic acid (AA) pathway and colorectal adenomas have been investigated in a Dutch case control study including 384 cases and 403 polyp-free controls. Twenty-one polymorphisms in seven candidate genes were studied and a potential modifying effect of fish consumption was considered. A protective effect on colorectal adenomas was found for the CT genotype of SNP H477H in PPARgamma and the GC genotype of SNP V102V in COX-2 (OR 0.63, 95% CI 0.45-0.89 and OR 0.65, 95% CI 0.46-0.92, respectively) compared with the homozygous major genotypes. An increase in adenoma risk was observed for the TC genotype of SNP c.2242T-->C in COX-2 (OR 1.47, 95% CI 1.07-2.00) compared with the TT genotype. Analysis with estimated haplotypes confirmed these associations and revealed three additional associations with COX-2, sPLA(2) and 15LOX haplotypes. Fish consumption modified the associations with COX-2 and PPARdelta genotypes. For SNP c.-789C-->T in PPARdelta the major genotype showed a decrease in adenoma risk for those in the highest tertile of fish consumption (T3), as compared with the lowest tertile (T1) (OR 0.65, 95% CI 0.41-1.02). Protective effects were also observed for SNPs V102V and c.2242T-->C in COX-2 and high fish intake. The interaction between fish consumption and c.2242T-->C was statistically significant, with an OR for the TT genotype and high fish consumption of 0.52 (95% CI 0.27-1.01) as compared with low fish intake. These results indicate that SNPs in genes involved in the AA pathway are associated with colorectal adenoma risk. Some of these associations are modified by fish consumption.     

Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma.

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.     

Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer

Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P(interaction) = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11-1.85, P(trend) = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30-0.84, P(trend) = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.     

Association study of prostate cancer susceptibility variants with risks of invasive ovarian, breast, and colorectal cancer

Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary test of association was a comparison of genotype frequencies between cases and controls, and a test for trend stratified by study where appropriate. Genotype-specific odds ratios (OR) were estimated by logistic regression. SNP rs2660753 (chromosome 3p12) showed evidence of association with ovarian cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor allele OR, 0.95; 95% CI, 0.91-0.99; P(trend) = 0.028). This association was somewhat stronger for estrogen receptor-positive tumors (OR, 0.92; 95% CI, 0.87-0.98; P = 0.011). None of these tag SNPs were associated with risk of colorectal cancer. In conclusion, loci associated with risk of prostate cancer may also be associated with ovarian and breast cancer susceptibility. However, the effects are modest and warrant replication in larger studies.     

CYP1A1 Val462 and NQO1 Ser187 polymorphisms, cigarette use, and risk for colorectal adenoma

Cigarette use is a risk factor for colorectal adenoma, a known precursor of colorectal cancer. Polymorphic variants in NQO1 and CYP1A1 influence the activation of carcinogenic substances in tobacco smoke, possibly impacting on tobacco-associated risks for colorectal tumors. We investigated the association of cigarette smoking with risk for advanced colorectal adenoma in relation to the CYP1A1 Val(462) and NQO1 Ser(187) polymorphic variants. Subjects were 725 non-Hispanic Caucasian cases with advanced colorectal adenoma of the distal colon (descending colon, sigmoid and rectum) and 729 gender- and ethnicity-matched controls, randomly selected from participants in the prostate, lung, colorectal and ovarian cancer screening trial. Subjects carrying either CYP1A1 Val(462) or NQO1 Ser(187) alleles were weakly associated with risk of colorectal adenoma; however, subjects carrying both CYP1A1 Val(462) and NQO1 Ser(187) alleles showed increased risks (OR = 2.2, 95% CI = 1.1-4.5), particularly among recent (including current) (OR = 17.4, 95% CI = 3.8-79.8, P for interaction = 0.02) and heavy cigarette smokers (>20 cigarettes/day) (OR = 21.1, 95% CI = 3.9-114.4, P for interaction = 0.03) compared with non-smokers who did not carry either of these variants. These genotypes were unassociated with risk in non-smokers. In analysis of adenoma subtypes, the combined gene variants were most strongly associated with the presence of multiple adenoma (P = 0.002). In summary, joint carriage of CYP1A1 Val(462) and NQO1 Ser(187) alleles, particularly in smokers, was related to colorectal adenoma risk, with a propensity for formation of multiple lesions.     

Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk

The double-strand break DNA repair (DSBR) pathway is implicated in maintaining genomic stability and therefore could affect bladder cancer risk. Here we present data evaluating 39 single-nucleotide polymorphisms (SNPs) in seven candidate genes whose products are involved in DNA break sensing (NBS1, BRCA1 interacting genes BRIP1 and ZNF350), non-homologous end-joining (NHEJ) DNA repair (XRCC4) and homologous recombination (HR) repair (RAD51, XRCC2 and XRCC3). SNPs for RAD51 and XRCC2 covered most of the common variation. Associations with bladder cancer risk were evaluated in 1,150 newly diagnosed cases of urinary bladder transitional cell carcinomas and 1,149 controls conducted in Spain during 1997-2001. We found that the genetic variants evaluated significantly contributed to bladder cancer risk (global likelihood ratio test P = 0.01). Subjects with the ZNF350 R501S (rs2,278,415) variant allele showed significantly reduced risk compared with common homozygote variants, odds ratio (OR) [95% confidence interval (95% CI)]: 0.76 (0.62-0.93) per variant allele. Carriers of a putative functional SNP in intron 7 of XRCC4 (rs1,805,377) had significantly increased bladder cancer risk compared with common homozygotes: 1.33 (1.08-1.64) per variant allele. Lastly, XRCC2 homozygote variants for three promoter SNPs (rs10,234,749, rs6,464,268, rs3,218,373) and one non-synonymous SNP (rs3,218,536, R188H) were associated with reduced bladder cancer risk (ORs ranging from 0.36 to 0.50 compared with common homozygotes). Meta-analysis for XRCC3 T241M (rs861,539) had a significant small increase in risk among homozygote variants: OR (95% CI) = 1.17 (1.00-1.36). Results from this study provide evidence for associations between variants in genes in the DSBR pathway and bladder cancers risk that warrant replication in other study populations.     

Impact of Polymorphism in Base Excision Repair and Nucleotide Excision Repair Genes and Risk of Cervical Cancer: A Case-Control Study

Background: Last few years, several studies all over the world revealed the association of DNA repair genes with risk of developing different type of cancers, but were ambiguous to support the evidences in case of cervical cancer risk. These differences in earlier studies directed us to study the association of polymorphisms of BER genes (XRCC1, hOGG1, XPC) and NER genes (XPC, XPD) with cervical cancer susceptibility in the women of rural population of Maharashtra. Materials and Methods: The genetic polymorphism in BER and NER pathway genes was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method using DNA isolated from intravenous blood samples of patients and normal controls. The study included 400 clinically confirmed cervical cancer patients and 400 healthy women from a tertiary care hospital (Krishna Hospital and Medical Research Centre) of south-western Maharashtra. The association of polymorphisms was confirmed by Odds ratio (OR) with 95% confidence interval. Results: The single nucleotide polymorphism (SNP) of BER genes including XRCC1, hOGG1 and APE1 were analyzed and the results were noted that 27466AA (OR=4.88; 95% CI: 3.61- 6.60; p<0.0001) and 28152AA (OR=2.89; 95% CI: 1.57- 5.31; p=0.0005) genotypes of XRCC1 (rs25489, rs25487) were significantly associated with cervical cancer risk. The 1245GG genotype of hOGG1 (rs1052133) (OR=45.30; 95% CI: 3.76- 7.46; p=0.001) also showed significant correlation, whereas 2197GG genotype of APE1 (rs1130409) gene showed negative association with cervical carcinogenesis (OR=0.59; 95% CI: 0.35- 0.97; p=0.005). Similarly when we studied SNPs of NER genes including XPC and XPD genes, 21151TT genotype of XPC (rs 2228000) was positively associated with cervical cancer development and 23591AA genotype of XPD (rs1799793) showed negative association (OR=0.34; 95% CI: 0.17- 0.64; p=0.001). Conclusion: The findings from this study supported that rs25489, rs25487SNPs of XRCC1, rs1052133 of hOGG1 and rs2228000 of XPC may increase cervical cancer risk, whereas rs1130409 SNP of APE1 and rs1799793 SNP of XPD gene lower the risk of cervical cancer in the studied population.     

Comprehensive pathway-based association study of DNA repair gene variants and the risk of nasopharyngeal carcinoma

DNA repair plays a central role in protecting against environmental carcinogenesis, and genetic variants of DNA repair genes have been reported to be associated with several human malignancies. To assess whether DNA gene variants were associated with nasopharyngeal carcinoma (NPC) risk, a candidate gene association study was conducted among the Cantonese population within the Guangdong Province, China, the ethnic group with the highest risk for NPC. A 2-stage study design was utilized. In the discovery stage, 676 tagging SNPs covering 88 DNA repair genes were genotyped in a matched case-control study (cases/controls = 755/755). Eleven SNPs with P(trend) < 0.01 were identified. Seven of these SNPs were located within 3 genes, RAD51L1, BRCA2, and TP53BP1. In the validation stage, these 11 SNPs were genotyped in a separate Cantonese population (cases/controls = 1,568/1,297). Two of the SNPs (rs927220 and rs11158728), both in RAD51L1, remained strongly associated with NPC. The SNP rs927220 had a significant P(combined) of 5.55 × 10(-5), with OR = 1.20 (95% CI = 1.10-1.30), Bonferroni corrected P = 0.0381. The other SNP (rs11158728), which is in strong linkage disequilibrium with rs927220 (r(2) = 0.7), had a significant P(combined) of 2.0 × 10(-4), Bonferroni corrected P = 0.1372. Gene-environment interaction analysis suggested that the exposures of salted fish consumption and cigarette smoking had potential interactions with DNA repair gene variations, but need to be further investigated. Our findings support the notion that DNA repair genes, in particular RAD51L1, play a role in NPC etiology and development.     

Leukocyte polycyclic aromatic hydrocarbon-DNA adduct formation and colorectal adenoma

Consumption of charbroiled red meat and meat-derived polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of colorectal adenoma, a precursor of colorectal cancer. Furthermore, leukocyte PAH-DNA adduct levels have been demonstrated to increase in response to charbroiled red meat intake but to date there have been no studies that have investigated the relationship between leukocyte PAH-DNA adduct levels and risk of colorectal adenoma. We investigated the relation of leukocyte PAH-DNA adduct formation and colorectal adenoma in a clinic-based case-control study of colorectal adenomas. The study comprised 82 cases of colorectal adenoma and 111 polyp-free controls, none of whom were current smokers. Leukocyte PAH-DNA adducts were measured by a sensitive chemiluminescence immunoassay using an antiserum elicited against DNA modified with (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydro-benzo[a]pyrene that recognizes several PAHs bound to human DNA. Leukocyte PAH-DNA adduct levels were higher among colorectal adenoma cases (median, 1.4 adducts per 10(8) nucleotides) than polyp-free controls (median, 1.2 adducts per 10(8) nucleotides) (P = 0.02). There was a positive association between PAH-DNA adduct level and adenoma prevalence: each unit increase in PAH-DNA adduct level (per 10(8) nucleotides) was associated with an odds ratio (OR) of 1.5 [95% confidence interval (CI), 1.1-2.2]. In addition, a comparison of the lowest quartile for PAH-DNA adduct level with the highest quartile yielded an OR of 2.8 (95% CI, 1.2-6.5; P(trend) = 0.048) for risk of colorectal adenoma. These data support a link between PAH exposure and colorectal adenoma.     

EGFR exon 19 in‐frame deletion and polymorphisms of DNA repair genes in never‐smoking female lung adenocarcinoma patients

We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never‐smoking patients with lung adenocarcinoma. Multivariate‐adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in‐frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0–4.8) in female never‐smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in‐frame deletion both in never‐smokers (aOR, 1.7 with 95% CI, 1.0–3.0) and female never‐smokers (aOR, 1.9 with 95% CI, 1.0–3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6‐fold increase in the occurrence of the EGFR exon 19 in‐frame deletion in female never‐smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in‐frame deletion both in never‐smokers (p = 0.007 for trend) and female never‐smokers (p = 0.002 for trend). Our findings suggest that the in‐frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never‐smoking lung adenocarcinoma patients, especially in females.     

Genetic polymorphisms in the Paraoxonase 1 gene and risk of ovarian epithelial carcinoma

Oxidative stress during successive ovulations increases the opportunity for DNA damage to ovarian epithelial cells and the potential for malignant transformation. Paraoxonase 1 (PON1) is an endogenous free radical scavenger that reduces oxidative stress. The association of two common functional single nucleotide polymorphisms (SNP), rs854560 T>A and rs662 A>G, with the risk of epithelial ovarian cancer was examined in a population-based case-control study in Hawaii. A personal interview and blood specimens were collected from 274 women with histologically confirmed, primary ovarian cancer and 452 controls frequency matched on age and ethnicity. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression. Both PON1 SNPs were significantly associated with ovarian cancer risk. The ORs were 0.53 (95% CI, 0.35-0.79; P for allele-dose effect = 0.01) for women carrying the rs854560 T allele compared with women with the AA genotype and 0.65 (95% CI, 0.44-0.95; P for allele-dose effect = 0.03) for women carrying the rs662 A allele compared with women with the GG genotype. The association of the rs854560 T genotype with risk was stronger among smokers (OR, 0.33; 95% CI, 0.17-0.64; P for allele-dose effect = 0.0007) than among nonsmokers (OR, 0.68; 95% CI, 0.40-1.18; P for allele-dose effect = 0.53). The decreased risk associated with the rs854560 T allele was also stronger among obese women (OR, 0.19; 95% CI, 0.06-0.55; P for allele-dose effect = 0.007) than among nonobese women (OR, 0.62; 95% CI, 0.40-0.98; P for allele-dose effect = 0.16). Our study provides evidence for an association of two PON1 SNPs with the risk of epithelial ovarian cancer. Possible effect modification of these associations by tobacco smoking and obesity needs confirmation in other studies.