Lung Cancer Risk In Caucasians Research Articles

Association Between the CYP1B1 Polymorphisms and Lung Cancer Risk: A Meta-Analysis.

The previously published data on the association between the cytochrome P450 1B1 Leu432Val, Asn453Ser, and Ala119Ser polymorphisms and lung cancer risk have remained controversial. Hence, we performed a meta-analysis to investigate the association between cytochrome P450 1B1 Leu432Val, Asn453Ser, and Ala119Ser polymorphisms and lung cancer risk under different inheritance models. A total of 22 studies were identified, including 2881 cases and 3653 controls for Leu432Val polymorphism (from 13 studies), 3009 cases and 3887 controls for Asn453Ser polymorphism (from 5 studies), and 1301 cases and 2045 controls for Ala119Ser polymorphism (from 4 studies). Overall, significant association was observed between cytochrome P450 1B1 Leu432Val polymorphism and lung cancer risk (dominant model: odds ratio = 1.29, 95% confidence interval = 1.08-1.53; recessive model: odds ratio = 1.21, 95% confidence interval = 1.05-1.39; additive model: odds ratio = 1.43, 95% confidence interval = 1.21-1.69) when all the eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significantly increased lung cancer risk was also observed in caucasians and smokers. No significant association was observed between cytochrome P450 1B1Asn453Ser and Ala119Ser polymorphisms and lung cancer risk in overall analysis. In summary, this meta-analysis suggests that cytochrome P450 1B1Leu432Val polymorphism is associated with increased lung cancer risk in caucasians and smokers.

Four polymorphisms in the cytochrome P450 1A2 (CYP1A2) gene and lung cancer risk: a meta-analysis.

Previous published data on the association between CYP1A2 rs762551, rs2069514, rs2069526, and rs2470890 polymorphisms and lung cancer risk have not allowed a definite conclusion. The present meta-analysis of the literature was performed to derive a more precise estimation of the relationship. 8 publications covering 23 studies were selected for this meta-analysis, including 1,665 cases and 2,383 controls for CYP1A2 rs762551 (from 8 studies), 1,456 cases and 1,792 controls for CYP1A2 rs2069514 (from 7 studies), 657 cases and 984 controls for CYP1A2 rs2069526 (from 5 studies) and 691 cases and 968 controls for CYP1A2 rs2470890 (from 3 studies). When all the eligible studies were pooled into the meta-analysis for the CYP1A2 rs762551 polymorphism, significantly increased lung cancer risk was observed in the dominant model (OR=1.21, 95 % CI=1.00-1.46). In the subgroup analysis by ethnicity, significantly increased risk of lung cancer was observed in Caucasians (dominant model: OR=1.29, 95%CI=1.11-1.51; recessive model: OR=1.33, 95%CI=1.01-1.75; additive model: OR=1.49, 95%CI=1.12-1.98). There was no evidence of significant association between lung cancer risk and CYP1A2 rs2069514, s2470890, and rs2069526 polymorphisms. In summary, this meta-analysis indicates that the CYP1A2 rs762551 polymorphism is linked to an increased lung cancer risk in Caucasians. Moreover, our work also points out the importance of new studies for rs2069514 associations in lung cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the rs2069514 polymorphism in lung cancer development.

BAT3 rs1052486 and rs3117582 polymorphisms are associated with lung cancer risk: a meta-analysis.

Several studies have examined the associations of polymorphisms in HLA-B-associated transcript 3 (BAT3) with lung cancer risk. However, the results were conflicting. Thus, a meta-analysis was conducted to determine the relationship between BAT3 polymorphisms and lung cancer risk. Databases including PubMed, EMBASE, and Wanfang were searched. Summary odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were estimated using random effects models or fixed effects models. Nine studies were included in this meta-analysis. BAT3 rs1052486 was associated with a significantly increased lung cancer risk (OR = 1.06, 95 % CI 1.01-1.12, P = 0.03). This polymorphism was also significantly associated with lung cancer risk in Caucasians (OR = 1.07; 95 % CI, 1.01-1.12; P = 0.02). Furthermore, BAT3 rs3117582 increased lung cancer risk (OR = 1.31, 95 % CI, 1.26-1.35, P < 0.00001). This polymorphism was also significantly associated with squamous carcinoma risk (OR = 1.30; 95 % CI, 1.11-1.52; P = 0.001) and lung cancer risk in smokers (OR = 1.23; 95 % CI, 1.10-1.38; P = 0.0005). This meta-analysis suggested that BAT3 polymorphisms contributed the development of lung cancer.

Association of vitamin D receptor gene polymorphism with the risk of lung cancer: a meta-analysis

Relationship between vitamin D receptor (VDR) gene polymorphism and the risk of lung cancer from the published reports are still conflicting. This study was conducted to evaluate the relationship between VDR TaqI (rs731236), BsmI (rs1544410) and ApaI (rs7975232) gene polymorphism and the risk of lung cancer using meta-analysis method. The association studies were identified from PubMed and Cochrane Library on 1 December 2013, and eligible investigations were included and synthesized using meta-analysis method. Six reports were recruited into this meta-analysis for the association of VDR gene polymorphism with lung cancer susceptibility. In the meta-analysis for ApaI gene polymorphism, AA genotype was associated with the risk of lung cancer in Asians. In the meta-analysis for BsmI gene polymorphism, B allele, BB genotype and bb genotype were associated with lung cancer in Asians, and B allele bb genotype were associated with lung cancer risk in overall populations; furthermore, bb genotype was associated with lung cancer risk in Caucasians. In the meta-analysis for TaqI gene polymorphism, t allele and TT genotype were associated with lung cancer in overall populations and in Caucasians. In conclusion, B allele bb genotype t allele and TT genotype were associated with lung cancer risk in overall populations. AA genotype, B allele, BB genotype and bb genotype were associated with the risk of lung cancer in Asians. Furthermore, bb genotype t allele and TT genotype was associated with lung cancer risk in Caucasians. However, more studies should be conducted to confirm it.

Cleft lip and palate transmembrane protein 1 rs31489 polymorphism is associated with lung cancer risk: a meta-analysis

The potentially functional polymorphism, rs31489, in the promoter region of cleft lip and palate transmembrane protein 1 (CLPTM1L) gene has been implicated in cancer risk. However, individual published studies showed inconclusive results. To obtain a more precise estimate of the association between CLPTM1L rs31489 and risk of lung cancer, we performed a meta-analysis. Summary odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were estimated using random-effects models. Ten individual case-control studies in eight publications with 20,680 cases and 28,330 controls were included. Overall, the variant genotypes were associated with a significantly increased lung cancer risk in different genetic models (CC + AC vs. AA: OR=1.20, 95 % CI 1.12-1.28, P<0.001; CC vs. AC + AA: OR=1.15, 95 % CI 1.07-1.23, P<0.001; CC vs. AA: OR=1.28, 95 % CI 1.17-1.41, P<0.001; CC vs. AC: OR=1.11, 95 % CI 1.05-1.17, P<0.001; C vs. A: OR=1.12, 95 % CI 1.06-1.18, P<0.001). In the stratified analyses, the increased lung risk remained for the studies of Caucasian populations. In conclusion, this meta-analysis suggested that CLPTM1L rs31489 was a potential biomarker for lung cancer risk in Caucasians.

Transforming growth factor-β1 rs1800470 polymorphism is associated with lung cancer risk: a meta-analysis.

BackgroundTransforming growth factor-β1 is a member of a large class of polypeptides that regulate the proliferation, differentiation, and carcinogenesis of epithelial cells. The rs1800470 polymorphism influences transforming growth factor-β1 expression and has been associated with lung cancer susceptibility. However, the association between the rs1800470 polymorphism and lung cancer risk remains controversial. Thus, a meta-analysis was conducted.Material/MethodsWe comprehensively searched PubMed and EMBASE databases. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models or fixed-effects models.ResultsOverall, there was a significant association between rs1800470 polymorphism and lung cancer susceptibility (OR=1.23; 95%CI, 1.03–1.47; P=0.02). In the stratified analysis by ethnicity, we found that this polymorphism was significantly associated with lung cancer in Asians (OR=1.26; 95%CI, 1.01–1.57; P=0.04). However, we did not find any significant association between this polymorphism and lung cancer risk in Caucasians (OR=1.04; 95%CI, 0.60–1.82; P=0.88). In the NSCLC subgroup, we found that rs1800470 polymorphism could increase NSCLC risk (OR=1.36; 95%CI, 1.06–1.74; P=0.02).ConclusionsThis meta-analysis suggested that rs1800470 polymorphism was a risk factor of lung cancer.

Association between the Telomerase Reverse Transcriptase (TERT) rs2736098 Polymorphism and Cancer Risk: Evidence from a Case-Control Study of Non-Small-Cell Lung Cancer and a Meta-Analysis

BackgroundA common genetic variant, telomerase reverse transcriptase (TERT) rs2736098, was recently reported to be associated with lung cancer risk in Caucasians. In addition, many studies have investigated the role of this polymorphism in the etiology of cancer of various organs. Nevertheless, the results of related case-control studies remain inconsistent.MethodsWe hypothesized that the genetic risk variant identified in Caucasians may potentially influence the susceptibility to lung cancer in the Chinese population. To test this hypothesis, a case-control study including 539 non-small-cell lung cancer (NSCLC) cases and 627 cancer-free controls was conducted. Furthermore, to investigate the association between rs2736098 and cancer risk, a meta-analysis based on previously published studies and our case-control study was also performed.ResultsMultivariate logistic regression demonstrated that individuals carrying the A allele or the AA genotype exhibited a significantly elevated risk of NSCLC compared with those carrying the G allele or GG genotype (A vs. G: OR = 1.21, 95% CI = 1.02–1.43, P = 0.028; AA vs. GG: OR = 1.48, 95% CI = 1.05–2.09, P = 0.025). Additionally, this association was stronger among adenocarcinoma cases (AA vs. GG: OR = 1.67, 95% CI = 1.12–2.50, P = 0.013; A vs. G: OR = 1.28, 95% CI = 1.05–1.57, P = 0.016). In the meta-analysis, a borderline significant association between the rs2736098 polymorphism and overall cancer risk was observed (AA vs. GG: OR = 1.25, 95% CI = 1.07–1.46; AA vs. AG+GG: OR = 1.22, 95% CI = 1.06–1.41; additive model: OR = 1.10, 95% CI = 1.02–1.18), and further stratifications demonstrated a moderately increased risk for lung and bladder cancer, Asian ethnicity and hospital-based studies.ConclusionsOur results suggest that the rs2736098 polymorphism may contribute to the risk of lung cancer, especially adenocarcinoma, in the Chinese population. In addition, the current meta-analysis indicates that this genetic variant is only weakly associated with overall cancer risk. However, the rs2736098 polymorphism may affect individual susceptibility to lung and bladder cancer. Further studies are needed to validate our findings.

NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism and lung cancer risk: a meta-analysis

No clear consensus has been reached on the quinone oxidoreductase 1 (NQO1) gene C609T polymorphism and lung cancer risk. We performed a meta-analysis to summarize the possible association. We conducted a computer retrieval of PubMed and Embase databases prior to May 2013. References of retrieved articles were also screened. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. According to the inclusion criteria, 25 articles (32 studies) were finally included. There was no statistical association between C609T polymorphism and lung cancer risk in overall, East Asians, African Americans, or Hispanics. In Caucasians, a significant association was found in allele comparison model (T vs. C) (P = 0.04, OR = 1.09, 95% CI 1.00-1.19, P(heterogeneity) = 0.24, fixed-effects model). In the subgroup of squamous cell carcinoma, a borderline significance could be found in the dominant genetic model (TT + CT vs. CC) (P = 0.05, OR = 1.20, 95% CI 1.00-1.43, P(heterogeneity) = 0.65, fixed-effects model). Significant association could also be found in allele comparison (T vs. C) (P = 0.03, OR = 1.21, 95% CI 1.01-1.44, P(heterogeneity) = 0.68, fixed-effects model). In the subgroup of small cell lung cancer risk, significant association were found in allele comparison (T vs. C) (P = 0.03, OR = 1.68, 95%CI 1.05-2.68, P(heterogeneity) = 0.10, random-effects model) and in the homozygote comparison (TT vs. CC) (P = 0.02, OR = 2.79, 95% CI 1.14-6.85, P heterogeneity = 0.72, fixed-effects model). No association was observed in adenocarcinoma subgroup. Our study suggested that NQO1 C609T polymorphism might associate with lung cancer risk in Caucasians. This polymorphism might also associate with squamous cell carcinoma and small cell lung cancer risk.

Current evidence on the relationship between five polymorphisms in the matrix metalloproteinases (MMP) gene and lung cancer risk: A meta-analysis

PurposeMatrix metalloproteinase (MMP) 1, MMP2, MMP3 and MMP9 are important members of the MMP family. Recently, many studies have been carried out on the association between polymorphisms of MMP1-1607 1G/2G, MMP2-735 C/T, MMP2-1306 C/T, MMP3-1171 5A/6A and MMP9-1562 C/T and lung cancer risk. However the results of these studies remained inconclusive due to conflicting results from different case–control studies. To clarify these associations, we conducted a meta-analysis. MethodsWe conducted a comprehensive search in Medline, EMBASE, OVID and Chinese Biomedical Literature Database (date from Jan 2000 to Aug 2012). Overall and subgroup analysis by the ethnicity of study population was carried out. Odds ratio (OR) with 95% confidence interval (95%CI) was used to assess the strength of the association. ResultsThere were 17 studies involving five polymorphic sites in four MMP genes. For MMP1-1607,increased lung cancer risk was found under dominant model (MMP1-1607 1G/2G: OR=1.14, 95%CI=1.03–1.26, P=0.01), but not in the Caucasian population. For MMP2-1306 C/T, T polymorphism decreased lung cancer risk under dominant and recessive models (dominant, OR=0.63, 95%CI=0.46–0.88, P=0.0006; recessive, OR=0.61, 95%CI=0.38–0.99, P=0.04). For MMP9-1562 C/T, TT genotype decreased this risk under the recessive model (OR=0.38, 95%CI=0.19–0.75, P=0.005), but not in the Asian population. For MMP2-735 C/T and MMP3-1171 5A/6A, there was no association between this polymorphism and lung cancer risk under the dominant and recessive models. ConclusionsMMP1-1607 1G/2G polymorphism increased lung cancer risk in Asians. It was also found thatMMP2-1306 C/T polymorphism decreased lung cancer risk in Asians, while MMP9-1562 C/T polymorphism decreased lung cancer risk in Caucasians. No significant difference was found in any genotype of MMP2-735 C/T and MMP3-1171 5A/6A. Further studies with larger sample sizes should be carried out.

The hOGG1Ser326Cys Polymorphism and Increased Lung Cancer Susceptibility in Caucasians: An Updated Meta-Analysis

hOGG1 encodes a DNA repair enzyme responsible for the excision of reactive oxygen species (ROS) in damaged DNA. Previous studies have obtained inconsistent results. To validate the association between the hOGG1Ser326Cys polymorphism and lung cancer risk, we performed an updated meta-analysis of 20 studies (8739 cases and 10385 controls) using STATA version 11.1. With this approach, we tested the overall and subgroup association between the SNP and lung cancer susceptibility stratified by ethnicity, control sources, cell histotypes, and smoking status. We demonstrated a novel, significant correlation between the hOGG1 Ser326Cys polymorphism and increased lung cancer susceptibility in Caucasians. Our findings indicate a need for larger-scale studies to verify the association of this SNP with lung cancer risk in Caucasians.

NAD(P)H: Quinone oxidoreductase 1 (NQO1) C609T polymorphism and lung cancer risk: A meta-analysis.

1551 Background: No clear consensus has been reached on the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene C609T polymorphism and lung cancer risk. We performed a meta-analysis to summarize the possible association. Methods: We conducted a computer retrieval of PUBMED and EMBASE databases prior to January 2012. References of retrieved articles were also screened. According to the inclusion criteria, 24 articles (31 studies) were finally included. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. Results: There was no statistical association between C609T polymorphism and lung cancer risk in overall, East Asians, African-Americans or Hispanics. In Caucasians, significant association was found in allele comparison model (T vs. C) (P=0.04, OR=1.09, 95%CI [1.00–1.19], Pheterogeneity=0.24, fixed-effects model). In Hawaiians, significant association could be found in dominant genetic model ((TT+CT) vs. CC) (P=0.04, OR=0.52, 95%CI [0.28–0.96], fixed-effects model). In the subgroup of squamous cell carcinoma, a borderline significance could be found in the dominant genetic model ((TT+CT) vs. CC) (P=0.05, OR=1.20, 95%CI [1.00–1.43], Pheterogeneity=0.65, fixed-effects model). Significant association could also be found in allele comparison (T vs. C) (P=0.03, OR=1.21, 95%CI [1.01–1.44], Pheterogeneity=0.68, fixed-effects model). In the subgroup of small cell lung cancer risk, significant association were found in allele comparison (T vs. C) (P=0.03, OR=1.68, 95%CI [1.05–2.68], Pheterogeneity=0.10, random-effects model) and in the homozygote comparison (TT vs. CC) (P=0.02, OR=2.79, 95%CI[1.14–6.85], Pheterogeneity=0.72, fixed-effects model). No association was observed in adenocarcinoma subgroup. Conclusions: NQO1 C609T polymorphism might associate with lung cancer risk in Caucasians and Hawaiians. NQO1 C609T polymorphism might also associate with squamous cell carcinoma and small cell lung cancer risk.

Effect of Emphysema on Lung Cancer Risk in Smokers: A Computed Tomography–Based Assessment

The contribution of emphysema to lung cancer risk has been recognized, but the effect size needs to be further defined. In this study, 565 primary lung cancer cases were enrolled though a prospective lung cancer cohort at Mayo Clinic, and 450 controls were smokers participating in a lung cancer screening study in the same institution using spiral computed tomography (CT). Cases and controls were frequency matched on age, gender, race, smoking status, and residential region. CT imaging using standard protocol at the time of lung cancer diagnosis (case) or during the study (control) was assessed for emphysema by visual scoring CT analysis as a percentage of lung tissue destroyed. The clinical definition of emphysema was the diagnosis recorded in the medical documentation. Using multiple logistic regression models, emphysema (≥ 5% on CT) was found to be associated with a 3.8-fold increased lung cancer risk in Caucasians, with higher risk in subgroups of younger (<65 years old, OR = 4.64), heavy smokers (≥ 40 pack-years, OR = 4.46), and small-cell lung cancer (OR = 5.62). When using >0% or ≥ 10% emphysema on CT, lung cancer risk was 2.79-fold or 3.33-fold higher than controls. Compared with CT evaluation (using criterion ≥ 5%), the sensitivity, specificity, positive and negative predictive values, and the accuracy of the clinical diagnosis for emphysema in controls were 19%, 98%, 73%, 84%, and 83%, respectively. These results imply that an accurate evaluation of emphysema could help reliably identify individuals at greater risk of lung cancer among smokers.

Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans

Several genome-wide association studies identified the chr15q25.1 region, which includes three nicotinic cholinergic receptor genes (CHRNA5-B4) and the cell proliferation gene (PSMA4), for its association with lung cancer risk in Caucasians. A haplotype and its tagging single nucleotide polymorphisms (SNPs) encompassing six genes from IREB2 to CHRNB4 were most strongly associated with lung cancer risk (OR = 1.3; P < 10(-20)). In order to narrow the region of association and identify potential causal variations, we performed a fine-mapping study using 77 SNPs in a 194 kb segment of the 15q25.1 region in a sample of 448 African-American lung cancer cases and 611 controls. Four regions, two SNPs and two distinct haplotypes from sliding window analyses, were associated with lung cancer. CHRNA5 rs17486278 G had OR = 1.28, 95% CI 1.07-1.54 and P = 0.008, whereas CHRNB4 rs7178270 G had OR = 0.78, 95% CI 0.66-0.94 and P = 0.008 for lung cancer risk. Lung cancer associations remained significant after pack-year adjustment. Rs7178270 decreased lung cancer risk in women but not in men; gender interaction P = 0.009. For two SNPs (rs7168796 A/G and rs7164594 A/G) upstream of PSMA4, lung cancer risks for people with haplotypes GG and AA were reduced compared with those with AG (OR = 0.56, 95% CI 0.38-0.82; P = 0.003 and OR = 0.73, 95% CI 0.59-0.90, P = 0.004, respectively). A four-SNP haplotype spanning CHRNA5 (rs11637635 C, rs17408276 T, rs16969968 G) and CHRNA3 (rs578776 G) was associated with increased lung cancer risk (P = 0.002). The identified regions contain SNPs predicted to affect gene regulation. There are multiple lung cancer risk loci in the 15q25.1 region in African-Americans.

6100 S-1 enhances radiosensitivity in a mouse xenograft model of human colon cancer

Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the association of 10 base-excision and nucleotide-excision repair gene polymorphisms (XRCC1 −77 T/C, Arg194Trp, Arg280His and Arg399Gln; APE1 Asp148Glu; OGG1 Ser326Cys; XPA −4 G/A; XPC PAT; XPD Asp312Asn and Lys751Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR–RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the APE1 Asp148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 (p = 0.001) for the Asp/Glu genotype and 2.39 (p = 0.038) for the Glu/Glu genotype. Gene–smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR = 4.92, p = 0.021 for XRCC1 399 Gln/Gln; OR = 3.62, p = 0.049 for XPD 751 Gln/Gln), but not in heavy smokers (≥25 PY; OR = 0.68, p = 0.566 for XRCC1 399 Gln/Gln; OR = 0.46, p = 0.295 for XPD 751 Gln/Gln). Both the XRCC1 Arg194Trp and Arg280His as well as the OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR = 0.32, p = 0.024; OR = 0.25, p = 0.028; OR = 0.51, p = 0.033, respectively). No associations with lung cancer risk were found for the XRCC1 −77 T/C, the XPA −4 G/A and the XPC PAT polymorphisms. In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPD Lys751Gln polymorphisms and lung cancer risk.

TP53 Arg72Pro polymorphism and lung cancer risk: A meta‐analysis

No clear consensus has been reached on the TP53 Arg72Pro polymorphism (G12139C) and lung cancer risk. Thus, a meta-analysis was conducted to summarize the possible association. There was no statistical association between 12139C (Pro allele) and lung cancer risk in Caucasians compared with 12139G allele. However, the association was observed in all subjects (9,387 patients and 9,922 controls, p=0.04, OR=1.08, 95% CI 1.00-1.17), as well as in Asians (p=0.0004, OR=1.14, 95% CI 1.06-1.22). The association was also found in Asians under recessive genetic model (p<0.00001, OR=1.37, 95% CI 1.20-1.57) and homozygote comparison (CC vs. GG) (p<0.0001, OR=1.34, 95% CI 1.16-1.56). 12139C allele might increase the lung adenocarcinoma risk compared with 12139G allele (p=0.01, OR=1.11, 95% CI 1.02-1.21), and the effect was also found under recessive genetic model (p=0.003, OR=1.28, 95% CI 1.09-1.50) and homozygote comparison (CC vs. GG) (p=0.007, OR=1.28, 95% CI 1.07-1.52). There was an elevated association between the 12139C and the stage I lung cancer under dominant genetic model (p=0.04, OR=1.48, 95% CI 1.02-2.16), but no association was observed in other stages. No association of smoking was found between 12139C allele and lung cancer under recessive genetic model. Our result indicated that 12139C might increase the risk of lung cancer under recessive genetic model in adenocarcinoma, in Asians, and in lung cancer stage I. More studies stratified for lung cancer stage-genotyping interaction should be performed to clarify the role of TP53 Arg72Pro polymorphism in the development of lung cancer.

International Lung Cancer Consortium: Pooled Analysis of Sequence Variants in DNA Repair and Cell Cycle Pathways

The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies.

Lung Cancer Risk Associated with Thr495Pro Polymorphism of GHR in Chinese Population

The incidence of lung cancer has been increasing over recent decades. Previous studies showed that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control comprise risk factors for lung cancer. Recent observations revealed that the growth hormone receptor (GHR) might play important roles in carcinogenesis and Rudd et al. found that the Thr495Pro polymorphism of GHR was strongly associated with lung cancer risk in Caucasians living in the UK (OR = 12.98, P = 0.0019, 95% CI: 1.77-infinity). To test whether this variant of GHR would modify the risk of lung cancer in Chinese population, we compared the polymorphism between 778 lung cancer patients and 781 healthy control subjects. Our results indicate that the frequency of 495Thr (2.8%) allele in cases was significantly higher than in controls (OR = 2.04, P = 0.006, 95% CI: 1.21-3.42) which indicated this allele might be a risk factor for lung cancer. Further analyses revealed Thr495Pro variant was associated with lung cancer in the subpopulation with higher risk for lung cancer: male subpopulation, still-smokers subpopulation and the subpopulation with familial history of cancer. In different histological types of lung cancer, Thr495Pro SNP was significantly associated with small cell and squamous cell lung cancer, but not with adenocarcinoma, which suggested a potential interaction between this polymorphism and metabolic pathways related to smoking. The potential gene-environment interaction on lung cancer risk was evaluated using MDR software. A significant redundant interaction between Thr495Pro polymorphism and smoking dose and familial history of cancer was identified and the combination of genetic factors and smoking status or familial history of cancer barely increased the cancer risk prediction accuracy. In conclusion, our results suggested that the Thr495Pro polymorphism of GHR was associated with the risk of lung cancer in a redundant interaction with smoking and familial history of cancer.

Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk

Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the association of 10 base-excision and nucleotide-excision repair gene polymorphisms ( XRCC1 −77 T/C, Arg194Trp, Arg280His and Arg399Gln; APE1 Asp148Glu; OGG1 Ser326Cys; XPA −4 G/A; XPC PAT; XPD Asp312Asn and Lys751Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR–RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the APE1 Asp148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 ( p = 0.001) for the Asp/Glu genotype and 2.39 ( p = 0.038) for the Glu/Glu genotype. Gene–smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR = 4.92, p = 0.021 for XRCC1 399 Gln/Gln; OR = 3.62, p = 0.049 for XPD 751 Gln/Gln), but not in heavy smokers (≥25 PY; OR = 0.68, p = 0.566 for XRCC1 399 Gln/Gln; OR = 0.46, p = 0.295 for XPD 751 Gln/Gln). Both the XRCC1 Arg194Trp and Arg280His as well as the OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR = 0.32, p = 0.024; OR = 0.25, p = 0.028; OR = 0.51, p = 0.033, respectively). No associations with lung cancer risk were found for the XRCC1 −77 T/C, the XPA −4 G/A and the XPC PAT polymorphisms. In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPD Lys751Gln polymorphisms and lung cancer risk.

Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in Caucasians

STK15/Aurora-A is a centrosome-localized serine/threonine kinase that functions primarily in centrosome maturation and mitotic spindle assembly. In a large lung cancer case-control study of 1401 cases and 1397 controls including three ethnic groups, we examined the associations between two non-synonymous SNPs (Phe31Ile and Val57Ile) of the STK15 gene and lung cancer risk. There were statistically significant differences in the distribution of the genotypes (P<0.0001) and haplotypes (P<0.0001) by ethnicity for the Phe31Ile, but not the Val57Ile variant. Caucasians with the homozygous variant Phe31Ile genotype (Ile/Ile) were at a significantly reduced risk for lung cancer [odds ratio (OR)=0.63, 95% confidence interval (CI)=0.41-0.96]. The variant allele of Val57Ile was not associated with lung cancer risk overall. However, men with the homozygous variant genotype (Ile/Ile) had a reduced lung cancer risk as compared with men with the wild-type genotype (Val/Val) (OR=0.42, 95% CI=0.19-0.94). When we performed joint analysis of these two polymorphisms, compared with the reference group (TT+GG, 40.99% of controls), homozygous Ile31 allele/wild-type Val57 allele (AA+GG) carriers (5.45% of controls) exhibited a reduced lung cancer risk (OR=0.78, 95% CI=0.63-0.97). This is the first epidemiological study to report significant associations between STK15 polymorphisms and lung cancer risk.

Risk of non-small cell lung cancer and the cytochrome P4501A1 Ile462Val polymorphism

The Ile462Val substitution in the cytochrome P450 1A1 gene (CYP1A1) results in increased enzymatic activity. Preliminary data suggesting a link between this polymorphism and lung cancer risk in Caucasians are inconsistent, reflecting small sample sizes and the relatively low frequency of the variant. The data set consisted of 1050 primary non-small cell lung cancer cases and 581 controls, a large homogenous population designed specifically to address previous inconsistencies. Patients were genotyped using a PCR-RFLP technique. Carriers of the valine allele, CYP1A1*2C, (Ile/Val or Val/Val genotypes) were significantly over-represented in non-small cell lung cancer compared to controls (OR=1.9; 95% CI=1.2-2.9; p=0.005) when adjusted for confounders, particularly in women (OR=4.6; 95% CI=1.7-12.4; p=0.003). The valine variant was statistically significantly over-represented in cases of lung cancer younger than the median age (64 years) (OR=2.5; 95% CI=1.3-4.8; p=0.005) and cases with less than the median cumulative tobacco-smoke exposure (46 pack-years) (OR=2.4; 95% CI=1.3-4.7; p=0.007). These new data establish an association between the CYP1A1 Ile462Val polymorphism and the risk of developing non-small cell lung cancer, especially among women.