A functional polymorphism on chromosome 15q25 associated with survival of early stage non-small-cell lung cancer.

INTRODUCTION: The 15q25 region has been associated with lung-cancer risk and might also be associated with the prognosis of lung cancer. This study was conducted to determine the impact of a functional polymorphism in the CHRNA3 gene on chromosome 15q25 in the survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Five hundred and eighty-three consecutive patients with surgically resected NSCLC were enrolled. The rs6495309C > T polymorphism in the promoter of the CHRNA3 gene was investigated. The association between genotype and overall survival (OS) and disease-free survival (DFS) was analyzed. RESULTS: Patients with the rs6495309 CT or TT genotype had a significantly better OS and DFS than the rs6495309 CC genotype (adjusted hazard ratio for OS = 0.56, 95% confidence interval = 0.41-0.75, p = 0.0001; and adjusted hazard ratio for DFS = 0.61, 95% confidence interval = 0.48-0.79, p = 0.0001). An association between the rs6495309C > T polymorphism and survival outcome was demonstrated in smokers and never-smokers, and in squamous-cell carcinomas and adenocarcinomas. CONCLUSION: The CHRNA3 rs6495309C > T polymorphism may affect survival in patients with early-stage NSCLC. Analysis of the rs6495309C > T polymorphism can help identify patients at high risk of a poor disease outcome.

Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia.

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.

EML4-ALK fusion gene in Korean non-small cell lung cancer.

A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has been identified in non-small cell lung cancers (NSCLCs). Although a few studies have evaluated EML4-ALK fusion genes in Korean NSCLCs, the prevalence of different EML4-ALK fusion variants has yet to be clearly assessed. Herein, we have examined the profiles of EML4-ALK fusion gene variants in Korean patients of NSCLCs. EML4-ALK fusion genes have been detected in 10 (6.0%) of 167 patients of NSCLCs and in 9 (7.4%) of 121 patients of adenocarcinoma. Of the 10 patients with fusion genes identified, 8 (80%) were E13;A20 (variant 1) and 2 (20%) were E6;A20, with an additional 33-bp sequence derived from intron 6 of EML4 (variant 3b). These results indicate that the profiles of EML4-ALK fusion gene variants in Korean patients of NSCLC may differ from those in other ethnic populations. Herein, we describe for the first time the profiles of EML4-ALK fusion variants of Korean patients with NSCLCs.

AKT1 polymorphisms and survival of early stage non-small cell lung cancer.

BACKGROUND AND OBJECTIVES: This study was conducted to investigate the impact of polymorphisms in the AKT1 gene on the survival of early stage non-small cell lung cancer (NSCLC) patients. METHODS: Three hundred and ten patients with surgically resected NSCLC were enrolled. The rs3803300, rs1130214, rs3730358, rs1130233, and rs2494732 single nucleotide polymorphisms (SNPs) in the AKT1 gene were investigated. The genotype and haplotype associations with overall survival (OS) and disease free survival (DFS) were analyzed. RESULTS: The three SNPs (rs3803300, rs1130214, and rs2494732) were significantly associated with survival outcomes on multivariate analysis. When the three SNPs were combined, OS and DFS were decreased in a dose-dependent manner as the number of bad genotypes increased (P(trend) = <1.0 × 10(-4) and 0.001, respectively). Patients with 2 bad genotypes had a significantly worse OS and DFS compared with those with 0 bad genotypes (adjusted hazard ratio (HR) = 3.08, 95% confidence interval (CI) = 1.61-5.89, P = 0.001; and adjusted HR = 2.04, 95% CI = 1.22-3.43, P = 0.01). CONCLUSIONS: These results suggest that the AKT1 polymorphisms could be used as prognostic markers for the patients with early-stage NSCLC.

Associations between polymorphisms in DNA repair genes and TP53 mutations in non-small cell lung cancer.

This study was conducted to identify genetic factors predisposing to TP53 mutations in patients with non-small cell lung cancer (NSCLC). A comprehensive panel of potentially functional single nucleotide polymorphisms (SNPs) in DNA repair genes was evaluated in relation to TP53 mutations. Thirty-seven SNPs in 28 DNA repair genes were genotyped by a sequenome mass spectrometry-based genotyping assay in 173 NSCLCs and the associations with TP53 mutations in the entire coding exons (exons 2-11), including splicing sites of the gene, were analyzed. Four SNPs (XPA rs1800975, OGG1 rs1052133, ADPRT rs1136410, and NBS1 rs1805794) were significantly associated with the prevalence of TP53 mutations in multivariate analysis for each SNP. When the 4 SNPs were combined, the prevalence of TP53 mutations was increased as the number of bad genotypes increased (P(trend)=0.001). Patients with 3 and 4 bad genotypes had a significantly higher frequency of TP53 mutations than those with 0-1 bad genotypes (adjusted odds ratio=5.18, 95% confidence interval=1.51-17.81, P=0.01 and adjusted odds ratio=18.26, 95% confidence interval=2.87-116.09, P=0.002, respectively). These findings suggest that the 4 SNPs may modulate the occurrence of TP53 mutations and contribute to lung carcinogenesis. However, larger studies are required to confirm our findings in other ethnic populations.

Dual roles of a variable number of tandem repeat polymorphism in the TERT gene in lung cancer.

This study was conducted to determine the impact of a functional tandem repeat minisatellite (MNS16A) polymorphism in the telomerase reverse transcriptase (TERT) gene on the risk of lung cancer, as well as on survival of patients with non-small-cell lung cancer (NSCLC). The effect of the MNS16A variable number of tandem repeat (VNTR) polymorphism on the risk of lung cancer was evaluated in a case-control study that consisted of 937 lung cancer patients and 943 healthy controls. The effect of the polymorphism on survival outcome was evaluated in 703 patients with surgically resected NSCLC. Compared with the VNTR-302 allele, the VNTR-243 allele was associated with a significantly increased risk of lung cancer (adjusted odds ratio, 1.55; 95% confidence interval [CI], 1.07-2.25; P = 0.02). In addition, the genotypes carrying at least one VNTR-243 allele were associated with a significantly increased risk of lung cancer compared with the genotypes with no VNTR-243 allele (adjusted odds ratio, 1.61; 95% CI, 1.09-2.38; P = 0.02). In contrast to the effect of the polymorphism on the risk of lung cancer, the genotypes carrying at least one VNTR-243 allele were associated with a significantly better overall survival in patients with surgically resected NSCLC (adjusted hazard ratio, 0.51; 95% CI, 0.28-0.93; P = 0.03). These findings suggest that the MNS16A VNTR polymorphism in the TERT gene has dual, conflicting roles in lung carcinogenesis. This polymorphism may increase the risk of lung cancer development, and may improve survival in lung cancer patients.

The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia.

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10(-7) or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30 x 10(-11)). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38 x 10(-11)). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60 x 10(-20), allelic risk = 1.54, 95% Confidence Interval (CI) 1.41-1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40-1.87), and 2.35 (95% CI: 1.95-2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.

Polymorphisms in apoptosis-related genes and survival of patients with early-stage non-small-cell lung cancer.

PURPOSE: This study was conducted to determine the association between single-nucleotide polymorphisms (SNPs) in apoptosis-related genes and survival outcomes of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Three hundred ten consecutive patients with surgically resected NSCLC were enrolled. Twenty-five SNPs in 17 apoptosis-related genes were genotyped by a sequenome mass spectrometry-based genotyping assay. The genotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: Three SNPs (TNFRSF10B rs1047266, TNFRSF1A rs4149570, and PPP1R13L rs1005165) were significantly associated with survival outcomes on multivariate analysis. When the three SNPs were combined, OS and DFS were decreased as the number of bad genotypes increased (P (trend) for OS and DFS = 7 × 10(-5) and 1 × 10(-4), respectively). Patients with one bad genotype, and patients with two or three bad genotypes had significantly worse OS and DFS compared with those with no bad genotypes [adjusted hazard ratio (aHR) for OS = 2.27, 95% confidence interval (CI) = 1.22-4.21, P = 0.01, aHR for DFS = 1.74, 95% CI = 1.08-2.81, P = 0.02; aHR for OS = 4.11, 95% CI = 2.03-8.29, P = 8 × 10(-5); and aHR for DFS = 2.89, 95% CI = 1.64-5.11, P = 3 × 10(-4), respectively]. CONCLUSION: Three SNPs in apoptosis-related genes were identified as possible prognostic markers of survival in patients with early-stage NSCLC. The SNPs, and particularly their combined genotypes, can be used to identify patients at high risk for poor disease outcome.

PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers.

Somatic mutations of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in non-small cell lung cancers (NSCLCs) have been investigated in but a small number of cases. In addition, the relationship between PTEN mutations and epidermal growth factor receptor (EGFR), KRAS, and TP53 mutations has not been investigated. Therefore, we investigated the frequency of PTEN mutations in 176 surgically resected NSCLCs and analyzed the relationship between PTEN mutations and EGFR, ERBB2, KRAS, and TP53 mutations. Mutations of PTEN (exons 1-9), EGFR (exons 18-21), ERBB2 (exons 19 and 20), KRAS (exon 1), and TP53 (exons 2-11) were determined by polymerase chain reaction and direct sequencing. PTEN mutations were present in 8 (4.5%) of the 176 tumors. PTEN mutations were only found in ever-smokers and were significantly more frequent in squamous cell carcinoma than in adenocarcinoma (10.2% vs 1.7%, P=0.02). Mutations of EGFR, ERBB2, KRAS, and TP53 genes were found in 36 (20.5%), 2 (1.1%), 11 (6.3%), and 66 (37.5%) cases, respectively. Of the 8 tumors with PTEN mutations, 1 case concurrently had an EGFR mutation and 4 cases had TP53 mutations. However, PTEN mutations were not found in the tumors with KRAS mutation. Our findings indicate that PTEN mutations are relatively common in NSCLC, and thus analysis of PTEN mutations may facilitate a comprehensive understanding of the genetic alterations related to the EGFR signaling pathway.

Polymorphisms in telomere maintenance genes and risk of lung cancer.

This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C > T and rs2736098 g.G > A, and TNKS1 rs6985140 g.A > G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (P(trend) < 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer.

Polymorphisms in the FAS and FASL genes and survival of early stage non-small cell lung cancer.

PURPOSE: This study was conducted to investigate the impact of functional polymorphisms in the FAS and FASL genes on the survival of early stage non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: Three hundred and thirty-eight consecutive patients with surgically resected NSCLC were enrolled. The FAS -1377G>A (rs2234767) and -670A>G (rs1800682) and FASL -844C>T (rs763110) polymorphisms were investigated. Immunohistochemistry was used to assess FAS protein expression in tumors. The genotype and haplotype associations with survival were analyzed using Cox proportional hazards model, Kaplan-Meier method, and the log-rank test. RESULTS: Patients with the GG and combined AG+GG genotypes of the FAS -670A>G locus had a significantly decreased survival when compared with patients with the AA genotype [adjusted hazard ratio=1.71, 95% confidence interval (95% CI)=1.06-2.77, and P=0.03; and adjusted hazard ratio=1.48, 95% CI=1.01-2.20, and P=0.047, respectively]. In addition, the FAS -1377G/-670G and -1377A/-670G haplotypes exhibited a significantly lower survival compared with the -1377G/-670A haplotype (adjusted hazard ratio=1.87, 95% CI=1.20-2.91, and P=0.006; and adjusted hazard ratio=1.31, 95% CI=1.05-1.65, P=0.02, respectively). Strongly positive FAS immunostaining was significantly less frequent in patients with the FAS -670 AG+GG genotype than in patients with the -670 AA genotype (4.5% versus 10.8%; P=0.04). CONCLUSION: The FAS -670A>G polymorphism may affect survival in early-stage NSCLC. The analysis of the FAS -670A>G polymorphism can help identify patients at high risk for a poor disease outcome.

Polymorphisms in the Caspase7 gene and the risk of lung cancer.

BACKGROUND: Caspase7 (CASP7) is an executioner CASP that conducted a coordinated program of proteolysis that results in the destruction of critical cell structures, and it plays an important role in the development and progression of cancer. The purpose of this study is to comprehensively evaluate potential functional polymorphisms in the CASP7 gene in relation to the risk of lung cancer. METHODS: We first captured seven single nucleotide polymorphisms (SNPs) in the regulating region, exons and exon-intron boundaries of the CASP7 gene using public database and then determined their frequencies in 27 healthy Korean individuals. Next, we examined four SNPs (rs12415607g.C>A; rs11593766g.T>G; rs2227310g.C>G; and rs10787498g.T>C) in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. RESULTS: Of the four SNPs studied in the case-control study, only the distribution of the rs2227310g.C>G genotypes differed significantly between the cases and controls (P=0.03). The rs2227310 GG genotype was associated with a significantly increased risk of lung cancer when compared with the rs2227310 CC genotype [adjusted odds ratio (OR)=1.42, 95% confidence interval (CI)=1.05-1.93, P=0.02] and with the combined rs2227310 CC and CG genotype (adjusted OR=1.38, 95% CI=1.05-1.81, P=0.02). Consistent with the results of genotyping analysis, the ATGT haplotype (rs12415607A/rs11593766T/rs2227310G/rs10787498T) was associated with a significantly increased risk of lung cancer when compared to other haplotypes (adjusted OR=1.21, 95% CI=1.04-1.42, P=0.02). CONCLUSION: These results suggest that the CASP7 polymorphisms contribute to the genetic susceptibility to lung cancer.

Aberrant methylation of ADAMTS1 in non-small cell lung cancer.

ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs) is an extracellular matrix metalloproteinase with protease activity and antiangiogenic activity. It has been suggested that ADAMTS1 plays an important role in tumor growth and metastasis. In this study, we examined ADAMTS1 expression in non-small cell lung cancer (NSCLC), and we also evaluated whether the loss of ADAMTS1 expression is due to aberrant methylation of the gene. In addition, we examined the relationship between ADAMTS1 methylation and clinicopathologic features in NSCLC patients. ADAMTS1 expression was examined using reverse-transcription polymerase chain reaction (PCR), and the methylation status of the gene was evaluated by methylation-specific PCR in NSCLC cell lines (n=10) and primary NSCLC tumors (n=98). Down-regulation of ADAMTS1 was observed in 30% (3/10) of the NSCLC cell lines, and this down-regulation was found to be concordant with aberrant methylation of the gene. Furthermore, ADAMTS1 expression was restored after treatment with the demethylating agent, 5-Aza-2'-deoxycytidine, in cell lines that lacked ADAMTS1 expression. Aberrant methylation of the gene was observed in 31.6% (31 of 98) of the NSCLC tumors, while it was found in only 7.1% (7/98) of the corresponding nonmalignant tissues. Methylation in NSCLC tumors was not correlated with the clinicopathologic features of the patients, such as age, gender, and histology and pathologic staging of the tumor. Taken together, these results suggest that aberrant methylation of ADAMTS1 frequently occurs in NSCLCs and that it may play a role in the pathogenesis of NSCLC.

Polymorphisms in interleukin-1B and its receptor antagonist genes and the risk of chronic obstructive pulmonary disease in a Korean population: a case-control study.

BACKGROUND: Although several studies have evaluated the association between interleukin-1B (IL1B) polymorphisms and the risk of chronic obstructive pulmonary disease (COPD), most of these studies have focused on -511C-->T and -31T-->C polymorphisms, and the results of these studies have been inconsistent. This study was conducted to investigate the association between four potentially functional polymorphisms of the IL1B gene (-3737C-->T, -1464G-->C, -511C-->T, and -31T-->C) and the risk of COPD. In addition, we examined a potential interaction of the IL1B polymorphisms with the VNTR polymorphism of the IL-1 receptor antagonist (IL1RN) gene in determining the risk of COPD. METHODS: The IL1B and IL1RN genotypes were determined in 311 COPD patients and 386 healthy controls. RESULTS: Individuals with at least one variant allele of the -511C-->T and -31T-->C polymorphisms were at a significantly increased risk for COPD when compared to carriers with each homozygous wild-type allele [adjusted odds ratio (OR) 1.53, 95% confidence interval (CI) 1.03-2.26, P=0.03; and adjusted OR 1.50, 95% CI 1.02-2.24, P=0.04, respectively]. When the COPD cases were stratified according to disease severity, the presence of at least one -511T and -31C alleles was significantly associated with severe COPD (adjusted OR 2.80, 95% CI 1.47-5.33, P=0.002; and adjusted OR 2.33, 95% CI 1.24-4.40, P=0.01, respectively), however, there was no significant association between the -511C-->T and -31T-->C genotypes and mild-to-moderate COPD. In addition, individuals carrying at least one IL1RN*2 allele were at a significantly lower risk for COPD compared to subjects carrying no IL1RN*2 allele (adjusted OR 0.51, 95% CI 0.26-0.98, P=0.04). In haplotype/diplotype analyses, individuals with one or two copies of the IL1B CCTC haplotype that carried the risk allele at all of the -3737C-->T, -1464G-->C, -511C-->T, and -31T-->C loci, were at a significantly increased risk of severe COPD when compared with subjects with zero copy of the CCTC haplotype (adjusted OR 1.96, 95% CI 1.16-3.29, P=0.01). CONCLUSION: These findings suggest that polymorphisms in the IL1B and IL1RN genes might be useful markers for determining genetic susceptibility to COPD in a Korean population.

Telomere length and the risk of lung cancer.

Telomeres play a key role in the maintenance of chromosome integrity and stability. There is growing evidence that short telomeres induce chromosome instability and thereby promote the development of cancer. We investigated the association of telomere length and the risk of lung cancer. Relative telomere length in peripheral blood lymphocytes was measured by quantitative polymerase chain reaction in 243 lung cancer patients and 243 healthy controls that were frequency-matched for age, sex and smoking status. Telomere length was significantly shorter in lung cancer patients than in controls (mean +/- standard deviation: 1.59 +/- 0.75 versus 2.16 +/- 1.10, P < 0.0001). When the subjects were categorized into quartiles based on telomere length, the risk of lung cancer was found to increase as telomere length shortened (P(trend) < 0.0001). In addition, when the median of telomere length was used as the cutoff between long and short telomeres, individuals with short telomeres were at a significantly higher risk of lung cancer than those with long telomeres (adjusted odds ratio = 3.15, 95% confidence interval = 2.12-4.67, P < 0.0001). When the cases were categorized by tumor histology, the effect of short telomere length on the risk of lung cancer was more pronounced in patients with small cell carcinoma than in those with squamous cell carcinoma and adenocarcinoma (P = 0.001, test for homogeneity). These findings suggest that shortening of the telomeres may be a risk factor for lung cancer, and therefore, the presence of shortened telomeres may be used as a marker for susceptibility to lung cancer.

SLC11A1 polymorphisms are associated with the risk of chronic obstructive pulmonary disease in a Korean population.

The solute carrier family 11 member 1 (SLC11A1) protein plays important roles in macrophage activation and displays pleiotropic effects on various macrophage functions, including the regulation of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and oxidative burst. Considering the important roles of macrophage in the pathogenesis of chronic obstructive pulmonary disease (COPD), we hypothesized that the SLC11A1 gene may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, we first examined the frequencies of 12 candidate polymorphisms in the SLC11A1 gene in 27 healthy Korean individuals, and then genotyped 3 haplotype-tagging polymorphisms [IVS4 + 14G > C (rs3731865), D543 N (rs17235409), and (*)86A > G (rs1059823)] in 83 COPD patients and 203 healthy controls. Individuals with at least one variant allele of the D543 N and (*)86A > G polymorphisms were at a significantly increased risk for COPD compared with carriers with each homozygous wild-type allele [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.24-4.02, P = 0.007; and adjusted OR = 1.92, 95% CI = 1.10-3.35, P = 0.022, respectively]. Consistent with the findings of the genotyping analysis, the 122 haplotype carrying both the 543 N and (*)86G alleles was associated with a significantly increased risk for COPD compared with the 111 haplotype with the 542D and (*)86A alleles (adjusted OR = 2.05, 95% CI = 1.19-3.51, P = 0.009 and Bonferroni corrected P = 0.027). These findings suggest that the SLC11A1 polymorphisms could be used as markers for genetic susceptibility to COPD. However, further studies with large numbers of subjects are needed to confirm our findings.

Identification of polymorphisms in the XIAP gene and analysis of association with lung cancer risk in a Korean population.

The X-linked inhibitor of apoptosis protein (XIAP) is a potent mammalian IAP, and has been shown to play an important role in development and progression of cancer. Polymorphisms in the XIAP gene may influence XIAP production or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we first screened for polymorphisms in the XIAP gene by direct sequencing of genomic DNA samples from 27 healthy Korean women and then performed a case-control study to evaluate the association between the polymorphisms and the risk of lung cancer. The XIAP genotypes were determined by polymerase chain reaction amplification and melting curve analysis in 582 lung cancer patients and in 582 healthy control subjects who were frequency-matched for age and sex. We identified 12 single nucleotide polymorphisms (SNPs), one novel SNP [30051C>G (A321G) in exon 3] and the following 11 known SNPs: 192G>C (rs5956578), 262C>T (rs28382699), 318C>T (rs5958318), and 374C>T (rs12687176) in the putative promoter; 26615A>G (rs2355676) in intron 1; 41725A>G (rs5958338) in intron 5; 42009A>C (Q423P, rs5956583) in exon 6; 48162T>C (rs17334739) and 48228C>T (rs28382739) in intron 6; and 48542A>G (rs28382740) and 49333G>T (rs28382742) in 3'-UTR. Four of these 12 SNPs were selected for large-scale genotyping based on their frequencies and haplotype tagging status: 262C>T, 318C>T, 374C>T, and 42009A>C. The four XIAP polymorphisms and their haplotypes exhibited no apparent relationship with the risk of lung cancer. In addition, we observed no evidence of effect modification by age, sex, smoking history, or tumor histology. These results suggest that XIAP polymorphisms do not significantly affect susceptibility to lung cancer in Koreans.

Identification of polymorphisms in the Caspase-3 gene and their association with lung cancer risk.

Caspase-3 (CASP-3) is a primary effector CASP that executes programmed cell death, and it plays an important role in the development and progression of cancer. Polymorphisms in the CASP-3 gene may influence CASP-3 production and/or activity, thereby modulating the susceptibility to lung cancer. To test this hypothesis, we first screened for polymorphisms in the CASP-3 gene by direct sequencing of genomic DNA samples from 27 healthy Koreans, and then evaluated their associations with lung cancer in a case-control study that consisted of 582 lung cancer patients and 582 healthy controls. Individuals with at least one variant allele of the -928A > G, 77G > A, and 17532A > C polymorphisms were at a significantly decreased risk for lung cancer in comparison to the carriers with each homozygous wild-type allele [adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.62-1.00, P = 0.05; adjusted OR = 0.78, 95% CI = 0.61-0.99, P = 0.04; and adjusted OR = 0.74, 95% CI = 0.58-0.95, P = 0.02, respectively]. Consistent with the results of genotyping analysis, the GAGC haplotype carrying the variant allele at all of the -928A > G, 77G > A, and 17532A > C loci was associated with a significantly decreased risk of lung cancer compared to the AGGA haplotype carrying no variant alleles at the three loci (adjusted OR = 0.66, 95% CI = 0.51-0.86, P = 0.002 and Bonferroni corrected P = 0.008). These results suggest that the CASP-3 polymorphisms and their haplotypes contribute to the genetic susceptibility to lung cancer.

Comprehensive assessment of P21 polymorphisms and lung cancer risk.

The purpose of this study is to comprehensively evaluate potential functional polymorphisms in the P21 gene in relation to the risk of lung cancer. We first determined the frequencies of P21 polymorphisms in 27 healthy Koreans, and then examined three polymorphisms (-2266G > A, S31R, and IVS2 + 16G > C), based on their frequencies and haplotype-tagging status, in a case-control study. Individuals with at least one -2266A allele were at a significantly decreased risk of lung cancer compared with those harboring the -2266 GG genotype [adjusted odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.53-0.95, P = 0.02). The haplotypes (ht2-4) carrying 31R or IVS2 + 16C alleles were associated with a significantly decreased risk of lung cancer compared with the haplotype 31S/IVS2 + 16G, which carried wild-type alleles at both loci (adjusted OR = 0.65, 95% CI = 0.50-0.83, P = 0.007)]. When the -2266A allele and ht2-4 were considered to be protective alleles, the risk of lung cancer decreased in a dose-dependent manner as the number of protective alleles increased (P = 0.0002). These results suggest that a combined analysis of these three P21 polymorphisms might better predict the risk of lung cancer than the analysis of a single polymorphism.