Sung Ick Cha

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 (Ptrend < 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. (Cancer Sci 2008; 99: 1385–1389)

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.

Lys751Gln polymorphism in the DNA repair gene XPD and risk of primary lung cancer.

a Department of Internal Medicine, School of Medicine, Kyungpook National Uni ersity Hospital, Samduk 2ga 50, Taegu 700-412, South Korea b Cancer Research Institute, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea c Department of Biochemistry, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea d Department of Thoracic Surgery, School of Medicine, Kyungpook National Uni ersity Hospital, Samduk 2ga 50, Taegu 700-412, South Korea e Department of Internal Medicine, School of Medicine, Keimyung Uni ersity, Dongsan Dong 194, Taegu 700-712, South Korea f Department of Pre enti e Medicine, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea

Combined effects of p73 and MDM2 polymorphisms on the risk of lung cancer.

p73, a structural and functional homologue of p53, plays an important role in modulating cell‐cycle control and apoptosis. MDM2 represses the transcriptional activity of p73 and thus attenuates its activity. Based on the interaction between p73 and MDM2 in cell‐cycle control and apoptosis, we investigated the association between p73 G4C14‐to‐A4T14 and MDM2 309Tu2009>u2009G polymorphisms, alone and in combination, on the risk of lung cancer in a Korean population. The p73 and MDM2 genotypes were determined in 582 lung cancer patients and in 582 healthy control subjects who were frequency‐matched for age and gender. The p73 AT/AT and MDM2 309 GG genotypes were associated with a nonsignificant increased risk of lung cancer (adjusted odds ratio [OR]u2009=u20091.37, 95% confidence interval [CI]u2009=u20090.83–2.24; and adjusted ORu2009=u20091.29, 95% CIu2009=u20090.92–1.80, respectively), compared with their wild‐type genotypes, respectively. When the p73 and MDM2 polymorphisms were combined, the risk of lung cancer increased in a dose‐dependent manner as the number of variant alleles increased (Ptrendu2009=u20090.01). Subjects with three or four variant alleles were at a significantly increased risk of lung cancer (adjusted ORu2009=u20091.74, 95% CIu2009=u20091.11–2.74, Pu2009=u20090.02) compared to subjects with zero variant allele. These results suggest an additive effect of the p73 and MDM2 variant alleles on an increased risk of lung cancer.

Polymorphisms in the Caspase7 gene and the risk of lung cancer

BACKGROUNDnCaspase7 (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.nnnMETHODSnWe 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.nnnRESULTSnOf 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).nnnCONCLUSIONnThese 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.

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 −928Au2009>u2009G, 77Gu2009>u2009A, and 17532Au2009>u2009C 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)u2009=u20090.79, 95% confidence interval (CI)u2009=u20090.62–1.00, Pu2009=u20090.05; adjusted ORu2009=u20090.78, 95% CIu2009=u20090.61–0.99, Pu2009=u20090.04; and adjusted ORu2009=u20090.74, 95% CIu2009=u20090.58–0.95, Pu2009=u20090.02, respectively]. Consistent with the results of genotyping analysis, the GAGC haplotype carrying the variant allele at all of the −928Au2009>u2009G, 77Gu2009>u2009A, and 17532Au2009>u2009C 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 ORu2009=u20090.66, 95% CIu2009=u20090.51–0.86, Pu2009=u20090.002 and Bonferroni corrected Pu2009=u20090.008). These results suggest that the CASP‐3 polymorphisms and their haplotypes contribute to the genetic susceptibility to lung cancer.

No Association Between p73 G4C14-to-A4T14 Polymorphism and the Risk of Lung Cancer in a Korean Population

A member of the p53 family, p73 may play an important role in the development of lung cancer. Variations in the DNA sequence in the p73 gene can lead to alterations in the production of p73 and/or activity, which can affect an individual’s susceptibility to lung cancer. To test this hypothesis, this study examined the association between the G4C14-to-A4T14 polymorphism in the p73 gene and the risk of lung cancer in a Korean population. The p73 G4C14-to-A4T14 genotypes were determined in 582 lung cancer patients and 582 healthy age- and gender-matched control subjects. Compared with the GC/GC genotype, the GC/AT and the AT/AT genotypes were not significantly associated with the risk of lung cancer [adjusted odds ratio (OR)u2009=u20091.08, 95% confidence interval (CI)u2009=u20090.84–1.38; and adjusted ORu2009=u20091.37, 95% CIu2009=u20090.83–2.24, respectively]. In addition, the risk estimate for the combined variant genotype (GC/ATu2009+u2009AT/AT) was similar to that of the GC/GC genotype (a dominant model for the AT allele, adjusted ORu2009=u20091.12, 95% CIu2009=u20090.88–1.41). These results suggest that the p73 G4C14-to-A4T14 polymorphism does not significantly affect susceptibility to lung cancer in the Korean population.

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

BACKGROUNDnAlthough 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.nnnMETHODSnThe IL1B and IL1RN genotypes were determined in 311 COPD patients and 386 healthy controls.nnnRESULTSnIndividuals 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).nnnCONCLUSIONnThese findings suggest that polymorphisms in the IL1B and IL1RN genes might be useful markers for determining genetic susceptibility to COPD in a Korean population.

Comprehensive assessment of P21 polymorphisms and lung cancer risk

AbstractThe 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.