Tae Hoon Jung

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.

XPC polymorphisms and lung cancer risk

Polymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individuals susceptibility to smoking‐related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (–449G→C, –371G→A, –27G→C, Val499Arg, PAT–/+, IVS11‐5C→A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency‐matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined –27CG+CC genotype was associated with a significantly increased risk for overall lung cancer compared to the –27GG genotype (adjusted OR = 1.97, 95% CI 1.22–3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the –371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined –371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09–4.00, p = 0.03). The PAT–/+, IVS11‐5C→A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29–0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36–1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35–0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11‐5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37–0.85, p = 0.007 and Bonferroni‐corrected p = 0.049), whereas haplotype 5 (1122111) containing the –27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41–5.87, p = 0.004 and Bonferroni‐corrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer.

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

-93G→A polymorphism of hMLH1 and risk of primary lung cancer

Polymorphisms in DNA repair genes may be associated with differences in the repair capacity of DNA damage and may thereby influence an individuals susceptibility to smoking‐related cancer. We investigated the association between the −93G→A polymorphism in the hMLH1 gene and the risk of lung cancer in a Korean population. The hMLH1 −93G→A polymorphism was typed in 372 lung cancer patients and 371 healthy controls that were frequency‐matched for age and sex. There was no significant association between the hMLH1 −93G→A genotype and the risk for adenocarcinoma or small cell carcinoma. However, the AA genotype was associated with a significantly increased risk for squamous cell carcinoma compared with both the GG genotype (adjusted OR = 2.02; 95% CI = 1.15–3.55; p = 0.014) and the combined GG and GA genotype (adjusted OR = 1.83; 95% CI = 1.24–2.71; p = 0.003). When the subjects were stratified by smoking exposure, the AA genotype was associated with a significantly increased risk for squamous cell carcinoma in lighter smokers (≤ 39 pack‐years; adjusted OR = 1.95; 95% CI = 1.03–3.66; p = 0.039) compared with the combined GG and GA genotype, whereas there was no significant association in heavier smokers (> 39 pack‐years; adjusted OR = 1.47; 95% CI = 0.82–2.61). These results suggest that the hMLH1 −93G→A polymorphism could be used as a marker of genetic susceptibility to squamous cell carcinoma of the lung.

Replication of results of genome-wide association studies on lung cancer susceptibility loci in a Korean population.

Background and objective:u2003 Genome‐wide association studies (GWAS) have identified the three chromosomal regions, 5p15, 6p21 and 15q25, as being associated with lung cancer risk in European populations. This study was performed to confirm these associations in Korean patients with lung cancer.

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.

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

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.