Eun Jin Kim

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.

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.

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.

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.

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-α (TNF-α), interleukin-1β (IL-1β), 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 [IVS4xa0+xa014Gxa0>xa0C (rs3731865), D543xa0N (rs17235409), and *86Axa0>xa0G (rs1059823)] in 83 COPD patients and 203 healthy controls. Individuals with at least one variant allele of the D543xa0N and *86Axa0>xa0G polymorphisms were at a significantly increased risk for COPD compared with carriers with each homozygous wild-type allele [adjusted odds ratio (OR)xa0=xa02.23, 95% confidence interval (CI)xa0=xa01.24–4.02, Pxa0=xa00.007; and adjusted ORxa0=xa01.92, 95% CIxa0=xa01.10–3.35, Pxa0=xa00.022, respectively]. Consistent with the findings of the genotyping analysis, the 122 haplotype carrying both the 543xa0N and *86G alleles was associated with a significantly increased risk for COPD compared with the 111 haplotype with the 542D and *86A alleles (adjusted ORxa0=xa02.05, 95% CIxa0=xa01.19–3.51, Pxa0=xa00.009 and Bonferroni corrected Pxa0=xa00.027). 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.