Lung cancer susceptibility locus at 5p15.33.
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ABSTRACT:
SUBMITTER: McKay JD
PROVIDER: S-EPMC2748187 | biostudies-literature | 2008 Dec
REPOSITORIES: biostudies-literature
Publications
Lung cancer susceptibility locus at 5p15.33.
McKay James D JD Hung Rayjean J RJ Gaborieau Valerie V Boffetta Paolo P Chabrier Amelie A Byrnes Graham G Zaridze David D Mukeria Anush A Szeszenia-Dabrowska Neonilia N Lissowska Jolanta J Rudnai Peter P Fabianova Eleonora E Mates Dana D Bencko Vladimir V Foretova Lenka L Janout Vladimir V McLaughlin John J Shepherd Frances F Montpetit Alexandre A Narod Steven S Krokan Hans E HE Skorpen Frank F Elvestad Maiken Bratt MB Vatten Lars L Njølstad Inger I Axelsson Tomas T Chen Chu C Goodman Gary G Barnett Matt M Loomis Melissa M MM Lubiñski Jan J Matyjasik Joanna J Lener Marcin M Oszutowska Dorota D Field John J Liloglou Triantafillos T Xinarianos George G Cassidy Adrian A Vineis Paolo P Clavel-Chapelon Francoise F Palli Domenico D Tumino Rosario R Krogh Vittorio V Panico Salvatore S González Carlos A CA Ramón Quirós José J Martínez Carmen C Navarro Carmen C Ardanaz Eva E Larrañaga Nerea N Kham Kay Tee KT Key Timothy T Bueno-de-Mesquita H Bas HB Peeters Petra Hm PH Trichopoulou Antonia A Linseisen Jakob J Boeing Heiner H Hallmans Göran G Overvad Kim K Tjønneland Anne A Kumle Merethe M Riboli Elio E Zelenika Diana D Boland Anne A Delepine Marc M Foglio Mario M Lechner Doris D Matsuda Fumihiko F Blanche Helene H Gut Ivo I Heath Simon S Lathrop Mark M Brennan Paul P
Nature genetics 20081102 12
We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer e ...[more]
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Project description:Cleft Lip and Palate Transmembrane Protein 1-Like (CLPTM1L), resides in a region of chromosome 5 for which copy number gain has been found to be the most frequent genetic event in the early stages of non-small cell lung cancer (NSCLC). This locus has been found by multiple genome wide association studies to be associated with lung cancer in both smokers and non-smokers. CLPTM1L has been identified as an overexpressed protein in human ovarian tumor cell lines that are resistant to cisplatin, which is the only insight thus far into the function of CLPTM1L. Here we find CLPTM1L expression to be increased in lung adenocarcinomas compared to matched normal lung tissues and in lung tumor cell lines by mechanisms not exclusive to copy number gain. Upon loss of CLPTM1L accumulation in lung tumor cells, cisplatin and camptothecin induced apoptosis were increased in direct proportion to the level of CLPTM1L knockdown. Bcl-xL accumulation was significantly decreased upon loss of CLPTM1L. Expression of exogenous Bcl-xL abolished sensitization to apoptotic killing with CLPTM1L knockdown. These results demonstrate that CLPTM1L, an overexpressed protein in lung tumor cells, protects from genotoxic stress induced apoptosis through regulation of Bcl-xL. Thus, this study implicates anti-apoptotic CLPTM1L function as a potential mechanism of susceptibility to lung tumorigenesis and resistance to chemotherapy.
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Project description:BackgroundCommon genetic polymorphisms on chromosome 5p15.33, including rs401681 in cleft lip and palate transmembrane 1-like gene (CLPTM1L), have been implicated in susceptibility to lung cancer through genome-wide association studies (GWAS); however, subsequent replication studies yielded controversial results.Methodology and findingsA hospital-based case-control study in a Chinese population was conducted to replicate the association, and then a meta-analysis combining our non-overlapping new data and previously published data was performed to clearly discern the real effect of lung cancer susceptibility. In our study with 611 cases and 1062 controls, the minor allele T carrier (TT plus CT) group conferred an OR of 0.801 (95% CI?=?0.654-0.981) under the dominant model. The meta-analysis comprising 9111 cases and 11424 controls further confirmed the significant association in the dominant model (OR?=?0.842, 95% CI?=?0.795-0.891). By stratified analysis, we revealed that ethnicity and study design might constitute the source of between-study heterogeneity. Besides, the sensitivity and cumulative analyses indicated the high stability of the results.ConclusionThe results from our case-control study and meta-analysis provide convincing evidence that rs401681 is significantly associated with lung cancer risk.
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Project description:BackgroundThe human 5p15.33 locus contains two well-known genes, the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes, which have been implicated in carcinogenesis. A common sequence variant, rs401681, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study. However, subsequent replication studies in diverse populations have yielded inconsistent results. In addition, genetic variants at 5p15.33, including rs401681, have been shown to be involved in the susceptibility to multiple malignancies. Nevertheless, the role of these TERT-CLPTM1L variants in the etiology of esophageal squamous cell carcinoma (ESCC) remains unknown.MethodsWe genotyped the rs401681 polymorphism using TaqMan methodology and analyzed its association with the risk of lung cancer and ESCC in a case-control study of 1,479 cancer patients (726 with lung cancer and 753 with ESCC) and 860 healthy individuals.ResultsLogistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR=0.782, 95% CI=0.625-0.978, P=0.031; CT/TT vs. CC: adjusted OR=0.786; 95% CI=0.635-0.972, P=0.026). Stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma. Furthermore, no significant association was observed between rs401681 and the risk of ESCC (CT vs. CC: adjusted OR=0.910, 95% CI=0.734-1.129, P=0.392; TT vs. CC: adjusted OR=0.897, 95%CI=0.624-1.290, P=0.558; CT/TT vs. CC: adjusted OR=0.908, 95% CI=0.740-1.114, P=0.355).ConclusionsOur findings provide further evidence supporting rs401681 as a genetic variant associated with the risk of lung cancer. In addition, we investigated the correlation between the rs401681 variant and the risk of ESCC in a Han Chinese population, and our results suggest that this genetic variant may not be involved in ESCC risk.
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Project description: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.
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