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International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.

ABSTRACT: BACKGROUND:Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3). METHODS:Genotype data from 15 ILCCO case-control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk. RESULTS:Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10(-4)). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11,722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89-0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85-0.95), P = 1 x 10(-4)]. CONCLUSION:This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.

SUBMITTER: Truong T

PROVIDER: S-EPMC2847090 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.

Truong Therese T Sauter Wiebke W McKay James D JD Hosgood H Dean HD Gallagher Carla C Amos Christopher I CI Spitz Margaret M Muscat Joshua J Lazarus Philip P Illig Thomas T Wichmann H Erich HE Bickeböller Heike H Risch Angela A Dienemann Hendrik H Zhang Zuo-Feng ZF Naeim Behnaz Pezeshki BP Yang Ping P Zienolddiny Shanbeh S Haugen Aage A Le Marchand Loïc L Hong Yun-Chul YC Kim Jin Hee JH Duell Eric J EJ Andrew Angeline S AS Kiyohara Chikako C Shen Hongbing H Matsuo Keitaro K Suzuki Takeshi T Seow Adeline A Ng Daniel P K DP Lan Qing Q Zaridze David D Szeszenia-Dabrowska Neonilia N Lissowska Jolanta J Rudnai Peter P Fabianova Eleonora E Constantinescu Vali V Bencko Vladimir V Foretova Lenka L Janout Vladimir V Caporaso Neil E NE Albanes Demetrius D Thun Michael M Landi Maria Teresa MT Trubicka Joanna J Lener Marcin M Lubinski Jan J Wang Ying Y Chabrier Amélie A Boffetta Paolo P Brennan Paul P Hung Rayjean J RJ

Carcinogenesis 20100127 4

<h4>Background</h4>Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B ...[more]

PMID: 20106900

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Project description:BackgroundGenome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies.MethodsGenotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided.ResultsAssociations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer.ConclusionsIn this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

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International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.

Publications

International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.

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