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International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways.

ABSTRACT: BACKGROUND:The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. METHODS:Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. RESULTS:Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. DISCUSSION:In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies.

SUBMITTER: Hung RJ

PROVIDER: S-EPMC2756735 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways.

Hung Rayjean J RJ Christiani David C DC Risch Angela A Popanda Odilia O Haugen Aage A Zienolddiny Shan S Benhamou Simone S Bouchardy Christine C Lan Qing Q Spitz Margaret R MR Wichmann H-Erich HE LeMarchand Loic L Vineis Paolo P Matullo Giuseppe G Kiyohara Chikako C Zhang Zuo-Feng ZF Pezeshki Benhnaz B Harris Curtis C Mechanic Leah L Seow Adeline A Ng Daniel P K DP Szeszenia-Dabrowska Neonila N Zaridze David D Lissowska Jolanta J Rudnai Peter P Fabianova Eleonora E Mates Dana D Foretova Lenka L Janout Vladimir V Bencko Vladimir V Caporaso Neil N Chen Chu C Duell Eric J EJ Goodman Gary G Field John K JK Houlston Richard S RS Hong Yun-Chul YC Landi Maria Teresa MT Lazarus Philip P Muscat Joshua J McLaughlin John J Schwartz Ann G AG Shen Hongbing H Stucker Isabelle I Tajima Kazuo K Matsuo Keitaro K Thun Michael M Yang Ping P Wiencke John J Andrew Angeline S AS Monnier Stephanie S Boffetta Paolo P Brennan Paul P

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20081101 11

<h4>Background</h4>The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies.<h4>Methods</h4>Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total ...[more]

PMID: 18990748

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Project description:Genome-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.Genotype 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.Associations 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.In 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: pooled analysis of sequence variants in DNA repair and cell cycle pathways.

Publications

International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways.

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