Abstract
Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10−6), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.
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References
Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40(5):616–622. doi:10.1038/ng.109
Aragaki CC, Greenland S, Probst-Hensch N, Haile RW (1997) Hierarchical modeling of gene-environment interactions: estimating NAT2 genotype-specific dietary effects on adenomatous polyps. Cancer Epidemiol Biomarkers Prev 6(5):307–314
Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE (2007) Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356(13):1317–1326. doi:10.1056/NEJMoa066157
Bailey-Wilson JE, Amos CI, Pinney SM, Petersen GM, de Andrade M, Wiest JS, Fain P, Schwartz AG, You M, Franklin W, Klein C, Gazdar A, Rothschild H, Mandal D, Coons T, Slusser J, Lee J, Gaba C, Kupert E, Perez A, Zhou X, Zeng D, Liu Q, Zhang Q, Seminara D, Minna J, Anderson MW (2004) A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am J Hum Genet 75(3):460–474
Bernatsky S, Clarke AE, Ramsey-Goldman R (2008) Cancer in systemic lupus: what drives the risk? Cancer Causes Control CCC 19(10):1413–1414. doi:10.1007/s10552-008-9191-0
Brennan P, Crispo A, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Fletcher T, Boffetta P (2006) High cumulative risk of lung cancer death among smokers and nonsmokers in Central and Eastern Europe. Am J Epidemiol 164(12):1233–1241
Brenner DR, Hung RJ, Tsao MS, Shepherd FA, Johnston MR, Narod S, Rubenstein W, McLaughlin JR (2010) Lung cancer risk in never-smokers: a population-based case–control study of epidemiologic risk factors. BMC Cancer 10:285. doi:10.1186/1471-2407-10-285
Brenner DR, McLaughlin JR, Hung RJ (2011) Previous lung diseases and lung cancer risk: a systematic review and meta-analysis. PLoS One (accepted)
Cantor RM, Lange K, Sinsheimer JS (2010) Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am J Hum Genet 86(1):6–22. doi:10.1016/j.ajhg.2009.11.017
Chen GK, Witte JS (2007) Enriching the analysis of genome wide association studies with hierarchical modeling. Am J Hum Genet 81(2):397–404
Engels EA (2008) Inflammation in the development of lung cancer: epidemiological evidence. Expert Rev Anticancer Ther 8(4):605–615
Engels EA, Wu X, Gu J, Dong Q, Liu J, Spitz MR (2007) Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer. Cancer Res 67(13):6520–6527
Gao X, Starmer J, Martin ER (2008) A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genet Epidemiol 32(4):361–369. doi:10.1002/gepi.20310
Heron EA, O’Dushlaine C, Segurado R, Gallagher L, Gill M (2011) Exploration of empirical Bayes hierarchical modeling for the analysis of genome-wide association study data. Biostatistics 12(3):445–461. doi:10.1093/biostatistics/kxq072
Hung RJ, Baragatti M, Thomas D, McKay J, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Chabrier A, Moullan N, Canzian F, Hall J, Boffetta P, Brennan P (2007) Inherited predisposition of lung cancer: a hierarchical modeling approach to DNA repair and cell cycle control pathways. Cancer Epidemiol Biomarkers Prev 16(12):2736–2744
Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chen C, Goodman G, Field JK, Liloglou T, Xinarianos G, Cassidy A, McLaughlin J, Liu G, Narod S, Krokan HE, Skorpen F, Elvestad MB, Hveem K, Vatten L, Linseisen J, Clavel-Chapelon F, Vineis P, Bueno-de-Mesquita HB, Lund E, Martinez C, Bingham S, Rasmuson T, Hainaut P, Riboli E, Ahrens W, Benhamou S, Lagiou P, Trichopoulos D, Holcatova I, Merletti F, Kjaerheim K, Agudo A, Macfarlane G, Talamini R, Simonato L, Lowry R, Conway DI, Znaor A, Healy C, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452(7187):633–637
Illumina (2006) Tecnhical Bulletin: whole-genome genotyping with the Sentrix HumanHap300 Genotyping BeadCHip and the Infinium II Assay. Illumina, San Diego
Illumina (2010) The power of intelligent SNP selection: a technical note. Illumina, San Diego
Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, de Bakker PI (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24(24):2938–2939. doi:10.1093/bioinformatics/btn564
Korotkova M, Daha NA, Seddighzadeh M, Ding B, Catrina AI, Lindblad S, Huizinga TW, Toes RE, Alfredsson L, Klareskog L, Jakobsson PJ, Padyukov L (2011) Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis. Eur J Hum Genet 19(8):908–914. doi:10.1038/ejhg.2011.50
Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM, Rotunno M, Mirabello L, Jacobs K, Wheeler W, Yeager M, Bergen AW, Li Q, Consonni D, Pesatori AC, Wacholder S, Thun M, Diver R, Oken M, Virtamo J, Albanes D, Wang Z, Burdette L, Doheny KF, Pugh EW, Laurie C, Brennan P, Hung R, Gaborieau V, McKay JD, Lathrop M, McLaughlin J, Wang Y, Tsao MS, Spitz MR, Krokan H, Vatten L, Skorpen F, Arnesen E, Benhamou S, Bouchard C, Metsapalu A, Vooder T, Nelis M, Valk K, Field JK, Chen C, Goodman G, Sulem P, Thorleifsson G, Rafnar T, Eisen T, Sauter W, Rosenberger A, Bickeboller H, Risch A, Chang-Claude J, Wichmann HE, Stefansson K, Houlston R, Amos CI, Fraumeni JF Jr, Savage SA, Bertazzi PA, Tucker MA, Chanock S, Caporaso NE (2009) A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 85(5):679–691. doi:10.1016/j.ajhg.2009.09.012
Lee WJ, Brennan P, Boffetta P, London SJ, Benhamou S, Rannug A, To-Figueras J, Ingelman-Sundberg M, Shields P, Gaspari L, Taioli E (2002) Microsomal epoxide hydrolase polymorphisms and lung cancer risk: a quantitative review. Biomarkers 7(3):230–241. doi:10.1080/13547500210121882
Lewinger JP, Conti DV, Baurley JW, Triche TJ, Thomas DC (2007) Hierarchical Bayes prioritization of marker associations from a genome-wide association scan for further investigation. Genet Epidemiol 31(8):871–882. doi:10.1002/gepi.20248
Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS (2001) eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ Res 89(9):793–798
McDevitt HO (1980) Regulation of the immune response by the major histocompatibility system. New Eng J Med 303(26):1514–1517. doi:10.1056/NEJM198012253032606
McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, McLaughlin J, Shepherd F, Montpetit A, Narod S, Krokan HE, Skorpen F, Elvestad MB, Vatten L, Njolstad I, Axelsson T, Chen C, Goodman G, Barnett M, Loomis MM, Lubinski J, Matyjasik J, Lener M, Oszutowska D, Field J, Liloglou T, Xinarianos G, Cassidy A, Vineis P, Clavel-Chapelon F, Palli D, Tumino R, Krogh V, Panico S, Gonzalez CA, Ramon Quiros J, Martinez C, Navarro C, Ardanaz E, Larranaga N, Kham KT, Key T, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Linseisen J, Boeing H, Hallmans G, Overvad K, Tjonneland A, Kumle M, Riboli E, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) Lung cancer susceptibility locus at 5p15.33. Nat Genet 40(12):1404–1406. doi:10.1038/ng.254
Parikh-Patel A, White RH, Allen M, Cress R (2008) Cancer risk in a cohort of patients with systemic lupus erythematosus (SLE) in California. Cancer Causes Control CCC 19(8):887–894. doi:10.1007/s10552-008-9151-8
Peek RM Jr, Mohla S, DuBois RN (2005) Inflammation in the genesis and perpetuation of cancer: summary and recommendations from a national cancer institute-sponsored meeting. Cancer Res 65(19):8583–8586
Petruzzelli S, Franchi M, Gronchi L, Janni A, Oesch F, Pacifici GM, Giuntini C (1992) Cigarette smoke inhibits cytosolic but not microsomal epoxide hydrolase of human lung. Hum Exp Toxicol 11(2):99–103
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575
Santos JH, Meyer JN, Skorvaga M, Annab LA, Van Houten B (2004) Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell 3(6):399–411. doi:10.1111/j.1474-9728.2004.00124.x
Sauter W, Rosenberger A, Beckmann L, Kropp S, Mittelstrass K, Timofeeva M, Wolke G, Steinwachs A, Scheiner D, Meese E, Sybrecht G, Kronenberg F, Dienemann H, Chang-Claude J, Illig T, Wichmann HE, Bickeboller H, Risch A (2008) Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidemiol Biomarkers Prev 17(5):1127–1135. doi:10.1158/1055-9965.EPI-07-2840
Shi J, Chatterjee N, Rotunno M, Wang Y, Pesatori AC, Consonni D, Peng L, Wheeler W, Broderick P, Henrion M, Eisen T, Wang Z, Chen W, Dong Q, Albanes D, Thun M, Spitz MR, Bertazzi PA, Caporaso NE, Chanock SJ, Amos CI, Houlston RS, Landi MT (2012) Inherited variation at chromosome 12p13.33, including RAD52, influences the risk of squamous cell lung carcinoma. Cancer Discovery 2(2):131–139
Siva N (2008) 1000 Genomes project. Nat Biotechnol 26(3):256. doi:10.1038/nbt0308-256b
Spitz M, Gorlov I, Dong Q, Wu X, Chen W, Chang D, Etzel C, Caporaso NE, Zhao Y, Christiani DC, Brennan P, Albanes D, Shi J, Thun MJ, Landi MT, Amos CI (2012) Multistage analysis of variants in the inflammation pathway and lung cancer risk in smokers. Cancer Discovery 3(1)
Spitz MR, Gorlov IP, Dong Q, Wu X, Chen W, Chang DW, Etzel CJ, Caporaso NE, Zhao Y, Christiani DC, Brennan P, Albanes D, Shi J, Thun M, Landi MT, Amos CI (2012b) Multistage analysis of variants in the inflammation pathway and lung cancer risk in smokers. Cancer Epidemiol Biomarkers Prev 21(7):1213–1221. doi:10.1158/1055-9965.EPI-12-0352-T
The International HapMap Project (2003) Nature 426(6968):789–796
Thompson JR, Attia J, Minelli C (2011) The meta-analysis of genome-wide association studies. Brief Bioinform 12(3):259–269. doi:10.1093/bib/bbr020
Thornquist MD, Omenn GS, Goodman GE, Grizzle JE, Rosenstock L, Barnhart S, Anderson GL, Hammar S, Balmes J, Cherniack M et al (1993) Statistical design and monitoring of the Carotene and Retinol Efficacy Trial (CARET). Control Clin Trials 14(4):308–324
Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, Qureshi M, Dong Q, Gu X, Chen WV, Spitz MR, Eisen T, Amos CI, Houlston RS (2008) Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet 40(12):1407–1409. doi:10.1038/ng.273
Wang K, Li M, Hakonarson H (2010) Analysing biological pathways in genome-wide association studies. Nat Rev Genet 11(12):843–854. doi:10.1038/nrg2884
Witte JS (1997) Genetic analysis with hierarchical models. Genet Epidemiol 14(6):1137–1142
Witte JS, Greenland S (1996) Simulation study of hierarchical regression. Stat Med 15(11):1161–1170
Yanai I, Benjamin H, Shmoish M, Chalifa-Caspi V, Shklar M, Ophir R, Bar-Even A, Horn-Saban S, Safran M, Domany E, Lancet D, Shmueli O (2005) Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification. Bioinformatics 21(5):650–659. doi:10.1093/bioinformatics/bti042
Yu YY, Pinsky PF, Caporaso NE, Chatterjee N, Baumgarten M, Langenberg P, Furuno JP, Lan Q, Engels EA (2008) Lung cancer risk following detection of pulmonary scarring by chest radiography in the prostate, lung, colorectal, and ovarian cancer screening trial. Arch Intern Med 168(21):2326–2332 (discussion 2332). doi:10.1001/archinte.168.21.2326
Acknowledgments
RJH holds a Cancer Care Ontario Chair in Population Studies. DRB holds a Canadian Institutes of Health Research Canada Graduate Scholarship. This research was supported by funding from Training grant GET-101831. DRB is a fellow of CIHR STAGE (Strategic Training for Advanced Genetic Epidemiology) – CIHR Training Grant in Genetic Epidemiology and Statistical Genetics. The work is supported by a Canadian Cancer Society Research Institute grant (no. 020214) and a U19 grant from the National Institutes of Health (U19 CA148127). The MD Anderson study was supported by a grant from the National Institutes of Health CA127219. The central Europe study was a multi-center study conducted in seven central European countries. The following investigators are responsible for the collection of data at each of the sites: Neonila Szeszenia-Dabrowska, Jolanta Lissowska, David Zaridze, Peter Rudnai, Eleonora Fabianova, Lenka Foretova, Vladimir Janout, Vladimir Bencko, Miriam Schejbalova.
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Brenner, D.R., Brennan, P., Boffetta, P. et al. Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls. Hum Genet 132, 579–589 (2013). https://doi.org/10.1007/s00439-013-1270-y
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DOI: https://doi.org/10.1007/s00439-013-1270-y