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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.pdf (1.38 MB)

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

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posted on 2019-07-01, 13:31 authored by X Ji, Y Bossé, MT Landi, J Gui, X Xiao, D Qian, P Joubert, M Lamontagne, Y Li, I Gorlov, M de Biasi, Y Han, O Gorlova, RJ Hung, X Wu, J McKay, X Zong, R Carreras-Torres, DC Christiani, N Caporaso, M Johansson, G Liu, SE Bojesen, L Le Marchand, D Albanes, H Bickeböller, MC Aldrich, WS Bush, A Tardon, G Rennert, C Chen, MD Teare, JK Field, LA Kiemeney, P Lazarus, A Haugen, S Lam, MB Schabath, AS Andrew, H Shen, Y-C Hong, J-M Yuan, PA Bertazzi, AC Pesatori, Y Ye, N Diao, L Su, R Zhang, Y Brhane, N Leighl, JS Johansen, A Mellemgaard, W Saliba, C Haiman, L Wilkens, A Fernandez-Somoano, G Fernandez-Tardon, EHFM van der Heijden, JH Kim, J Dai, Z Hu, MPA Davies, MW Marcus, H Brunnström, J Manjer, O Melander, DC Muller, K Overvad, A Trichopoulou, R Tumino, J Doherty, GE Goodman, A Cox, F Taylor, P Woll, I Brüske, J Manz, T Muley, A Risch, A Rosenberger, K Grankvist, F Shepherd, M-S Tsao, SM Arnold, EB Haura, C Bolca, I Holcatova, V Janout, M Kontic, J Lissowska, A Mukeria, S Ognjanovic, TM Orlowski, G Scelo, B Swiatkowska, D Zaridze, P Bakke, V Skaug, S Zienolddiny, EJ Duell, LM Butler, W-P Koh, Y-T Gao, R Houlston, J McLaughlin, V Stevens, DC Nickle, M Obeidat, W Timens, B Zhu, L Song, MS Artigas, MD Tobin, LV Wain, F Gu, J Byun, A Kamal, D Zhu, RF Tyndale, W-Q Wei, S Chanock, P Brennan, CI Amos
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.


This work was supported by National Institutes of Health (NIH) for the research of lung cancer (grants P30CA023108, P20GM103534, and R01LM012012); Transdisciplinary Research in Cancer of the Lung (TRICL) (grant U19CA148127); UICC American Cancer Society Beginning Investigators Fellowship funded by the Union for International Cancer Control (UICC) (to X.J.). CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA) of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN.CARET study was supported by NIH awards UM1 CA167462, UO1-CA6367307, CA111703, and R01 CA151989. The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by NIH grants CA092824, CA090578, and CA074386. The Multiethnic Cohort Study was partially supported by NIH grants CA164973, CA033619, CA63464, and CA148127. The MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. R.T is supported by a Canada Research Chair in Pharmacogenomics, CIHR grant (FDN-154294), and CAMH. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study was supported by NIH R01 CA144034 and UM1 CA182876. The Singapore Chinese Health Study (SCHS) was supported by NIH R01 CA144034 and UM1 CA182876. The TLC study has been supported in part by the James & Esther King Biomedical Resear



Nature Communications, 2018, 9:3221

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The data that support the findings of this study are available. The access numbers are “phs000336.v1.p1.c1” for EAGLE study, “phs000753.v1.p1” for MDACC study, and “phs001273” for Oncoarray study in dbGAP. The IARC study was made available at



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