Lung Cancer OncoArray Project Identified New Lung Cancer Susceptibility Loci

Rayjean HUNG, Mount Sinai Hospital, Canada
HAN Y. 3 , LI Y. 3 , ZONG X. 1 , XIAO X. 3 , MCKAY J. 2 , LANDI M. 4 , CAPORASO N. 4 , CHRISTIANI D. 5 , WU X. 6 , LE MARCHAND L. 7 , FIELD J. 8 , BICKEBÖLLER H. 9 , JOHANSSON M. 2 , TRICL, ILCCO AND LC3 I. 10 , BRENNAN P. 2 , AMOS C. 3

1 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada
2 International Agency for Research on Cancer, Lyon, France
3 Geisel School of Medicine, Dartmouth College, Lebanon, USA
4 National Cancer Institute, Bethesda, USA
5 Harvard School of Public Health, Boston, USA
6 MD Anderson Cancer Center, Texas USA
7 University of Hawaii Cancer Center, Honolulu, USA
8 University of Liverpool Cancer Research Centre, Liverpool, UK
9 Georg-August-University Göttingen, Göttingen, Germany
10 Demetrius Albanes, NCI, USA; Melinda C. Aldrich, Vanderbilt University, USA; Angeline S. Andrew, Dartmouth Medical School; Susanne Arnold, Markey Cancer Center, USA; Chu Chen and Gary E. Goodman, Fred Hutchinson Cancer Research Center, USA; Jennifer Doherty, Dartmouth Medical School, USA; Yun-Chul Hong, Seoul National University, Korea; Lambertus A. Kiemeney, Radboud University Nijmegen Medical Centre, The Netherlands; Aage Haugen, National Institute of Occupational Health, Norway; Stephen Lam, University of British Columbia, Canada; Philip Lazarus, Washington State University, USA; Geoffrey Liu, Princess Margaret Cancer Center, Canada; Jonas Manjer, Lund University, Sweden; Gad Rennert, Carmel Medical Center, Israel; Matthew B. Schabath, Moffitt Cancer Center, USA; Adonina Tardon, Universidad de Oviedo and CIBERESP, Spain; Dawn Teare, University of Sheffield, UK; Jian-Min Yuan, University of Pittsburgh Cancer Institute, USA

Background: Genome-wide association studies(GWAS) have identified several lung cancer loci in CHRNA3/5, TERT, HLA, BRCA2, CHEK2 and more, although much of its heritability remains unexplained.  With comprehensively characterize lung cancer genetic susceptibility, the investigators in Transdisciplinary Research of the Lung(TRICL), International Lung Cancer Consortium(ILCCO) and Lung Cancer Cohort Consortium(LC3) launched the Lung Cancer OncoArray project. Method: In collaboration with NCI GAME-ON Network, a customized OncoArray with cancer-specific contents and genome-wide backbone was developed. A total of 18,251 lung cases and 15,220 controls from 29 studies were genotyped.  Standard QC procedures were applied resulting in 17,889 cases and 14,969 controls with European ancestry, and imputation was performed based on 1000 genome reference panel. The associations were estimated by unconditional logistic regression under log-additive model. To maximize the statistical power, we conducted a combined analysis with previous GWAS data, adding to a total of 28,082 cases and 54,395 controls. The effects by histological subtypes and smoking status were evaluated and the heterogeneity was assessed based on Q and I2 statistics.  Results: We identified 10 novel lung cancer loci with p-value less than 5x10-8 and odds ratios ranged from 0.83 to 1.85, including those in 1p31(p=6.77x10-11), 2p15(p=1.92x10-9), 6p25(p=1.54x10-8), 8p12(p=2.06x10-10), 10q24(p=3.22x10-9), 11q23(9.84x10-11), 12p13(1.19x10-10), 15q21(p=2.65x10-8), 19q13(p=9.12x10-19) and 20q13(p=6.05x10-9).  The genetic region in 1p31, 11q23, 15q21 and 19q13 were associated with lung cancer risk overall, while 2p15 and 12p13 were associated with squamous cell carcinoma.  The rest were predominately associated with lung adenocarcinoma. Notably these regions encode genes related to cancer biology(NRG1, IRF4), tobacco metabolism(CYP2A6), and telomere regulation(RTEL1, OBFC1). Conclusions: Based on the largest collaborative analysis for lung cancer genetics to date, we identified additional novel loci specific for histological subtypes.  Independent validation and functional characterization are currently underway. These results further our understanding of lung cancer etiology overall and for specific histological subtypes.