Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

2nd Faculty of Medicine Institute of Public Health and Preventive Medicine Charles University Prague CZ 128 00 Czech Republic

Biomedical Data Science Geisel School of Medicine at Dartmouth Hanover 03755 NH USA

British Columbia Cancer Agency Vancouver V5Z 1M9 Canada

Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine Haifa 3525433 Israel

Clinical Center of Serbia Belgrade 11000 Serbia

Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen 2730 Denmark Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen 2730 Denmark Faculty of Health and Medical Sciences University of Copenhagen Copenhagen 2730 Denmark

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa 33612 FL USA

Department of Clinical Sciences Malmö Lund University Malmö 221 00 Sweden Department of Internal Medicine Skåne University Hospital Malmö Sweden

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Lodz 91 348 Poland

Department of Environmental Health Harvard TH Chan School of Public Health Massachusetts General Hospital Harvard Medical School Boston 02115 MA USA

Department of Epidemiology and Biostatistics Jiangsu Collaborative Innovation Center for Cancer Medicine School of Public Health Nanjing Medical University Nanjing 211166 China

Department of Epidemiology The University of Texas MD Anderson Cancer Center Houston 77030 TX USA

Department of Epidemiology University of Washington School of Public Health and Community Medicine Seattle 98195 WA USA

Department of Epidemiology University of Washington School of Public Health and Community Medicine Seattle 98195 WA USA Fred Hutchinson Cancer Research Center Seattle 98109 WA USA

Department of Genetic Epidemiology University Medical Center Georg August University Göttingen Göttingen 37073 Germany

Department of Medical Biosciences Umeå University Umeå 901 85 Sweden

Department of Oncology University of Sheffield Sheffield S10 2RX UK

Department of Pathology National Tuberculosis and Lung Diseases Research Institute Warsaw 01 138 Poland

Department of Pharmaceutical Sciences College of Pharmacy Washington State University Spokane 99202 WA USA

Department of Preventive Medicine Seoul National University College of Medicine Seoul 110 799 Republic of Korea

Department of Radiation Sciences Umeå University Umeå 901 85 Sweden

Department of Thoracic Surgery Clinical Center of Serbia Belgrade Belgrade 11000 Serbia

Department of Thoracic Surgery Division of Epidemiology Vanderbilt University Medical Center Nashville 37232 4682 TA USA

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda 20892 9768 MD USA

Epidemiology Program University of Hawaii Cancer Center Honolulu 96813 HI USA

Faculty of Medicine University of Olomouc Olomouc 701 03 Czech Republic

Institute of Medical Informatics Biometry and Epidemiology Chair of Epidemiology Ludwig Maximilians University Munich D 85764 Germany Helmholtz Center Munich Institute of Epidemiology 2 Munich D 85764 Germany Institute of Medical Statistics and Epidemiology Technical University Munich Munich D 80333 Germany

Institute of Pneumology Marius Nasta Bucharest RO 050159 Romania

Institute of Translational Medicine University of Liverpool Liverpool L3 9TA UK

International Agency for Research on Cancer World Health Organization Lyon 69372 cedex 08 France

International Organization for Cancer Prevention and Research Belgrade 11070 Serbia

Laboratory Medicine Region Skåne Department of Clinical Sciences Lund Pathology Lund University Lund 221 00 Sweden

Lunenfeld Tanenbaum Research Institute of Sinai Health System University of Toronto Toronto M5G 1X5 Canada

M Sklodowska Curie Cancer Center Institute of Oncology Warsaw 02 034 Poland

National Institute of Occupational Health Oslo N 0033 Norway

Princess Margaret Cancer Centre Toronto ON M5G 1L7 Canada

Radboud University Medical Center Nijmegen 9500 The Netherlands

Russian N N Blokhin Cancer Research Centre Moscow 115478 Russian Federation

School of Health and Related Research University Of Sheffield England S1 4DA UK

Swedish Medical Group Seattle 98104 WA USA

Unit of Nutrition and Cancer Catalan Institute of Oncology Barcelona 08908 Spain

University of Kentucky Markey Cancer Center Lexington 40536 0098 KY USA

University of Oviedo and CIBERESP Faculty of Medicine Oviedo 33006 Spain

University of Pittsburgh Cancer Institute Pittsburgh 15232 PA USA

University of Salzburg and Cancer Cluster Salzburg Salzburg 5020 Austria Translational Lung Research Center Heidelberg Heidelberg 69121 Germany

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$a Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity / $c A. Ferreiro-Iglesias, C. Lesseur, J. McKay, RJ. Hung, Y. Han, X. Zong, D. Christiani, M. Johansson, X. Xiao, Y. Li, DC. Qian, X. Ji, G. Liu, N. Caporaso, G. Scelo, D. Zaridze, A. Mukeriya, M. Kontic, S. Ognjanovic, J. Lissowska, M. Szołkowska, B. Swiatkowska, V. Janout, I. Holcatova, C. Bolca, M. Savic, M. Ognjanovic, SE. Bojesen, X. Wu, D. Albanes, MC. Aldrich, A. Tardon, A. Fernandez-Somoano, G. Fernandez-Tardon, L. Le Marchand, G. Rennert, C. Chen, J. Doherty, G. Goodman, H. Bickeböller, HE. Wichmann, A. Risch, A. Rosenberger, H. Shen, J. Dai, JK. Field, M. Davies, P. Woll, MD. Teare, LA. Kiemeney, EHFM. van der Heijden, JM. Yuan, YC. Hong, A. Haugen, S. Zienolddiny, S. Lam, MS. Tsao, M. Johansson, K. Grankvist, MB. Schabath, A. Andrew, E. Duell, O. Melander, H. Brunnström, P. Lazarus, S. Arnold, S. Slone, J. Byun, A. Kamal, D. Zhu, MT. Landi, CI. Amos, P. Brennan,

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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700    1_

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