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

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen 2730 Denmark

Department of Clinical Sciences Malmö Lund University Malmö 221 00 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 Genetic Epidemiology University Medical Center Georg August University Göttingen Göttingen 37073 Germany

Department of Internal Medicine Skåne University Hospital Malmö Sweden

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 Health and Medical Sciences University of Copenhagen Copenhagen 2730 Denmark

Faculty of Medicine University of Olomouc Olomouc 701 03 Czech Republic

Fred Hutchinson Cancer Research Center Seattle 98109 WA USA

German Center for Lung Research Heidelberg 69121 Germany

Helmholtz Center Munich Institute of Epidemiology 2 Munich D 85764 Germany

Institute of Medical Informatics Biometry and Epidemiology Chair of Epidemiology Ludwig Maximilians University 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

Translational Lung Research Center Heidelberg Heidelberg 69120 Germany

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

Zobrazit více v PubMed

Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nat. Rev. Cancer. 2007;7:778–790. doi: 10.1038/nrc2190. PubMed DOI

Brennan P, Hainaut P, Boffetta P. Genetics of lung-cancer susceptibility. Lancet Oncol. 2011;12:399–408. doi: 10.1016/S1470-2045(10)70126-1. PubMed DOI

Timofeeva MN, et al. Influence of common genetic variation on lung cancer risk: meta-analysis of 14900 cases and 29485 controls. Hum. Mol. Genet. 2012;21:4980–4995. doi: 10.1093/hmg/dds334. PubMed DOI PMC

McKay JD, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat. Genet. 2017;49:1126–1132. doi: 10.1038/ng.3892. PubMed DOI PMC

Lan Q, et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat. Genet. 2012;44:1330–1335. doi: 10.1038/ng.2456. PubMed DOI PMC

de Bakker PIW, et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 2006;38:1166–1172. doi: 10.1038/ng1885. PubMed DOI PMC

Sanchez-Mazas A, Buhler S, Nunes JM. A new HLA map of Europe: regional genetic variation and its implication for peopling history, disease-association studies and tissue transplantation. Hum. Hered. 2013;76:162–177. doi: 10.1159/000360855. PubMed DOI

Buhler S, Sanchez-Mazas A. HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events. PLoS ONE. 2011;6:e14643. doi: 10.1371/journal.pone.0014643. PubMed DOI PMC

Leslie S, Donnelly P, McVean G. A statistical method for predicting classical HLA alleles from SNP data. Am. J. Hum. Genet. 2008;82:48–56. doi: 10.1016/j.ajhg.2007.09.001. PubMed DOI PMC

de Bakker PIW, Raychaudhuri S. Interrogating the major histocompatibility complex with high-throughput genomics. Hum. Mol. Genet. 2012;21:R29–R36. doi: 10.1093/hmg/dds384. PubMed DOI PMC

Neefjes J, Jongsma MLM, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat. Rev. Immunol. 2011;11:823. doi: 10.1038/nri3084. PubMed DOI

Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res. 2015;21:687–692. doi: 10.1158/1078-0432.CCR-14-1860. PubMed DOI PMC

Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–1570. doi: 10.1126/science.1203486. PubMed DOI

Lesseur C, et al. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat. Genet. 2016;48:1544–1550. doi: 10.1038/ng.3685. PubMed DOI PMC

Chen D, et al. Genome-wide association study of susceptibility loci for cervical cancer. J. Natl Cancer Inst. 2013;105:624–633. doi: 10.1093/jnci/djt051. PubMed DOI

Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer. 2014;14:135–146. doi: 10.1038/nrc3670. PubMed DOI

Kachuri L, et al. Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci. Carcinogenesis. 2016;37:96–105. doi: 10.1093/carcin/bgv165. PubMed DOI PMC

Zheng X, et al. HIBAG—HLA genotype imputation with attribute bagging. Pharm. J. 2014;14:192–200. PubMed PMC

Price P, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol. Rev. 1999;167:257–274. doi: 10.1111/j.1600-065X.1999.tb01398.x. PubMed DOI

Candore G, Lio D, Colonna Romano G, Caruso C. Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: effect of multiple gene interactions. Autoimmun. Rev. 2002;1:29–35. doi: 10.1016/S1568-9972(01)00004-0. PubMed DOI

Miller FW, et al. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes. Genes Immun. 2015;16:470–480. doi: 10.1038/gene.2015.28. PubMed DOI PMC

Trowsdale J. The MHC, disease and selection. Immunol. Lett. 2011;137:1–8. doi: 10.1016/j.imlet.2011.01.002. PubMed DOI

Sharon E, et al. Genetic variation in MHC proteins is associated with T cell receptor expression biases. Nat. Genet. 2016;48:995–1002. doi: 10.1038/ng.3625. PubMed DOI PMC

Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu. Rev. Genom. Hum. Genet. 2013;14:301–323. doi: 10.1146/annurev-genom-091212-153455. PubMed DOI PMC

Thibodeau J, Bourgeois-Daigneault MC, Lapointe R. Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy. Oncoimmunology. 2012;1:908–916. doi: 10.4161/onci.21205. PubMed DOI PMC

Comber JD, Philip R. MHC class I antigen presentation and implications for developing a new generation of therapeutic vaccines. Ther. Adv. Vaccin. 2014;2:77–89. doi: 10.1177/2051013614525375. PubMed DOI PMC

Amos CI, et al. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers. Cancer Epidemiol. Biomark. Prev. 2017;26:126–135. doi: 10.1158/1055-9965.EPI-16-0106. PubMed DOI PMC

Price AL, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 2006;38:904–909. doi: 10.1038/ng1847. PubMed DOI

Brown WM, et al. Overview of the MHC fine mapping data. Diabetes Obes. Metab. 2009;11:2–7. doi: 10.1111/j.1463-1326.2008.00997.x. PubMed DOI PMC

Pillai NE, et al. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations. Hum. Mol. Genet. 2014;23:4443–4451. doi: 10.1093/hmg/ddu149. PubMed DOI

Okada Yukinori, Kim Kwangwoo, Han Buhm, Pillai Nisha E., Ong Rick T.-H., Saw Woei-Yuh, Luo Ma, Jiang Lei, Yin Jian, Bang So-Young, Lee Hye-Soon, Brown Matthew A., Bae Sang-Cheol, Xu Huji, Teo Yik-Ying, de Bakker Paul I.W., Raychaudhuri Soumya. Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Human Molecular Genetics. 2014;23(25):6916–6926. doi: 10.1093/hmg/ddu387. PubMed DOI PMC

Jia X, et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS ONE. 2013;8:e64683. doi: 10.1371/journal.pone.0064683. PubMed DOI PMC

Browning BL, Browning SR. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 2009;84:210–223. doi: 10.1016/j.ajhg.2009.01.005. PubMed DOI PMC

Mcmahon G, Ring SM, Davey-Smith G, Timpson NJ. Genome-wide association study identifies SNPs in the MHC class II loci that are associated with self-reported history of whooping cough. Hum. Mol. Genet. 2015;24:5930–5939. doi: 10.1093/hmg/ddv293. PubMed DOI PMC

Jeanmougin M, Noirel J, Coulonges C, Zagury JF. HLA-check: evaluating HLA data from SNP information. BMC Bioinf. 2017;18:334. doi: 10.1186/s12859-017-1746-1. PubMed DOI PMC

Karnes JH, et al. Comparison of HLA allelic imputation programs. PLoS ONE. 2017;12:e0172444. doi: 10.1371/journal.pone.0172444. PubMed DOI PMC

Raychaudhuri S, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 2012;44:291–296. doi: 10.1038/ng.1076. PubMed DOI PMC

Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–D934. doi: 10.1093/nar/gkr917. PubMed DOI PMC

Mägi R, Morris AP. GWAMA: software for genome-wide association meta-analysis. BMC Bioinf. 2010;11:288. doi: 10.1186/1471-2105-11-288. PubMed DOI PMC

Okada Y, et al. HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases risk for ulcerative colitis but reduces risk for Crohn’s disease. Gastroenterology. 2011;141:864–871.e5. doi: 10.1053/j.gastro.2011.05.048. PubMed DOI

Okada Y, et al. Construction of a population-specific HLA imputation reference panel and its application to Graves’ disease risk in Japanese. Nat. Genet. 2015;47:798–802. doi: 10.1038/ng.3310. PubMed DOI

Burnham, K. P., Anderson, D. R. & Burnham, K. P. Model Selection and Multimodel Inference: A Practical Information-theoretic Approach. Ch.6 (Springer, 2002).

Morris DL, et al. Unraveling Multiple MHC Gene Associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans. Am. J. Hum. Genet. 2012;91:778–793. doi: 10.1016/j.ajhg.2012.08.026. PubMed DOI PMC

Pettersen EF, et al. UCSF Chimera? A visualization system for exploratory research and analysis. J. Comput. Chem. 2004;25:1605–1612. doi: 10.1002/jcc.20084. PubMed DOI

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden