• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland. zhiwei.liu@nih.gov.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
• Division of Cancer Epidemiology and Genetics, Cancer Genomics Research Laboratory, National Cancer Institute, Bethesda, Maryland.
• Department of Microbiology and Immunology and Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
• Genomics Research Center, Academia Sinica, Taipei, Taiwan.
• Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
• Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
• International Agency for Research on Cancer, World Health Organization, Lyon, France.

Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case-control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4⁺ T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis. SIGNIFICANCE: GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.