Association between cancer risk and HLA genotype can be explained by anti-tumor immunity

Abstract Over recent decades, efforts to explain the heritability of developing cancer have focused on identifying high-risk genes and common genetic variants. However, no studies considered genetic factors regulating tumor-specific immune responses. By developing a novel human leukocyte antigen (HLA) score, determined by autologous HLA allele-binding epitopes of tumor-specific antigens, we showed that individuals with HLA allele sets supporting broader tumor-specific T cell responses have lower risk of developing melanoma. The risk ratio between the highest risk and most protected groups was 5.69 comparing the top and bottom 20% of the HLA score distribution (p < 0.05). Similar results were obtained for other cancers, including non-small cell lung, renal, and bladder cancers, but not colorectal cancer. Our findings suggest that subjects with a low HLA score have an increased genetic risk of developing certain cancers.