Analysis of HLA class I allele genotypes and immune-related gene alterations in patients with pan-cancer using whole-exome and whole-genome sequencing

In this study, 300 immune-related genes were analyzed in tumor tissues from 6,130 Japanese patients.Human leukocyte antigen (HLA) class I subunit B2M exhibited the highest fold change in mutation frequency in tumors with high tumor mutational burden (TMB).Stratified gene expression analysis revealed that tumors with a high TMB (10-100 mutations/Mb) exhibited increased expression of interferon- (IFN-) and upregulation of downstream genes, including CXCL9, TAP, PD-L1, and LAG3.In tumors with TMB > 100, expression of these genes was modest and accompanied by a marked increase in immunoregulatory gene expression and a high frequency of mutations in genes involved in antigen presentation and the IFN- signaling pathway, such as B2M, TAP2, TYK2, and JAK2.To assess whether hotspot mutations in cancer driver genes are subject to immune pressure, the frequency of gene mutations and HLA allele genotype combinations were evaluated, resulting in the identification of three hotspot mutations in EGFR, KRAS, and TP53 that may be recognized by the immune system.Furthermore, comprehensive HLA allele genotyping of 369 patients identified the HLA-C*15:02 allele, present in 6% of Japanese patients, as a potential prognostic marker.