Sensitive and precise detection of somatic changes of the class I HLA loci using exome-capture sequencing

Abstract:

The highly polymorphic nature of the HLA gene locus leads to its suboptimal alignment to the canonical reference genome in whole-exome sequencing (WES) data, and hence somatic changes in this important class of genes are likely less sensitively detected in sequenced tumor exomes. We developed an algorithm POLYSOLVER (POLYmorphic loci reSOLVER) for accurate inference of class I HLA-A, -B and -C alleles from WES data through optimized alignment and calculation of posterior probability-derived scores. When applied to 133 HapMap samples of known HLA type, POLYSOLVER achieved 97% accuracy in protein-level HLA typing. Analysis of WES data from 3768 tumor/normal pairs (from 13 cancers) by POLYSOLVER together with somatic change detection tools revealed 131 class I mutations in 114 patients (3%). Somatic HLA mutations were enriched for truncations and frameshifts (p<0.001), consistent with loss-of-function and 95 of 131 (72.5%) localized within exons 2-3 and 4 which have known interactions with the T cell receptor and peptide binding domains. Recurrent hotspot sites of missense, nonsense and splice-site mutations were discovered that suggest positive selection, and support immune evasion by alteration of HLA function as an important pathway in cancer.