Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes

Abstract

Detection of somatic mutations in HLA genes using whole-exome sequencing (WES) is hampered by the high polymorphism of the HLA loci, which prevents alignment of sequencing reads to the human reference genome. We describe a computational pipeline that enables accurate inference of germline alleles of class I HLA-A, -B and -C genes and subsequent detection of mutations in these genes using the inferred alleles as a reference. Analysis of WES data from 7,930 pairs of tumor and healthy tissue from the same patient revealed 298 non-silent HLA mutations in tumors from 266 patients. These 298 mutations are enriched for likely functional mutations, including putative loss-of-function events. Recurrence of mutations suggested that these ‘hotspot’ sites were positively selected. Cancers with recurrent somatic HLA mutations were associated with upregulation of signatures of cytolytic activity characteristic of tumor infiltration by effector lymphocytes, supporting immune evasion by altered HLA function as a contributory mechanism in cancer.

Tumor Evolution as a Therapeutic Target

“…In this context, liquid biopsies could be particularly effective in tracking dynamics of the targeted neoantigens, and, coupled with T cell-receptor sequencing from blood, in predicting the odds of relapse (98). However, immune evasion from T cells aimed at clonal neoantigens could, for example, arise through clonal selection of tumor cells bearing mutations or loss of HLA (99,100); the latter was recently reported in a patient with metastatic CRC who relapsed after adoptive T-cell transfer (101); alterations of IFNγ pathway effectors could also impair a targeted T cell-mediated immune response (51). This suggests that immunotherapy alone might not be sufficient to eradicate a tumor, and integration with other forms of therapy coupled with diagnostic monitoring of tumor evolution might be needed to maximize efficacy.…”

Current tools for predicting cancer-specific T cell immunity

“…27 However, variants present in only a small fraction of cancer cells or in highly polymorphic regions may be missed and efforts to improve mutation-calling pipelines are still ongoing. 28,29 In addition, RNA sequencing allows for the identification of gene products selectively expressed by cancer cells like TA, cancer-specific splice variants, or gene fusions (Fig. 1B).…”

Comparative Analyses of Low, Medium and High-Resolution HLA Typing Technologies for Human Populations

“…The HLA loci sequencing have inherent limitations due to extreme polymorphism, ambiguities in haplotype phasing, unknown reference standards, technical problems like shorter read lengths etc [3,4]. The analysis of whole exome sequences of over 7000 pairs of tumor and healthy tissues (http://www.1000genomes.org) has revealed large-scale mutations in HLA genes, which is proposed to be immune evasion by altering HLA protein function as a contributory mechanism in cancer [19].…”