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Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

11-2015

Journal or Book Title

Nature Biotechnology

Volume

33

Issue

11

First Page

1152

Last Page

1158

DOI

10.1038/nbt.3344

Abstract

Detection of somatic mutations in human leukocyte antigen (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 nonsilent 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.

Comments

This is a manucript of an article published as Shukla, Sachet A., Michael S. Rooney, Mohini Rajasagi, Grace Tiao, Philip M. Dixon, Michael S. Lawrence, Jonathan Stevens et al. "Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes." Nature biotechnology 33, no. 11 (2015): 1152. doi: 10.1038/nbt.3344. Posted with permission.

Copyright Owner

Nature America, Inc.

Language

en

File Format

application/pdf

Published Version

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