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

Sachet A. Shukla, Michael S. Rooney, Mohini Rajasagi, Grace Tiao, Philip M. Dixon, Michael S. Lawrence, Jonathan Stevens, William J. Lane, Jamie L. Dellagatta, Scott Steelman, Carrie Sougnez, Kristian Cibulskis, Adam Kiezun, Nir Hacohen, Vladimir Brusic, Catherine J. Wu, Gad Getz

Research output: Journal PublicationArticlepeer-review

452 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1152-1158
Number of pages7
JournalNature Biotechnology
Issue number11
Publication statusPublished - 1 Oct 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering


Dive into the research topics of 'Comprehensive analysis of cancer-associated somatic mutations in class i HLA genes'. Together they form a unique fingerprint.

Cite this