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: Contribution to journalArticle

155 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1152-1158
Number of pages7
JournalNature Biotechnology
Volume33
Issue number11
DOIs
Publication statusPublished - Oct 1 2015
Externally publishedYes

Fingerprint

Antigens
HLA Antigens
Genes
Mutation
Tumors
Neoplasms
Exome
Alleles
Lymphocytes
Immune Evasion
Polymorphism
Infiltration
Human Genome
Pipelines
Tissue
Up-Regulation
Recurrence

ASJC Scopus subject areas

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

Cite this

Shukla, S. A., Rooney, M. S., Rajasagi, M., Tiao, G., Dixon, P. M., Lawrence, M. S., ... Getz, G. (2015). Comprehensive analysis of cancer-associated somatic mutations in class i HLA genes. Nature Biotechnology, 33(11), 1152-1158. https://doi.org/10.1038/nbt.3344

Comprehensive analysis of cancer-associated somatic mutations in class i HLA genes. / Shukla, Sachet A.; Rooney, Michael S.; Rajasagi, Mohini; Tiao, Grace; Dixon, Philip M.; Lawrence, Michael S.; Stevens, Jonathan; Lane, William J.; Dellagatta, Jamie L.; Steelman, Scott; Sougnez, Carrie; Cibulskis, Kristian; Kiezun, Adam; Hacohen, Nir; Brusic, Vladimir; Wu, Catherine J.; Getz, Gad.

In: Nature Biotechnology, Vol. 33, No. 11, 01.10.2015, p. 1152-1158.

Research output: Contribution to journalArticle

Shukla, SA, Rooney, MS, Rajasagi, M, Tiao, G, Dixon, PM, Lawrence, MS, Stevens, J, Lane, WJ, Dellagatta, JL, Steelman, S, Sougnez, C, Cibulskis, K, Kiezun, A, Hacohen, N, Brusic, V, Wu, CJ & Getz, G 2015, 'Comprehensive analysis of cancer-associated somatic mutations in class i HLA genes', Nature Biotechnology, vol. 33, no. 11, pp. 1152-1158. https://doi.org/10.1038/nbt.3344
Shukla SA, Rooney MS, Rajasagi M, Tiao G, Dixon PM, Lawrence MS et al. Comprehensive analysis of cancer-associated somatic mutations in class i HLA genes. Nature Biotechnology. 2015 Oct 1;33(11):1152-1158. https://doi.org/10.1038/nbt.3344
Shukla, Sachet A. ; Rooney, Michael S. ; Rajasagi, Mohini ; Tiao, Grace ; Dixon, Philip M. ; Lawrence, Michael S. ; Stevens, Jonathan ; Lane, William J. ; Dellagatta, Jamie L. ; Steelman, Scott ; Sougnez, Carrie ; Cibulskis, Kristian ; Kiezun, Adam ; Hacohen, Nir ; Brusic, Vladimir ; Wu, Catherine J. ; Getz, Gad. / Comprehensive analysis of cancer-associated somatic mutations in class i HLA genes. In: Nature Biotechnology. 2015 ; Vol. 33, No. 11. pp. 1152-1158.
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