title: Comprehensive analysis of cancer-associated somatic  mutations in class I HLA genes.
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.
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.forename: Michael S
authors.initials: MS
authors.lastname: Rooney
authors.forename: Mohini
authors.initials: M
authors.lastname: Rajasagi
authors.forename: Grace
authors.initials: G
authors.lastname: Tiao
authors.forename: Philip M
authors.initials: PM
authors.lastname: Dixon
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stevens
authors.forename: William J
authors.initials: WJ
authors.lastname: Lane
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Dellagatta
authors.forename: Scott
authors.initials: S
authors.lastname: Steelman
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Adam
authors.initials: A
authors.lastname: Kiezun
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brusic
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
mesh_terms: D019295:Computational Biology; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D012984:Software
chemical_list: D015395:Histocompatibility Antigens Class I