Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes.
Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes.
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DOI：
10.1038/nbt.3344
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发表时间：
2015-11
影响因子：
46.9
通讯作者：
Getz G
中科院分区：
文献类型：
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作者：
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
使用全外显子组测序（WES）检测HLA基因中的体细胞突变受到HLA基因座的高多态性的阻碍，这阻止了测序读数与人参考基因组的比对。我们描述了一种计算管道，其能够准确推断I类HLA-A、-B和-C基因的种系等位基因，并随后使用推断的等位基因作为参考检测这些基因中的突变。来自同一患者的7，930对肿瘤和健康组织的WES数据分析显示，来自266名患者的肿瘤中有298个非沉默HLA突变。这298个突变富含可能的功能突变，包括推定的功能丧失事件。突变的复发表明这些“热点”位点是积极选择的。具有复发性体细胞HLA突变的癌症与效应淋巴细胞肿瘤浸润的细胞溶解活性特征的上调相关，通过改变HLA功能支持免疫逃避作为癌症中的贡献机制。
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.