不同的突变过程塑造了主要和转移性肿瘤中 MHC Ⅰ类和Ⅱ类突变的选择。
Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors.
机构信息
Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
出版信息
Cell Rep. 2023 Aug 29;42(8):112965. doi: 10.1016/j.celrep.2023.112965. Epub 2023 Aug 21.
Disruption of antigen presentation via loss of major histocompatibility complex (MHC) expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. Here, we develop the personalized genomics algorithm Hapster and accurately call somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1,663 non-synonymous mutations that provide key insights into MHC mutagenesis. We find that MHC class I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC class II mutations are more restricted. Recurrent deleterious mutations are found within haplotype- and cancer-type-specific hotspots associated with distinct mutational processes. Functional classification of MHC residues reveals significant positive selection for mutations disruptive to the B2M, peptide, and T cell binding interfaces, as well as to MHC chaperones.
通过主要组织相容性复合体 (MHC) 表达的丧失来破坏抗原呈递是一种策略，通过这种策略，癌细胞逃避免疫监视并对免疫疗法产生耐药性。在这里，我们开发了个性化基因组学算法 Hapster，并准确地在 10001 个原发和 2199 个转移肿瘤的 MHC 基因中调用体细胞突变，创建了一个包含 1663 个非同义突变的目录，这些突变为 MHC 诱变提供了关键见解。我们发现，MHC 类 I 基因是原发和转移肿瘤中最常突变的基因之一，而 MHC 类 II 突变则更为局限。在与不同突变过程相关的单倍型和癌症类型特异性热点中发现了复发性有害突变。MHC 残基的功能分类显示出对破坏 B2M、肽和 T 细胞结合界面以及 MHC 伴侣的突变的显著正选择。
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