通过丧失重要组织相容性复合体（MHC）的表达而破坏抗原呈递是癌细胞逃避免疫监视和患者对免疫治疗产生抵抗性的一种策略。在这里，我们开发了个性化基因组算法Hapster，能够准确地识别出10,001个原发性肿瘤和2,199个转移性肿瘤中MHC基因的体细胞突变，建立了一个包含1,663个非同义突变的目录，这为MHC突变形成提供了重要见解。我们发现MHC I类基因在原发性和转移性肿瘤中是最常见的突变基因之一，而MHC II类基因的突变则更为局限。在特定的单倍型和癌症类型的热点区域中发现了反复有害的突变，这些热点区域与不同的突变过程相关联。对MHC残基的功能分类揭示了对损害B2M、肽和T细胞结合界面以及MHC伴侣的突变创新的显著正选择。版权所有 © 2023 作者。由 Elsevier Inc. 发布，版权所有。

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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.