HLA破坏中的基因与非基因机制：由MHC Hammer揭示的癌症演化中的遗传与非遗传HLA失调

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution

NATURE GENETICS

影响因子:29

分区:生物学1区 Top / 遗传学1区

发表日期:2024 Oct

作者: Clare Puttick, Thomas P Jones, Michelle M Leung, Felipe Galvez-Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Oriol Pich, Carlos Martinez-Ruiz, Robert Bentham, Krijn K Dijkstra, James R M Black, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A Quezada, , Charles Swanton, Nicholas McGranahan

DOI: 10.1038/s41588-024-01883-8

摘要

人类白细胞抗原（HLA）I类分子的破坏在免疫逃逸和肿瘤演化中具有重要意义。我们开发了主要组织相容性复合体（MHC）缺失等位基因纯合性（LOH）、等位基因特异性突变，以及表达与抑制的测定工具（MHC Hammer）。研究发现正常肺和乳腺组织中HLA等位基因表达存在广泛变异，且存在普遍的HLA可变剪接。在肺TRACERx队列及肺、乳腺癌TCGA队列中，61%的肺腺癌（LUAD）、76%的肺鳞状细胞癌（LUSC）和35%的雌激素受体阳性（ER+）癌症表现出I类HLA转录抑制，HLA的肿瘤富集可变剪接在LUAD、LUSC和ER+癌症中分别发生在31%、11%和15%。HLA功能障碍在肿瘤演化中的重要性得到验证：LUAD中，HLA LOH与转移相关，且种子区域的原发肿瘤具有较低的新抗原负荷。这些数据强调了HLA转录组水平破坏的广泛性和重要性，包括抑制和可变剪接，在肿瘤演化中的作用。

Abstract

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.