MHC Hammer揭示了癌症进化中的遗传和非遗传HLA破坏
MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
影响因子:29.00000
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
摘要
I级人类白细胞抗原（HLA）分子的破坏对免疫逃避和肿瘤进化具有重要意义。我们开发了杂合性（LOH），等位基因特异性突变以及表达和抑制的测量（MHC Hammer）的主要组织相容性复合损失（MHC Hammer）。我们确定了正常肺和乳腺组织中HLA等位基因表达和普遍的HLA替代剪接的广泛差异。 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% luad，lusc和er+癌症。与HLA功能障碍在肿瘤进化中的重要性一致，在LUADS中，HLA LOH与转移的转移区域和luAD原发性肿瘤区域相关，其有效的新抗原负担低于非种植区。这些数据突出了HLA转录组破坏的程度和重要性，包括癌症进化中的抑制和替代剪接。
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.