Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
Nat Genet. 2024 Oct;56(10):2121-2131. doi: 10.1038/s41588-024-01883-8. Epub 2024 Oct 2.
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.
人类白细胞抗原（HLA）I 类分子的破坏对免疫逃逸和肿瘤进化具有重要意义。我们开发了主要组织相容性复合体杂合性丢失（LOH）、等位基因特异性突变以及表达和抑制的测量（MHC Hammer）。我们在正常肺和乳腺组织中发现了 HLA 等位基因表达的广泛变异性和普遍的 HLA 选择性剪接。在肺 TRACERx 和肺及乳腺 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+）癌症存在 HLA I 类转录抑制，而 HLA 肿瘤富集的选择性剪接则发生在 31%、11%和 15%的 LUAD、LUSC 和 ER+癌症中。与 HLA 功能障碍在肿瘤进化中的重要性一致，在 LUAD 中，HLA LOH 与转移有关，并且 LUAD 原发肿瘤区域播种转移的有效新抗原负担低于非播种区域。这些数据突出了 HLA 转录组破坏（包括抑制和选择性剪接）在癌症进化中的程度和重要性。
