Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma. Homo sapiens

Aberrant expression of cancer genes and non-canonical RNA species is a hallmark of cancer. However, the mechanisms driving such atypical gene expression programs are incompletely understood. Here, our transcriptional profiling of a cohort of 50 primary clear cell renal cell carcinoma (ccRCC) samples from The Cancer Genome Atlas (TCGA) reveals that transcription read-through beyond the termination site is a source of transcriptome diversity in cancer cells. Amongst the genes most frequently mutated in ccRCC, we identified SETD2 inactivation as a potent enhancer of transcription read-through. We further show that invasion of neighbouring genes and generation of RNA chimeras are functional outcomes of transcription read-through. We identified the BCL2 oncogene as one of such invaded genes and detected a novel chimera, the CTSC-RAB38, in 20% of ccRCC samples. Collectively, our data highlight a novel link between transcription read-through and aberrant expression of oncogenes and chimeric transcripts that is prevalent in cancer. Overall design: RNA-seq of SETD2 mutant and wild-type ccRCC cell lines.

癌基因异常表达与非经典RNA物种的积累是癌症的标志性特征。然而，介导这类非典型基因表达程序的分子机制尚未完全阐明。本研究通过对癌症基因组图谱（TCGA）中50例原发性透明细胞肾细胞癌（ccRCC）原发样本队列开展转录组分析，揭示了转录通读（transcription read-through）现象——即转录过程越过转录终止位点——是癌细胞转录组多样性的重要来源。在ccRCC最常发生突变的基因中，我们发现SETD2失活是转录通读的强效增强因子。我们进一步证实，邻近基因的侵入性转录与RNA嵌合体的生成，是转录通读的两类功能性结局。我们将原癌基因BCL2鉴定为这类受侵入的基因之一，并在20%的ccRCC样本中检测到一种新型嵌合转录本CTSC-RAB38。综上，本研究数据揭示了转录通读与癌基因异常表达及嵌合转录本生成之间的新型关联，这类关联在癌症中广泛存在。实验整体设计：对SETD2突变型与野生型ccRCC细胞系开展RNA测序（RNA-seq）。