Grosso Ana R, Leite Ana P, Carvalho Sílvia, Matos Mafalda R, Martins Filipa B, Vítor Alexandra C, Desterro Joana M P, Carmo-Fonseca Maria, de Almeida Sérgio F
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
Elife. 2015 Nov 17;4:e09214. doi: 10.7554/eLife.09214.
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.
癌症基因和非经典RNA种类的异常表达是癌症的一个标志。然而，驱动这种非典型基因表达程序的机制尚未完全了解。在这里，我们对来自癌症基因组图谱（TCGA）的50个原发性透明细胞肾细胞癌（ccRCC）样本进行转录谱分析，发现转录通读终止位点以外的区域是癌细胞转录组多样性的一个来源。在ccRCC中最常发生突变的基因中，我们确定SETD2失活是转录通读的一个有效增强子。我们进一步表明，邻近基因的侵入和RNA嵌合体的产生是转录通读的功能结果。我们将BCL2癌基因确定为其中一个被侵入的基因，并在20%的ccRCC样本中检测到一种新的嵌合体CTSC-RAB38。总体而言，我们的数据突出了转录通读与癌基因和嵌合转录本异常表达之间的新联系，这种联系在癌症中很普遍。
