title: Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma.
abstract: 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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Grosso
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana P
authors.identifier: http://orcid.org/0000-0001-5773-3211
authors.initials: AP
authors.lastname: Leite
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Mafalda R
authors.initials: MR
authors.lastname: Matos
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Filipa B
authors.initials: FB
authors.lastname: Martins
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Vítor
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Joana M P
authors.initials: JM
authors.lastname: Desterro
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Maria
authors.initials: M
authors.lastname: Carmo-Fonseca
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Sérgio F
authors.identifier: http://orcid.org/0000-0002-7774-1355
authors.initials: SF
authors.lastname: de Almeida
mesh_terms: D002292:Carcinoma, Renal Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D015870:Gene Expression; D020869:Gene Expression Profiling; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D011995:Recombination, Genetic; D014158:Transcription, Genetic
chemical_list: C000595707:BCL2 protein, human; D015513:Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human
keywords: BCL2 oncogene; RNA chimeras; cancer genes; chromosomes; clear cell renal cell carcinoma; genes; human; human biology; medicine; transcription read-through