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Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma
Ana R Grosso1, Ana P Leite1, Sílvia Carvalho1
1Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
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.
Insights
Transcription read-through beyond normal termination sites creates diverse RNA in cancer. SETD2 gene inactivation in clear cell renal cell carcinoma (ccRCC) enhances this, leading to oncogene activation and novel chimeric transcripts.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Aberrant gene expression and non-canonical RNA species characterize cancer.
- Mechanisms driving atypical gene expression in cancer remain unclear.
Purpose of the Study:
- Investigate the role of transcription read-through in cancer transcriptome diversity.
- Identify factors influencing transcription read-through in clear cell renal cell carcinoma (ccRCC).
Main Methods:
- Transcriptional profiling of 50 primary ccRCC samples from The Cancer Genome Atlas (TCGA).
- Analysis of gene mutations, specifically SETD2 inactivation.
- Identification and characterization of RNA chimeras.
Main Results:
- Transcription read-through contributes to transcriptome diversity in ccRCC.
- SETD2 inactivation significantly enhances transcription read-through.
- Read-through leads to invasion of neighboring genes, including the BCL2 oncogene.
- A novel CTSC-RAB38 chimera was detected in 20% of ccRCC samples.
Conclusions:
- Transcription read-through is a novel mechanism linked to aberrant oncogene expression in cancer.
- This phenomenon generates chimeric transcripts, contributing to cancer development.
- Findings highlight a new avenue for understanding cancer transcriptome alterations.
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