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.

DOI: http://dx.doi.org/10.7554/eLife.09214.001

eLife digest

Mutations in genes play important roles in many types of cancer. However, mutations alone cannot explain all the biological changes that occur to cancer cells. For example, very few mutations have been linked with a type of kidney cancer called clear cell renal cell carcinoma (or ccRCC for short). Instead, scientists suspect that this cancer is largely caused by changes in the expression of particular genes so that certain cancer-promoting genes are more highly expressed, while other genes that would prevent tumor growth become less active.

One of the few genes that is often mutated in ccRCC is called SETD2. This gene is involved in processes that alter the structure of DNA, but do not alter the genes themselves. These “epigenetic” changes can alter how the instructions in genes are used to make proteins. The first step in making proteins is to use a section of DNA as a template to make molecules of messenger ribonucleic acid (mRNA) in a process called transcription. There are markers within a gene that show where transcription should start and stop to produce the mRNA required to make a particular protein. Epigenetic changes can mask these markers so that the cell produces longer mRNAs that incorporate instructions from neighboring genes.

It was not known how often these stop signs are ignored in ccRCC cells. Here, Grosso et al. compared transcription in normal cells and in ccRCC tumor cells from 50 different patients. The experiments show that more stop signs were ignored in many of the cancer cells, especially in cells with mutations in SETD2. This caused all or parts of neighboring genes to be transcribed along with the target gene and led to changes in the expression levels of these genes. For example, a cancer-promoting gene called BCL2 was more highly expressed in these cells.

Furthermore, some of the mRNA molecules produced in these cancer cells may make “fusion” proteins that combine elements from several proteins. These fusion proteins may work differently to normal cell proteins and therefore might also promote the development of tumors. Grosso et al.’s findings reveal a new link between epigenetic changes and cancer.

DOI: http://dx.doi.org/10.7554/eLife.09214.002