Characterising RNA alterations in cancer

The largest and most comprehensive catalogue of cancer-specific RNA alterations reveals new insights into the cancer genome

Artists impression of a gene fusion network. Credit: Image courtesy of Nuno Fonseca, edited by Spencer Phillips.

Researchers at EMBL-EBI were among the leaders of a large international consortium that carried out a joint analysis of data from over 1000 donors of more than 25 cancer types, studying data on their whole genomes along with tumour transcriptome data, which indicates the genes that are active within a tumour. These data represent the largest comparative resource to date of cancer-specific RNA alterations matched with whole-genome sequencing data.


  • RNA alterations: Any alteration in the editing of an RNA sequence.
  • Alternative promoters: Alternative regions of the same gene that can act as starting points for transcription – the process in which RNA copies (transcripts) are made from the cell’s DNA. These transcripts have a variety of functions, including carrying instructions for making proteins.
  • Gene fusions: Gene hybrids resulting from rearrangements of the genome that cause two previously separate genes to be joined together.
  • Isoform variation: Variation between RNAs transcribed from the same part of the genome but differing in their transcription start site or produced by different splicing.
  • Splicing: RNA processing that removes non-coding regions and splices together the coding regions.
  • Transcript expression: The abundance of an RNA transcript in a sample.
  • Transcriptomic profiling: Sequencing the expression patterns of the RNA transcripts found within a sample.

Cancer is a disease driven by mutations arising within our DNA, caused by environmental factors or ageing. It is less studied how these alterations in the genome change our RNA. More research is required to understand which of the alterations in RNA are a consequence of the mutations and which contribute to cancer progression.

This research was published in Nature as part of an international collaboration of over 1300 scientists known as the Pan-Cancer Analysis of Whole Genomes (PCAWG). This study involved more then 10 research groups as part of the larger Pan-Cancer project and aimed to develop the most comprehensive catalogue of RNA alterations in cancer including transcript expression, splicing, alternative promoter activity, and fusions.

The Pan-Cancer project

The Pan-Cancer Analysis of Whole Genomes project is a collaboration involving more than 1300 scientists and clinicians from 37 countries. It involved analysis of more than 2600 genomes of 38 different tumour types, creating a huge resource of primary cancer genomes. This was the starting point for 16 working groups to study multiple aspects of cancer development, causation, progression, and classification.

RNA alterations in cancer

Differences in RNA expression, splicing, and isoform variation are associated with many types of cancer. Here, the researchers used transcriptomic profiling to analyse cancer-specific alterations found in the tumour’s RNA. From this they identified many diverse and underappreciated mechanisms of cancer genome alterations yet to be detected by DNA analysis alone.

“Although cancer is caused by changes in an organism’s DNA, these changes also manifest via RNA,” says Alvis Brazma, Functional Genomics Senior Team Leader and Senior Scientist at EMBL-EBI. “We showed that often it is easier to detect important DNA changes by looking at RNA.”

Cancer-specific fusions

“We found hundreds of changes in the cancer genome that we could link to other molecular changes occurring in the cell,” says Brazma. “Some of the most interesting were chimera genes, in which part of one gene is fused to part of another. We were able to build a classification of how these chimera genes emerge in cancer.”

Gene fusions are known to play an important role in cancer-driving events and can be used for disease diagnosis. This study represents the first comparative analysis of both gene and RNA fusions across a large collection of tumour datasets. The researchers were able to identify over 2000 new cancer-specific gene fusions, 78 of which appeared more than once. This fusion data is freely available to download from Synapse.

Tags: cancer, ebi, genome, pan cancer, rna, tumour


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