Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks

We have recently studied the variability of the cell transcriptome in several tumours to describe new relevant alterations in cancer. The genetic information of cells is encoded in the DNA. This information is read by the cellular machinery, which will generate the so-called RNA and then translate it into proteins. Sometimes, the same gene can give rise to different RNA molecules, which may produce proteins with potentially very different functions. This is due to a process known as alternative splicing, which influences the synthesis of most of the RNAs and proteins of eukaryotic cells and its regulation depends on the RNA-binding proteins (RBPs).

Despite the importance of alternative splicing in cell function being widely known by the scientific community, the role it plays in cancer is only beginning to be realized. This has been possible thanks to new sequencing technologies and the availability of RNA sequencing data of multiple tumours through projects such as The Cancer Genome Atlas (TCGA). Although cancer originates from mutations in DNA, they have an impact on the set of RNA molecules of the cell, known as the transcriptome, which can induce and maintain mechanisms linked to the development of cancer. We have now studied the alterations in RBPs that could cause changes in alternative splicing linked to the development of cancer.

For this analysis, we have used various tools developed in our lab. Among them, we used SUPPA a fast and accurate tool to study splicing from multiple samples. Thanks to SUPPA, we could calculate the splicing profiles of more than 4000 samples in less than one day. We then carried out a comprehensive analysis of the mutations, copy number alterations and expression differences in genes, as well as the alternative splicing changes associated to them, for these samples from eleven different types of cancer taken from the TCGA project. This analysis showed RBPs are often altered in human tumours and that these alterations determine the cell transcriptome and induce cell transformations related to the development of cancer. Until now, these alterations remained invisible to the methods used in major cancer genome analysis projects.

With the collaboration of Juan Valcárcel’s lab (CRG) and Miguel Ángel Pujana’s lab (ICO), we were able to show that introducing the identified alterations of the transcriptome in non-tumour cells, these acquire tumourigenic properties. In addition to expanding our knowledge on the role of RBPs in tumours, these results highlight the importance of alternative splicing as a complementary mechanism in the development of cancer, becoming a new relevant factor to be taken into account in the study of this disease. This research opens up new ways of understanding the biology of cancer and searching for new therapeutic strategies. The alterations in alternative splicing are particularly important in the context of those tumours that do not harbour known mutations and for which no therapy is known, and, therefore, they may open new opportunities to understand tumour biology and search for new therapies.

This study was made possible thanks to the funding from the Sandra Ibarra Foundation, the Consolider RNAREG project from MINECO, the funding from AGAUR, as well as from other projects of the Spanish Government and FEDER funds.

Sebestyén E, Singh B, Miñana B, Pagès A, Mateo F, Pujana MA, Valcárcel J, Eyras E. Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks. Genome Res. 2016 Jun;26(6):732-44.

Figure_1Allegoric representation of the variability of the transcriptome through changes in alternative splicing in difference cancer types. Illustration by Babita Singh.