The alternative ways of cancer

The alternative processing of genomic loci through alternative splicing (AS) to produce multiple transcripts is a prevalent mode of gene expression regulation in multicellular organisms. Although the specific function of the majority of alternative transcripts remains unknown, the differential production of transcript isoforms has been related to essential biological processes, such as the acquisition of tissue-specific functions, and it has been long recognized that disruption of splicing mechanisms can cause disease, including cancer. Cancer arises from genetic and epigenetic alterations that interfere with essential mechanisms of the normal life cycle of cells, such as replication control, DNA repair and cell death, and multiple cancer-related alterations have been described to induce AS changes in tumor transcriptomes. Cancer-related mutations that disrupt splicing regulatory motifs or create cryptic ones, as well as mutations and expression alterations in splicing factors and chromatin regulators, can lead to alterations in RNA processing and splicing of genes, which in turn impact their function and contribute to the pathological properties of tumors. The prevalence of AS in cancer genomes and its prominent role in cancer-related processes indicates that these alterations may be related to significant functional impacts and may explain some of the observed oncogenic properties.

AS_drivers

With the aim to address this question, we have recently performed an exhaustive analysis of the functional impacts produced by AS changes in tumors (Climente-Gonzalez et al. 2017). We described how cancer specific AS changes lead frequently to shorter protein products and sometimes, although less often, to a non-coding transcript. As a consequence, transcript isoforms that are more highly expressed in tumors encode for fewer functional domains, i.e. there is a potential loss of functional capacities of genes in cancer. Interestingly, the protein domains more frequently affected by AS belong to functional families classically affected by somatic mutations in tumors. Additionally, these functional domain losses are in fact strongly associated to protein-protein interactions, and often affect partners of classical cancer drivers. Moreover, since we analyzed the splicing changes occurring in each individual tumor sample, we were able to observe that protein affecting mutations and splicing changes that affect similar functional domain families tend to occur in different patients, suggesting an equivalence between the mutations and splicing changes. Splicing alterations may thus recapitulate similar functional impacts to those observed through genetic alterations, namely protein affecting mutations and copy number alterations, more commonly associated with cancer. Transcriptome data thus shows that alternative splicing has a functional impact similar to other alterations, and may also play a driving role in cancer progression.

Climente-González H, Porta-Pardo E, Godzik A, Eyras E. The Functional Impact of Alternative Splicing in Cancer. Cell Rep. 2017 Aug 29;20(9):2215-2226.