Analysis of Splicing Aberrations in Liver Hepatocellular Carcinoma

Splicing is a fundamental biological process affecting every aspect of cell’s life. To date, a diverse spectrum of human diseases associated with dysregulation of splicing is identified. It includes cancer, the main “disease of the genome”, characterized by a high number of somatic mutations, leading to malignant transformation of cells and tissues. Splicing breakages can also contribute to carcinogenesis, since they directly impact protein production. In this work we focus on local splicing aberrations, defined as splice site shifts within 30-nucleotide neighborhood of the annotated sites, and estimate their association with cancers, particularly with human hepatocellular carcinoma (HCC). We use LINC-JP project dataset from ICGC depository, that consists of 57 paired patient samples. Splicing aberrations can be caused by the disruption of cis- and trans-regulatory elements (splice sites and splicing factors binding sites’ sequences), or more general breakages affecting the splicing machinery, the changes of its components expression, and other reasons such as epigenetic changes. We investigate the first two issues, integrating genomic and transcriptomic ICGC data. We show that more aberrant splice sites gain expression in cancer compared to normal tissue than vice versa. Several trends for strong aberrations are identified: they tend to maintain the coding frame; they are associated with somatic mutations within 50bp proximity, and they are more frequent in tumor suppressor genes. There is also positive, but insignificant association with the mutations in splicing factors, suggesting that not the splicing machinery in general, but individual cancer genes are affected in HCC. In one patient we find a significantly altered aberration pattern and a mutation in TP53 gene, while in other patients other cancer-related genes are affected.