TRANSCRIPTOME-WIDE STUDY OF ALTERNATIVE SPLICING ACROSS MULTIPLE CANCER TYPES

Alternative splicing (AS) is a very important cellular process in eukaryote, which contribute to both the proteome diversity and control of gene expression levels. It is tightly regulated in different tissues and developmental stages and dysregulation of splicing can lead to many human diseases. Cancer is one of the extreme examples where splicing is highly altered. However the underline mechanism responsible for such dysregulation is largely unclear. Moreover, identification of cancer specific AS events is complicated by the large noise of different tissues-specific splicing. In the chapters that follow, we first explore the evolution and functionality of RNA binding proteins which is one of the key regulators of AS. We then use the RNA-seq data from TCGA (The Cancer Genome Atlas) to identify AS events that are significantly altered between tumor and normal samples across multiple cancer types. We also show that these cancer-specific AS events are highly conserved, more likely to maintain protein reading frame, and mainly function in cell cycle, cell adhesion/migration, and insulin signaling pathway. Furthermore, these events can serve as new molecular biomarkers to distinguish cancer from normal tissues, to separate cancer subtypes, and to predict patient survival. We also demonstrate that most genes whose expression is closely associated with cancer-specific splicing are key regulators of the cell cycle. Our study uncovers a common set of cancer-specific AS events altered across multiple cancers, providing mechanistic insight into how splicing is mis-regulated in cancers. Lastly we show that kidney tumors harbor significantly higher intron retention than other tumor types and such increase of splicing alteration in kidney cancer is highly correlated with patient survival. Together our works have helped to better understand AS across multiple human cancers and how it might be regulated and its connection to some important cancer pathways.Doctor of Philosoph