The Causes and Consequences of Somatic Genome Rearrangements in Human Cancer

Genome rearrangements are large-scale structural changes of DNA including deletions, duplications, inversions, translocations and other complex forms. Somatic genome rearrangements are abundant in human cancer as genome instability is a hallmark of cancer. My lab has been studying how somatic rearrangements occur and how they drive cancer. Using nearly 3000 whole-genome sequenced tumor samples across 40 tumor types, we found half of the tumors carry highly complex rearrangements. We then developed a new method to model the topology of complex rearrangements and discovered six signatures which suggested that there are likely multiple independent molecular mechanisms leading to the formation of complex rearrangements. Furthermore, we developed another algorithm to study the functional consequences of somatic rearrangements located in non-coding regions since the vast majority of them do not disrupt protein-coding genes. We discovered and experimentally validated several oncogenic non-coding RNAs activated by relocated enhancers. Our studies have provided new insights to disease etiology and can potentially improve patient care.