טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentGalili Sheli
SubjectThe Somatic Evolution of Cancer
DepartmentDepartment of Medicine
Supervisor Professor Ruth Hershberg
Full Thesis textFull thesis text - English Version


Abstract

In somatic evolution, mutations accumulate in the cells of a body through its lifetime and are subject to natural selection according to their effect on cellular fitness. The classic model of carcinogenesis describes multiple, successive clonal expansions driven by the accumulation of somatic mutations that are preferentially selected by the tumor environment. A significant amount of research was done to catalogue the somatic mutations appearing in each cancer type. However, the evolutionary dynamics under which those mutations accumulate during cancer initiation and progression remain poorly characterized. In the work presented in this thesis, we investigated cancer from the evolutionary perspective. Our research moved from the level of a single cancer gene, to the entire genome, to probing what makes the cancer disease so unique. At the single gene level, we were able to disentangle the effects of mutation and natural selection in determining the patterns of driver substitutions within the important KRAS oncogene. At the level of the entire genome, we demonstrated that natural selection works differently in cancer somatic evolution than in germline evolution, with a much higher contribution of positive selection, and lower contribution of purifying selection. We further showed that globally expressed genes are under positive selection in many cancer types, and that they are enriched for yet undiscovered cancer functions. When investigating cancer as a disease, we demonstrated that it is the largely somatic nature of cancer that allows it to stand out among genetic disorders in affecting the most important genes and the most basic of cellular functions.