Identifying driver mutations in cancer genomes [electronic resource]

Identifying the genetic basis of tumorigenesis is perhaps the greatest challenge and the greatest opportunity of medicine in the coming decade. The hallmarks of cancer progression are uncontrolled cell proliferation, the evasion of the host immune system, and the hijacking and redirection of the body's resources towards the growing tumor -- all accomplished by cells that start out with the same blueprints and operating system as the body's native cells but transform, through a series of genetic twists, and take over their parent organism. Understanding the path from a molecular machine under the strict control of a physiological central authority to an unregulated competitor will help explain the nature of cancer and present more options for defeating it. The significance of learning the precise genomic drivers of cancer lies in the recent success of genome-based targeted therapy. Despite the progress, many of these therapies target oncogenes and driver mutations known to oncologists for decades. The initial "hallmarks of cancer" were a handful of significant oncogenes and tumor suppressors common to a large fraction of cancer patients1. Prior to the advent of DNA sequencing, cancer cases were stratified (and still are) by the tissue in which the tumor grew or originated, the potency of the cancer growth, and histological markers. As assays for these indicators improved, the number of cancer types increased, in the eyes of the pathologist: in [19X] there were two types of "blood cancers", now there are 89 classifications of leukemias and lymphomas. Treatments were tailored to the specific characteristics of each cancer. With the discovery of the genetic markers of cancer, the opportunity to further segment the patient population, this time at the DNA level, led to the explosion of targeted therapies. As of this writing, around 25% of oncology therapies in clinical trials come with a companion diagnostic and approximately 15% of advanced stage patients employ gene panel sequencing as part of their treatment regiment (personal communication, Robert Green, MD). The real promise of cancer genomics is that there are millions more variables, yet to be discovered, that can be used to further segment the phenomenon of pathological, uncontrolled cell growth in the human body. In this dissertation, we start by introducing "DNA elements", the known categories of genomic building blocks, and how DNA sequencing technology is used to probe these genomic elements to best estimate the molecular uniqueness of any individual. In Chapter 2, we focus on Single Nucleotide Variants (SNVs) in the exome of cancer patients collected and sequenced by the landmark consortium The Cancer Genome Atlas2. We use a novel algorithm to analyze the extent to which somatic SNVs re-appear across tumor samples, and how this measure can be used to identify candidate drivers of tumorigenesis. A significant aspect of cancer transformation and growth is the appropriation of cellular signaling mechanisms for the purposes of optimizing tumor proliferation. One of the most important signaling processes is the phosphorylation of protein residues. In Chapter 3 we present a study in the yeast model system of the evolutionary mechanism by which proteins gain new function through the acquisition or loss of phosphorylation sites. Taken together, this dissertation is a survey in the use of bioinformatics and genomics to better understand disease. Much is left to be done.

Keywords: Genetics.
Advisor: Snyder Michael
Altman Russ advisor. Thesis advisor
Fraser Hunter B. advisor. Thesis advisor
Li Jin (Billy) advisor. Thesis advisor