Mutational Heterogeneity in Cancer

Thesis (Ph.D.)--University of Washington, 2014-06

Somatic mutation plays a key role in the formation and progression of cancer. Differences in mutation patterns likely explain much of the heterogeneity seen in prognosis and treatment response among patients. Recent advances in massively parallel sequencing have greatly expanded our capability to investigate somatic mutation. Genomic profiling of tumor biopsies could guide the administration of targeted therapeutics on the basis of the tumor’s collection of mutations. Central to the success of this approach is the general applicability of targeted therapies to a patient’s entire tumor burden. This requires a better understanding of the genomic heterogeneity present both within individual tumors (intratumoral) and amongst tumors from the same patient (intrapatient). My dissertation is broadly organized around investigating mutational heterogeneity in cancer. Three projects are discussed in detail: analysis of (1) interpatient and (2) intrapatient heterogeneity in men with disseminated prostate cancer, and (3) investigation of regional intratumoral heterogeneity in gliomas. I conclude with a summary of my research and a discussion of future directions.