Evolution and vulnerabilities of somatic copy number alterations in cancer

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015.Cataloged from PDF version of thesis.Includes bibliographical references.Cancer is a Darwinian evolutionary process in which rounds of mutation and selection lead to increasingly fit clones. Understanding how cancers evolve and in particular how they form lethal metastases is critical to informing the design of new therapies. In the first part of this thesis, we performed whole-exome sequencing of paired endometrial cancer primaries and metastases to explore how tumors sample the genetic landscape. We find that mutations of PTEN, and TP53 occur early in the evolution of endometrial cancers, whereas BAF complex alterations occur late. We identified novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIPJ in 12% of patients. Phylogenetic analyses in cases with multiple metastases indicated these metastases typically arose from one lineage of the primary tumor. We observed subclones within the sequenced part of the primary tumor that seeded metastases. We document extensive heterogeneity and genomic disruption across the various clinical stages in endometrial cancers. In the second part of this thesis we explore how the widespread genomic disruption observed in tumors can generate therapeutic opportunities. We use data from genome-scale shRNA screens to perform an unbiased analysis of all copynumber: gene dependency interactions. We identify a class of interactions called CYCLOPS interactions in which genomic loss of essential genes sensitizes cancer cells to their further suppression. We explore the properties of CYCLOPS genes and show that the splicing factor SF3B1 is one of them. Biochemical analyses showed that cancer cells harboring hemizygous loss of SF3BI lack a buffer of SF3BI present in cells whose SF3BI locus is intact. These data provide evidence for the utility of developing nononcogene targeted therapies as a means of advancing cancer therapeutics.by William J. Gibson.Ph. D