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dc.contributor.advisorBeroukhim, Rameen
dc.contributor.authorZack, Travis Ian
dc.date.accessioned2014-10-21T17:45:54Z
dc.date.issued2014-10-21
dc.date.submitted2014
dc.identifier.citationZack, Travis Ian. 2014. Exploring Cancer's Fractured Genomic Landscape: Searching for Cancer Drivers and Vulnerabilities in Somatic Copy Number Alterations. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard.inactive:11723en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13065031
dc.description.abstractSomatic copy number alterations (SCNAs) are a class of alterations that lead to deviations from diploidy in developing and established tumors. A feature that distinguishes SCNAs from other alterations is their genomic footprint. The large genomic footprint of SCNAs in a typical cancer's genome presents both a challenge and an opportunity to find targetable vulnerabilities in cancer. Because a single event affects many genes, it is often challenging to identify the tumorigenic targets of SCNAs. Conversely, events that affect multiple genes may provide specific vulnerabilities through "bystander" genes, in addition to vulnerabilities directly associated with the targets. We approached the goal of understanding how the structure of SCNAs may lead to dependency in two ways. To improve our understanding of how SCNAs promote tumor progression we analyzed the SCNAs in 4934 primary tumors in 11 common cancers collected by the Cancer Genome Atlas (TCGA). The scale of this dataset provided insights into the structure and patterns of SCNA, including purity and ploidy rates across disease, mechanistic forces shaping patterns of SCNA, regions undergoing significantly recurrent SCNAs, and correlations between SCNAs in regions implicated in cancer formation. In a complementary approach, we integrating SCNA data and pooled RNAi screening data involving 11,000 genes across 86 cell lines to find non-driver genes whose partial loss led to increased sensitivity to RNAi suppression. We identified a new set of cancer specific vulnerabilities predicted by loss of non-driver genes, with the most significant gene being PSMC2, an obligate member of the 26S proteasome. Biochemically, we found that PSMC2 is in excess of cellular requirement in diploid cells, but becomes the stoichiometric limiting factor in proteasome formation after partial loss of this gene. In summary, my work improved our understanding of the structure and patterns of SCNA, both informing how cancers develop and predicting novel cancer vulnerabilities. Our characterization of the SCNAs present across 5000 tumors uncovered novel structure in SCNAs and significant regions likely to contain driver genes. Through integrating SCNA data with the results of a functional genetic screen, we also uncovered a new set of vulnerabilities caused by unintended loss of non-driver genes.en_US
dc.language.isoen_USen_US
dash.licenseLAA
dc.subjectBioinformaticsen_US
dc.subjectCellular biologyen_US
dc.subjectBiostatisticsen_US
dc.subjectCanceren_US
dc.subjectcancer dependencyen_US
dc.subjectCopy numberen_US
dc.subjectnon-driveren_US
dc.titleExploring Cancer's Fractured Genomic Landscape: Searching for Cancer Drivers and Vulnerabilities in Somatic Copy Number Alterationsen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorZack, Travis Ian
dc.date.available2014-10-21T17:45:54Z
thesis.degree.date2014en_US
thesis.degree.disciplineBiophysicsen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberMeyerson, Matthewen_US
dc.contributor.committeeMemberGarraway, Levien_US
dc.contributor.committeeMemberEbert, Benjaminen_US
dash.contributor.affiliatedZack, Travis Ian


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