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dc.contributor.advisorMirny, Leonid Alex
dc.contributor.authorMcFarland, Christopher Dennis
dc.date.accessioned2014-10-21T19:32:15Z
dc.date.issued2014-10-21
dc.date.submitted2014
dc.identifier.citationMcFarland, Christopher Dennis. 2014. The role of deleterious passengers in cancer. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard.inactive:11802en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13070047
dc.description.abstractThe development of cancer from a population of precancerous cells is a rapid evolutionary process. During progression, cells evolve several new traits for survive and proliferation via a few key `driver' mutations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional `passenger' mutations. Passengers are widely believed to have no role in cancer, yet many passengers fall within functional genomic elements that may have potentially deleterious effects on the cancer cells. Here we investigate the potential of moderately deleterious passengers to accumulate and alter neoplastic progression. Evolutionary simulations suggest that moderately-deleterious passengers accumulate during progression and largely evade natural selection. Accumulation is possible because of cancer's unique evolutionary constraints: an initially small population size, an elevated mutation rate, and a need to acquire several driver mutations within a short evolutionary timeframe. Cancer dynamics can be theoretically understood as a tug-of-war between rare, strongly-beneficial drives and frequent mildly-deleterious passengers. In this formalism, passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers collapse. In essence, cancer progression can be subverted by its own unique evolutionary constraints. The collective burden of passengers explain several oncological phenomena that are difficult to explain otherwise. Genomics data confirms that many passengers are likely damaging and have largely evaded negative selection, while age-incidence curves and the distribution of mutation totals suggests that drivers and passengers exhibit competing effects. These data also provide estimates of the strength of drivers and passengers. Finally, we use our model to explore cancer treatments. We identify two broad regimes of adaptive evolutionary dynamics and use these regimes to understand outcomes from various treatment strategies. Our theory explains previously paradoxical treatment outcomes and suggest that passengers could serve as a biomarker of response to mutagenic therapies. Deleterious passengers are targetable by either (i) increasing the mutation rate or (ii) exacerbating their deleterious effects. Our results suggest a unique framework for understanding cancer progression as a balance between driver and passenger mutations.en_US
dc.language.isoen_USen_US
dash.licenseLAA
dc.subjectBiophysicsen_US
dc.subjectEvolution & developmenten_US
dc.subjectGeneticsen_US
dc.subjectCancer Progressionen_US
dc.subjectEvolutionary Modelingen_US
dc.subjectGenomicsen_US
dc.titleThe role of deleterious passengers in canceren_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorMcFarland, Christopher Dennis
dc.date.available2014-10-21T19:32:15Z
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.committeeMemberDesai, Michaelen_US
dc.contributor.committeeMemberGetz, Gaden_US
dc.contributor.committeeMemberVan Allen, Eliezeren_US
dash.contributor.affiliatedMcFarland, Christopher Dennis


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