--- _id: '1400' abstract: - lang: eng text: Cancer results from an uncontrolled growth of abnormal cells. Sequentially accumulated genetic and epigenetic alterations decrease cell death and increase cell replication. We used mathematical models to quantify the effect of driver gene mutations. The recently developed targeted therapies can lead to dramatic regressions. However, in solid cancers, clinical responses are often short-lived because resistant cancer cells evolve. We estimated that approximately 50 different mutations can confer resistance to a typical targeted therapeutic agent. We find that resistant cells are likely to be present in expanded subclones before the start of the treatment. The dominant strategy to prevent the evolution of resistance is combination therapy. Our analytical results suggest that in most patients, dual therapy, but not monotherapy, can result in long-term disease control. However, long-term control can only occur if there are no possible mutations in the genome that can cause cross-resistance to both drugs. Furthermore, we showed that simultaneous therapy with two drugs is much more likely to result in long-term disease control than sequential therapy with the same drugs. To improve our understanding of the underlying subclonal evolution we reconstruct the evolutionary history of a patient's cancer from next-generation sequencing data of spatially-distinct DNA samples. Using a quantitative measure of genetic relatedness, we found that pancreatic cancers and their metastases demonstrated a higher level of relatedness than that expected for any two cells randomly taken from a normal tissue. This minimal amount of genetic divergence among advanced lesions indicates that genetic heterogeneity, when quantitatively defined, is not a fundamental feature of the natural history of untreated pancreatic cancers. Our newly developed, phylogenomic tool Treeomics finds evidence for seeding patterns of metastases and can directly be used to discover rules governing the evolution of solid malignancies to transform cancer into a more predictable disease. alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Johannes full_name: Reiter, Johannes id: 4A918E98-F248-11E8-B48F-1D18A9856A87 last_name: Reiter orcid: 0000-0002-0170-7353 citation: ama: Reiter J. The subclonal evolution of cancer. 2015. apa: Reiter, J. (2015). The subclonal evolution of cancer. Institute of Science and Technology Austria. chicago: Reiter, Johannes. “The Subclonal Evolution of Cancer.” Institute of Science and Technology Austria, 2015. ieee: J. Reiter, “The subclonal evolution of cancer,” Institute of Science and Technology Austria, 2015. ista: Reiter J. 2015. The subclonal evolution of cancer. Institute of Science and Technology Austria. mla: Reiter, Johannes. The Subclonal Evolution of Cancer. Institute of Science and Technology Austria, 2015. short: J. Reiter, The Subclonal Evolution of Cancer, Institute of Science and Technology Austria, 2015. date_created: 2018-12-11T11:51:48Z date_published: 2015-04-01T00:00:00Z date_updated: 2023-09-07T11:40:44Z day: '01' degree_awarded: PhD department: - _id: KrCh language: - iso: eng month: '04' oa_version: None page: '183' publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria publist_id: '5807' related_material: record: - id: '1709' relation: part_of_dissertation status: public - id: '2000' relation: part_of_dissertation status: public - id: '2247' relation: part_of_dissertation status: public - id: '2816' relation: part_of_dissertation status: public - id: '2858' relation: part_of_dissertation status: public - id: '3157' relation: part_of_dissertation status: public - id: '3260' relation: part_of_dissertation status: public status: public supervisor: - first_name: Krishnendu full_name: Chatterjee, Krishnendu id: 2E5DCA20-F248-11E8-B48F-1D18A9856A87 last_name: Chatterjee orcid: 0000-0002-4561-241X title: The subclonal evolution of cancer type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2015' ...