Reconstructing Complex Cancer Evolutionary Histories from Multiple Bulk DNA Samples

Cancers are composed of genetically distinct subpopulations of malignant cells. By sequencing DNA from cancer tissue samples, we can characterize the somatic mutations specific to each population and build clone trees describing the evolutionary relationships between these populations. These trees reveal critical points in disease development and inform treatment. This thesis describes Pairtree, which is a new method for constructing clone trees using DNA sequencing data from one or more bulk samples of an individual cancer. It uses Bayesian inference to compute posterior distributions over the evolutionary relationships between every pair of identified subpopulations, then uses these distributions in a Markov Chain Monte Carlo algorithm to perform efficient inference of the posterior distribution over clone trees. Pairtree also uses the pairwise relationships to detect mutations that violate the infinite sites assumption. Unlike previous methods, Pairtree can perform clone tree reconstructions using as many as 100 samples per cancer that reveal 30 or more cell subpopulations. On simulated data, Pairtree is the only method whose performance reliably improves when provided with additional bulk samples from a cancer. On 14 B-progenitor acute lymphoblastic leukemias with up to 90 samples from each cancer, Pairtree was the only method that could reproduce or improve upon expert-derived clone tree reconstructions. Beyond describing Pairtree and evaluating it relative to previous methods, we develop extensions for profiling the degree of uncertainty that exists in its solution set, quantifying the degree of heterogeneity that occurs in different cancer samples, and deciding whether two cancer samples are genetically similar. By scaling to more challenging problems, Pairtree supports new biomedical research applications that can improve our understanding of the natural history of cancer, as well as better illustrate the interplay between cancer, host, and therapeutic interventions.Ph.D