Year: 2022
Type: dissertation
Abstract: Cancer consists of genetically heterogeneous populations of cells that arise through a process of subclonal evolution.Reconstructing the evolutionary processes that give rise to cancer can help us better understand cancer progression and prioritize treatment targets.The subclonal reconstruction of cancer gives us the information about the co-occurrence of mutations within the same subclone, the underlying proportion of cells belonging to each subclone, and the ancestral relationships between them.The evolutionary process can be described by inferring tumor phylogenetic trees.The majority of current approaches focus only on either mutation clustering or tree inference in isolation, or rely on computationally expensive algorithms to holistically consider clustering and tree inference concurrently.In this dissertation, we formalize the problem of reconstructing subclonal structure for cancer via probabilistic modeling.Using variant and total read count obtained from bulk DNA sequencing data as input, we introduce a tree-constrained binomial mixture model and an expectation-maximization (EM) method to estimate the clustering assignment for each mutation and the underlying frequency for each cluster.Our EM algorithm employs a linear programming approach to accurately maximize the likelihood bound subject to tree constraints.We choose the optimal tree topology by repeating the process across all possible tree topologies.Compared to existing work, the resulting ClusTree algorithm more accurately identifies mutation clusters, estimates frequencies for each cluster, and detects the proper tree topology, especially for low-depth sequencing data.I would like to thank my advisor Professor Oluwasanmi Koyejo for his advice and patience.His guidance kept me on the right track to finish my Ph.D. journey.Without his support and encouragement, it would not have been possible to complete this dissertation.I was fortunate to join his research group and
Author: Kim, Juho
Institution: University of Illinois Urbana-Champaign
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7220826057