Causes and consequences of damaging mutation accumulation in cancer
Abstract/Contents
- Abstract
- Cancer develops from an accumulation of somatic mutations over time. While a small subset of these mutations contribute directly to tumor progression, the vast majority of the remaining mutations that accrue in cancer - which can often reach up to thousands and even tens of thousands - are thought to have little functional relevance to tumor growth. However, a growing body of literature also supports that many of these mutations could instead be damaging to cancers - potentially through gene loss of function, immune surveillance, or induction of protein misfolding stress. This dissertation explores the causes and consequences of damaging mutation accumulation in cancer in two parts. First, I use a combination of evolutionary simulations from population genetics modeling and analysis of empirical cancer sequencing data to demonstrate that Hill-Robertson interference causes negative selection to become rapidly inefficient in most cancers. I find that low mutational burden tumors, which experience weak linkage effects, demonstrate strong patterns of positive and negative selection, while high mutational burden tumors, which endure strong linkage effects between mutations, exhibit patterns of neutral tumor evolution. Collectively, these results suggest that the vast majority of tumors (> 95%) are accumulating damaging mutations which are not being removed. Second, I explore how tumors can successfully survive the deleterious consequences of this damaging mutation accumulation. I use functional genomics and statistical analysis to examine how tumors phenotypically respond to damaging mutation accumulation by examining changes in gene expression. I combine this analysis with loss-of-function experiments in cancer cell lines to demonstrate that high mutational burden cancer cell lines maintain their viability by utilizing mechanisms that largely mitigate and prevent protein misfolding stress. Ultimately, these results elucidate potential mechanisms and physiological consequences of inefficient negative selection in somatic evolution, and add to potential therapeutics that can be applied to target high mutational load tumors.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Tilk, Susanne |
|---|---|
| Degree supervisor | Curtis, Christina |
| Degree supervisor | Petrov, Dmitri Alex, 1969- |
| Thesis advisor | Curtis, Christina |
| Thesis advisor | Petrov, Dmitri Alex, 1969- |
| Thesis advisor | Good, Benjamin |
| Thesis advisor | Winslow, Monte |
| Degree committee member | Good, Benjamin |
| Degree committee member | Winslow, Monte |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Susanne Tilk. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/qk528tq6001 |
Access conditions
- Copyright
- © 2022 by Susanne Tilk
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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