The role of differential carcinogen susceptibility in melanoma mutagenesis
Abstract/Contents
- Abstract
- Cancer cells evolve through the acquisition of mutations that confer selective advantages associated with malignant transformation. Mutagenesis is preceded by DNA damaging events that occur during exposure to environmental carcinogens or from sporadic cell-intrinsic processes. The acquisition of DNA damage in the presence of genotoxic stressors is determined by the underlying DNA sequence and the surrounding chromatin, a highly dynamic environment involved in the coordination of all DNA-templated processes (such as transcription and replication). If unrepaired, or repaired with poor fidelity, DNA damage causes mutations that increase the probability of sporadic acquisition of malignant characteristics. This work investigates the precise molecular determinants that initiate carcinogenesis. Specifically, we introduce a new DNA sequencing technology to map and quantify various types of DNA damage at ultra-high resolution across the genome. We demonstrate the ability to map DNA lesions induced by UV exposure, heat, oxidative stress, and other conditions at single-base resolution from low input samples. We utilize this technology to provide a detailed atlas of photoproduct acquisition after acute UV exposure in model human cells, and then leverage extensive epigenomic characterizations of these cells to infer novel mechanisms of carcinogenesis. We next introduce genetic alterations that mimic early stages of tumorigenesis and reveal the previously unreported phenomenon of differential susceptibility, whereby tumor-promoting genetic and epigenetic changes alter genome susceptibility to carcinogen exposure and bias subsequent mutagenic potential. We observe unique mutational signatures in melanoma associated with these differentially susceptible regions and suggest that altered carcinogen susceptibility is a generalized principle of human cancer. In summary we have uncovered previously unreported aspects of genome stability and the associated epigenetic mechanisms that underlie them. This work provides the foundation for the development of new therapeutic approaches that interrupt the earliest stages of tumorigenesis. Excitingly, as this novel phenomenon is regulated by reversible epigenetic alterations, the next generation of "epi-drugs" may be thoughtfully designed to override differential susceptibility and prevent cancer.
Description
Type of resource | text |
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Form | electronic resource; remote; computer; online resource |
Extent | 1 online resource. |
Place | California |
Place | [Stanford, California] |
Publisher | [Stanford University] |
Copyright date | 2021; ©2021 |
Publication date | 2021; 2021 |
Issuance | monographic |
Language | English |
Creators/Contributors
Author | King, Devin Aalpoel |
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Degree supervisor | Morrison, Ashby J |
Thesis advisor | Morrison, Ashby J |
Thesis advisor | Cyert, Martha S, 1958- |
Thesis advisor | Gozani, Or Pinchas |
Thesis advisor | Snyder, Michael, Ph. D. |
Degree committee member | Cyert, Martha S, 1958- |
Degree committee member | Gozani, Or Pinchas |
Degree committee member | Snyder, Michael, Ph. D. |
Associated with | Stanford University, Department of Biology |
Subjects
Genre | Theses |
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Genre | Text |
Bibliographic information
Statement of responsibility | Devin Aalpoel King. |
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Note | Submitted to the Department of Biology. |
Thesis | Thesis Ph.D. Stanford University 2021. |
Location | https://purl.stanford.edu/zs597fq6946 |
Access conditions
- Copyright
- © 2021 by Devin Aalpoel King
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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