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The Functional and Clinical Conseque...

Fischer, Nicholas William.

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The Functional and Clinical Consequences of TP53 Mutations in Cancer.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Functional and Clinical Consequences of TP53 Mutations in Cancer./
作者:	Fischer, Nicholas William.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	161 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Contained By:	Dissertations Abstracts International81-04B.
標題:	Biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10981205
ISBN:	9781085760225

The Functional and Clinical Consequences of TP53 Mutations in Cancer.
Fischer, Nicholas William.

The Functional and Clinical Consequences of TP53 Mutations in Cancer. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 161 p.

Source: Dissertations Abstracts International, Volume: 81-04, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

This item must not be sold to any third party vendors.

The discovery of genetic variants linked to cancer have provided useful biomarkers for diagnostics, prognostics, and therapeutic targets. Mutations in the TP53 gene that encodes the p53 tumor suppressor protein are the most abundant genetic variants in human cancers, yet their clinical utility has not been fully explored. Normally, the p53 protein plays a crucial role as a barrier to cancer. Hundreds of different sporadic and germline (Li-Fraumeni syndrome) pathogenic p53 mutants have been identified; some with loss of function or partial function, and others gaining oncogenic activity. Currently, there is no clinical distinction between different p53 mutants as a biomarker despite evidence of substantial functional disparity. A greater understanding of the functional diversity between different variants will be necessary to improve the clinical utility of TP53 mutations. The central theme of this thesis was to characterize the cellular functions of different p53 mutants and translate this knowledge to the clinic as informative biomarkers. Specifically, the thesis focuses on how the oligomerization and residual transcriptional activity of p53 mutants can impact oncologic outcomes. First, I describe the preliminary study that compared the cellular activities of oligomeric p53 variants, reporting that p53 cellular activities are modulated by its oligomeric state. Second, in a follow-up study, I outline the clinical consequences of each clinically-relevant germline TP53 mutation in the oligomerization domain. A strong genotype-phenotype relationship was observed where the ability of mutant p53 to oligomerize prognosticated more favourable clinical outcomes. Lastly, I describe a functionally integrated meta-analysis that stratified cancer patients with TP53 mutations according to their mutant-specific level of residual transcriptional activity. A male-specific linkage between increased residual activity and prolonged survival was uncovered in glioma and gastric adenocarcinoma patients. This association was recapitulated in the lifetime cancer survival of Li-Fraumeni syndrome, where brain and gastric tumors are more common among men. Together, this thesis demonstrates that a wide spectrum of functionality exists between different p53 mutants that should be considered in clinical decision-making.

ISBN: 9781085760225Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

Cancer

The Functional and Clinical Consequences of TP53 Mutations in Cancer.
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