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Regulations of DNA Damage Response via Gene Copy Number Variations

Li, Sihan (2019) Regulations of DNA Damage Response via Gene Copy Number Variations. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Both endogenous and exogenous factors may damage DNA. DNA damage response genes work together in different pathways are responsible for the repair of the damaged genome. DNA damage deficiency is one of the most important reasons for cancer initiation and progression. To date, studies have demonstrated that gain of function alteration of DNA damage genes and pathways could cause therapeutic resistance to the genome-instability drugs. In the first section, based on TCGA and GDSC database, the landscape of the copy number alterations of the DDR genes was first depicted and we demonstrated that their overexpression is mainly driven by the copy number amplification. Then we delineated reduced mutation burdens/signatures and poorer survival correlate with the amplification of DDR genes. At last, we showed the landscape of the correlation between cell line genome-instability drug response and DDR gene copy number. This study gave us confidence that DDR gene amplification could serve as a biomarker for the clinical outcome and possible mechanism of chemotherapy resistance. In the second section, focusing on one DNA damage response gene, TP53, and a specific cancer type, colorectal cancer, we performed a genome-wide correlation analysis to identify p53 protein regulating gene. Multi-omics data including TCGA gene expression, copy number variations, and RPPA protein level were integrated into this analysis. After identifying several candidate genes in 8q24.21, in vitro study and clinical relevance analysis further demonstrated a p53 protein inhibiting lncRNA, named PiHL.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Li, Sihansil51@pitt.eduSIL51
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDa, Yangdyang@pitt.edu
Committee MemberMa, Xiaochaomxiaocha@pitt.edu
Committee MemberChristian, Fernandezchf63@pitt.edu
Date: 10 April 2019
Date Type: Publication
Defense Date: 27 March 2019
Approval Date: 10 April 2019
Submission Date: 5 April 2019
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 67
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: copy number variations, DNA damage response, cancer, lncRNA, TP53
Date Deposited: 10 Apr 2019 12:16
Last Modified: 10 Apr 2019 12:16
URI: http://d-scholarship.pitt.edu/id/eprint/36371

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