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Insights into Recurring Intragenic Rearrangements in High-Grade Serous Carcinoma

Wexler, Matthew (2018) Insights into Recurring Intragenic Rearrangements in High-Grade Serous Carcinoma. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

High grade serous ovarian cancer (HGSC) accounts for 80% of ovarian cancer mortality, and no targeted therapies are available for this disease. Although gene fusions have been a significant focus of cancer genetics studies, other types of genomic rearrangements are known to be cancer-driving, including intragenic genetic rearrangements (IGRs) that result in exons within genes being duplicated or deleted. Some IGRs have been reported to drive growth in tumors, such as EGFR and ERBB2 exon rearrangements, which are known to cause activation of these kinases, but IGRs have not been systematically analyzed in cancer.
Here, we performed a comprehensive bioinformatics analysis to identify potential recurrent intragenic rearrangements in high-grade serous carcinoma. Of note, we identified a potential intragenic duplication of exon 4-5 in EPHA3 based on copy number data analysis; we term this duplication EPHA3d45. We examined the presence of EPHA3d45 transcript by reverse-transcription PCR and capillary sequencing in positive cell lines identified by RNA-seq, and we showed that the siRNA designed to specifically target the duplication junction inhibits the growth of a duplication-positive cell line, TOV112D, but not in a duplication-negative cell line. Additional analysis will be needed to understand the origin and oncogenic potential of EPHA3d45, and further in silico validation, followed by experimental confirmation, could lead to the identification of other novel recurring IGRs in HGSC.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wexler, Matthewmaw266@pitt.edumaw266
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHwang, Hun-Wayhunway.hwang@pitt.edu
Committee MemberLee, Adrianleeav@upmc.edu
Thesis AdvisorWang, Xiaosongwangx13@pitt.edu
Date: 1 June 2018
Date Type: Publication
Defense Date: 14 May 2018
Approval Date: 1 June 2018
Submission Date: 1 June 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 30
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Cancer, Genomics, EPHA3, Intragenic Rearrangements
Date Deposited: 01 Jun 2018 18:13
Last Modified: 01 Jun 2018 18:13
URI: http://d-scholarship.pitt.edu/id/eprint/34579

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