Basudan, Ahmed
(2018)
Comprehensive molecular and clinicopathological characterization of breast cancer metastasis - emphasis on invasive lobular carcinoma.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Metastatic breast cancer (MBC) has been the main cause of death in breast cancer patients, demonstrating a major public health burden. Estrogen receptor-alpha (ER; ESR1) is expressed in nearly 70% of breast tumors and has been a key target for endocrine therapy. Yet, 20-40% of patients eventually develop relapse. Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer, characterized by near universal expression of ER, and by frequent late recurrences. The goal of my studies was to identify genetic changes that might cause endocrine resistance and metastases, with emphasis on ILC.
While many studies have identified ESR1 mutations in recurrent tumors, less is known about changes in ESR1 DNA copy number (CN) changes and their clinical relevance. First, sensitive nanoString-technology was used to comprehensively investigate the role of these alterations in MBC. Our analysis identified substantial rates of ESR1 gains and amplifications in MBC that were of metastatic-site tropism and showed significant association with poor overall survival. Additionally, mutually exclusive amplifications of CCND1 and deletions of CDKN1B and CDKN2A were identified, potentially defining a subset of patients with improved response to CDK4/6 inhibition. I also identified frequent ESR1 amplifications in ILC, and they were significantly enriched in tumors with recurrence and showed association with recurrence-free survival. CN analysis also discovered a unique group of tumors negative for HER2 by IHC characterized by HER2 DNA amplifications, which correlated with high mRNA and protein expression, and enrichment of molecular HER2 signature. Lastly, in addition to clinicopathological evaluation, I utilized RNA-seq approach to understand transcriptomic changes involved in unique ILC metastasis to the ovaries. Our analyses revealed unique transcriptomic alterations in WNT, glutamate/calcium receptors, and MAPK/ERK pathways. Analysis of clinically actionable genes identified MYCN as potential mediator of endocrine resistance. Using targeted sequencing, I further validated previously reported PIK3CA and FOXA1 mutations, and identified novel NCOR1 mutations enriched in the metastases. Collectively, these studies address distinct molecular changes involved in endocrine resistance and metastasis. Such findings are of public health significance, as they can serve as novel therapeutic targets for the leading cause of death in women.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
28 June 2018 |
| Date Type: |
Publication |
| Defense Date: |
3 April 2018 |
| Approval Date: |
28 June 2018 |
| Submission Date: |
21 March 2018 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
183 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
NA |
| Date Deposited: |
28 Jun 2018 20:28 |
| Last Modified: |
28 Jun 2023 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33914 |
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