Molecular investigations of ovarian clear cell carcinoma – a treatment resistant malignancy

Ma, Yue

Molecular investigations of ovarian clear cell carcinoma – a treatment resistant malignancy

Ma, Yue

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Publication Type:: Thesis
Issue Date:: 2024

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Field	Value	Language
dc.contributor.author	Ma, Yue
dc.date.accessioned	2025-05-27T00:37:11Z
dc.date.available	2025-05-27T00:37:11Z
dc.date.issued	2024
dc.identifier.uri	http://hdl.handle.net/10453/187535
dc.description	University of Technology Sydney. Faculty of Science.	en_US.UTF-8
dc.description.abstract	Ovarian cancer (OC) is the eighth most common cancer and the deadliest gynaecological malignancy worldwide. Among epithelial ovarian cancers (EOCs), ovarian clear cell carcinoma (OCCC) is the second most common subtype, marked by poor prognosis and frequent mutations in SWI/SNF chromatin remodelling complex genes including ARID1A. This study aimed to identify new therapeutic compounds for OCCC and develop CRISPR-Cas9 models for future research. Seven OCCC cell lines (e.g., RMG-I, OVISE) were authenticated through short tandem repeat (STR) analysis and Sanger sequencing, confirming ARID1A/ARID1B mutations. Platinum sensitivity assays showed no correlation between these mutations and platinum response. Drug screening using the Tocriscreen Epigenetics Library revealed that the BTK inhibitor ibrutinib significantly reduced OCCC cell viability, with higher IC50 (inhibitory concentration 50) values in 3D bioprinted models compared to 2D. Using CRISPR-Cas9 tools, isogenic ARID1A/ARID1B knockout (KO) cell lines were created. Data supported that dual knockout of ARID1A and ARID1B was likely synthetic lethal, while individual KOs affected cell proliferation and cisplatin sensitivity. ARID1A KO decreased STAG1 expression, implicating DNA repair pathways. This study highlights the potential of ibrutinib as a novel OCCC therapeutic. The engineered cell models and CRISPR-Cas9 pipelines will facilitate future research into ARID1A-mutated OCCC and targeted drug development.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/187535/1/thesis.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2024 Yue Ma
dc.rights	au.edu.uts.lib/cph
dc.title	Molecular investigations of ovarian clear cell carcinoma – a treatment resistant malignancy	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Ovarian cancer (OC) is the eighth most common cancer and the deadliest gynaecological malignancy worldwide. Among epithelial ovarian cancers (EOCs), ovarian clear cell carcinoma (OCCC) is the second most common subtype, marked by poor prognosis and frequent mutations in SWI/SNF chromatin remodelling complex genes including ARID1A. This study aimed to identify new therapeutic compounds for OCCC and develop CRISPR-Cas9 models for future research. Seven OCCC cell lines (e.g., RMG-I, OVISE) were authenticated through short tandem repeat (STR) analysis and Sanger sequencing, confirming ARID1A/ARID1B mutations. Platinum sensitivity assays showed no correlation between these mutations and platinum response. Drug screening using the Tocriscreen Epigenetics Library revealed that the BTK inhibitor ibrutinib significantly reduced OCCC cell viability, with higher IC50 (inhibitory concentration 50) values in 3D bioprinted models compared to 2D. Using CRISPR-Cas9 tools, isogenic ARID1A/ARID1B knockout (KO) cell lines were created. Data supported that dual knockout of ARID1A and ARID1B was likely synthetic lethal, while individual KOs affected cell proliferation and cisplatin sensitivity. ARID1A KO decreased STAG1 expression, implicating DNA repair pathways. This study highlights the potential of ibrutinib as a novel OCCC therapeutic. The engineered cell models and CRISPR-Cas9 pipelines will facilitate future research into ARID1A-mutated OCCC and targeted drug development.

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http://hdl.handle.net/10453/187535