Investigating the role of the UbcH10 proto-oncogene product in high grade serous ovarian cancer

Elshennawy, Rawda Ahmed Tawfiq Mahmoud (2024). Investigating the role of the UbcH10 proto-oncogene product in high grade serous ovarian cancer. University of Birmingham. Ph.D.

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Abstract

High grade serous carcinoma (HGSOC) is the 5th leading cause of cancer related deaths in females worldwide. According to the Cancer Genome Atlas (TCGA), HGSOC is marked by early TP53 mutation and has four molecular subtypes; Mesenchymal, Immunoreactive, Proliferative and Differentiated. Despite advances in our understanding of the molecular background of HGSOC, treatment modalities have not improved patient survival. UbcH10/Ube2C is an E2-conjugating enzyme that regulates cell-cycle progression, by promoting the degradation of mitotic regulators through the ubiquitin-proteasome pathway. UbcH10 is also a proto-oncogene whose aberrant expression has been reported in numerous cancers.
Research carried throughout this thesis aimed at investigating UbcH10 as a potential biomarker for the prognostication and molecular stratification of HGSOC. We aimed to study its relative protein expression in HGSOC, relation to TP53 mutations, molecular subtypes of HGSOC and its effect on patient outcome. In addition, we aimed to identify its role in the progression of HGSOC by studying its expression in its precursor lesions; serous tubal intraepithelial carcinomas (STIC) and p53 signatures. Three experimental cohorts were investigated in the present study and the publicly available TCGA cohort of ovarian serous carcinomas was also interrogated.
Immunohistochemistry (IHC) was used to investigate UbcH10 and p53 protein expression in a training cohort which included 100 full-faced HGSOC sections and a validation cohort of 81 cases of tissue microarrays were used. UbcH10 was scored according to the IRS and H-scores, and the X-tile tool was used to generate biologically significant cut-off values. Ki-67 and CD8 IHC were used for molecular subtyping of the training cohort according to TCGA groups. Multiplex IHC was used to investigate the co-expression of UbcH10/Ki-67 as well as UbcH10/p53 in a third cohort of 24 STIC samples and their matched HGSOC.
UbcH10 overexpression was detected in 29-33% and 16-17% of the training and validation cohorts respectively. In the training cohort, UbcH10 overexpression did not significantly impact survival nor correlate with p53 mutations, prognostic, or predictive parameters. Additionally, UbcH10 expression was positively correlated with Ki-67 index and significantly associated with the aggressive and treatment resistant Proliferative molecular subtype of HGSOC.
In the validation cohort, Ubch10 negatively impacted overall survival. The trend was maintained in progression-free survival but was not significant. Results from both cohorts therefore conclude that UbcH10 is significantly related to the proliferative state of the cell and has a borderline poor prognostic significance in HGSOC.
In STIC/HGSOC cohort, like p53, UbcH10 is expressed early in STICs and is positively correlated with Ki-67 index. A heterogeneous rather than a directly proportional relationship exists between p53 and UbcH10 in STICs and their corresponding HGSOC.
Analysis on TCGA cohort confirms results from the experimental cohorts at the gene level. Ube2C is significantly co-expressed with genes involved in cell-cycle regulation and has no impact on HGSOC mortality or progression. Ube2C gene expression levels do not correlate with TP53 mutations and are significantly associated with the Proliferative molecular subtype of HGSOC. So, whilst UbcH10 is only a borderline prognostic marker in HGSOC, it is more beneficial as a predictor of treatment response when interpreted in the context of the molecular subgroup of HGSOC.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):