Analysis of Defects in Transcriptional Regulation Mechanisms in High-Grade Serous Ovarian Cancer and Their Correlation with Clinic-Pathological Features

Paracchini, Lara (2020). Analysis of Defects in Transcriptional Regulation Mechanisms in High-Grade Serous Ovarian Cancer and Their Correlation with Clinic-Pathological Features. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00012052

Abstract

High grade serous epithelial ovarian cancer (HGS-EOC) is the most lethal gynaecological disease, usually diagnosed at advanced stages. Although most HGS-EOC patients are initially sensitive to therapy, about 20% of them does not respond to front-line platinum (Pt)-based chemotherapy, relapsing within 6 months from treatment. No molecular biomarkers are as yet available in the clinical practice to discriminate, at the time of diagnosis, the patients who will respond or not to first-line Pt treatment. The identification of a molecular signature associated with intrinsic Pt resistance would allow to select patients who will not respond to Pt compound, thus avoiding ineffective treatment and related toxicities.

In this thesis, defects in transcriptional regulation mechanisms associated to intrinsic Pt resistance were investigated using two different omic approaches – microarray and RNA sequencing. Moreover, considering the correlation between defects in DNA repair Homologous Recombination and Pt sensitivity, we have started to develop an academic assay which exploits high-throughput DNA sequencing to evaluate Homologous Recombination Deficiency (HRD).

Results obtained from three independent HGS-EOC cohorts (n=1080) indicate that the combined expression profile of three genes – PRKG1, SDF2L1 and PPP1R12A – could represent an independent prognostic biomarker for Pt response and survival. In addition, 25 transcripts, 16 of which are unknown or partially known variants, have been identified that are differentially expressed between Pt-sensitive and Pt-resistant patients. These results, once validated, integrated and associated with the HRD status, could identify a molecular signature applicable in the clinical setting to enable stratification of patients at time of diagnosis, allowing to choose the best therapeutic option.

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