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Expression profiles of PRKG1, SDF2L1 and PPP1R12A are predictive and prognostic factors for therapy response and survival in high-grade serous ovarian cancer |
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| Authors: | Giuseppe Benvenuto Paola Todeschini Lara Paracchini Enrica Calura Robert Fruscio Chiara Romani Luca Beltrame Paolo Martini Antonella Ravaggi Lorenzo Ceppi Gabriele Sales Federica Donati Patrizia Perego Laura Zanotti Sara Ballabio Tommaso Grassi Martina Delle Marchette Germana Tognon Enrico Sartori Marco Adorni Franco Odicino Maurizio D'Incalci Eliana Bignotti Chiara Romualdi Sergio Marchini |
| Affiliation: | 1. Department of Biology, University of Padova, Padova, Italy;2. 'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy;3. Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy;4. Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy;5. 'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy;6. 'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy Department of Clinical and Experimental Sciences, Division of Obstetrics and Gynecology, University of Brescia, Brescia, Italy;7. Pathology Unit, San Gerardo Hospital, Monza, Italy;8. 'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy;9. Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy |
| Abstract: | High-grade serous ovarian cancer (HGS-EOCs) is generally sensitive to front-line platinum (Pt)-based chemotherapy although most patients at an advanced stage relapse with progressive resistant disease. Clinical or molecular data to identify primary resistant cases at diagnosis are not yet available. HGS-EOC biopsies from 105 Pt-sensitive (Pt-s) and 89 Pt-resistant (Pt-r) patients were retrospectively selected from two independent tumor tissue collections. Pathway analysis was done integrating miRNA and mRNA expression profiles. Signatures were further validated in silico on a cohort of 838 HGS-EOC cases from a published dataset. In all, 131 mRNAs and 5 miRNAs belonging to different functionally related molecular pathways distinguish Pt-s from Pt-r cases. Then, 17 out of 23 selected elements were validated by orthogonal approaches (SI signature). As resistance to Pt is associated with a short progression-free survival (PFS) and overall survival (OS), the prognostic role of the SI signature was assessed, and 14 genes associated with PFS and OS, in multivariate analyses (SII signature). The prognostic value of the SII signature was validated in a third extensive cohort. The expression profiles of SDF2L1, PPP1R12A and PRKG1 genes (SIII signature) served as independent prognostic biomarkers of Pt-response and survival. The study identified a prognostic molecular signature based on the combined expression profile of three genes which had never been associated with the clinical outcome of HGS-EOC. This may lead to early identification, at the time of diagnosis, of patients who would not greatly benefit from standard chemotherapy and are thus eligible for novel investigational approaches. |
| Keywords: | high-grade serous epithelial ovarian cancer prognostic signature PRKG1 SDF2L1 PPP1R12A integrative pathway analyses |