Expression profiles of PRKG1, SDF2L1 and PPP1R12A are predictive and prognostic factors for therapy response and survival in high-grade serous ovarian cancer
Giuseppe Benvenuto
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorPaola Todeschini
'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
Search for more papers by this authorLara Paracchini
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorEnrica Calura
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorRobert Fruscio
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorChiara Romani
'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
Search for more papers by this authorLuca Beltrame
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorPaolo Martini
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorAntonella Ravaggi
'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
Search for more papers by this authorLorenzo Ceppi
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorGabriele Sales
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorFederica Donati
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorPatrizia Perego
Pathology Unit, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorLaura Zanotti
'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy
Search for more papers by this authorSara Ballabio
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorTommaso Grassi
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorMartina Delle Marchette
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorGermana Tognon
Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy
Search for more papers by this authorEnrico Sartori
Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy
Search for more papers by this authorMarco Adorni
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorFranco Odicino
Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy
Search for more papers by this authorCorresponding Author
Maurizio D'Incalci
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Correspondence to: Maurizio D'Incalci, E-mail: [email protected]Search for more papers by this authorEliana Bignotti
'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
Search for more papers by this authorChiara Romualdi
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorSergio Marchini
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorGiuseppe Benvenuto
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorPaola Todeschini
'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
Search for more papers by this authorLara Paracchini
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorEnrica Calura
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorRobert Fruscio
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorChiara Romani
'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
Search for more papers by this authorLuca Beltrame
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorPaolo Martini
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorAntonella Ravaggi
'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
Search for more papers by this authorLorenzo Ceppi
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorGabriele Sales
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorFederica Donati
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorPatrizia Perego
Pathology Unit, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorLaura Zanotti
'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy
Search for more papers by this authorSara Ballabio
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorTommaso Grassi
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorMartina Delle Marchette
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorGermana Tognon
Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy
Search for more papers by this authorEnrico Sartori
Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy
Search for more papers by this authorMarco Adorni
Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
Search for more papers by this authorFranco Odicino
Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy
Search for more papers by this authorCorresponding Author
Maurizio D'Incalci
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Correspondence to: Maurizio D'Incalci, E-mail: [email protected]Search for more papers by this authorEliana Bignotti
'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
Search for more papers by this authorChiara Romualdi
Department of Biology, University of Padova, Padova, Italy
Search for more papers by this authorSergio Marchini
Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, Milano, Italy
Search for more papers by this authorAbstract
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.
Abstract
What's new?
About 20% of women with high-grade serous epithelial ovarian carcinoma do not respond to platinum-based chemotherapy but molecular parameters are lacking to predict if a tumor is responsive or not. The authors compared transcriptomic data of more than a thousand tumor biopsies and show that differences in the expression profile of five functionally related pathways distinguish the biology of platinum-sensitive from resistant cases. Three genes in these networks, SDF2L1, PPP1R12A and PRKG1, were independently associated with survival, and may thus provide a molecular signature for patients' stratification at diagnosis.
Conflict of interest
The authors declare no competing financial interest in relation to the work described.
Supporting Information
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