Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts
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Federica Guffanti1, Maddalena Fratelli2, Monica Ganzinelli3, Marco Bolis2, Francesca Ricci1, Francesca Bizzaro1, Rosaria Chilà1, Federica Paola Sina4, Robert Fruscio4, Michela Lupia5, Ugo Cavallaro5, Maria Rosa Cappelletti6, Daniele Generali6,7, Raffaella Giavazzi1 and Giovanna Damia1
1Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
2Department of Biochemistry, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
3Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
4Clinic of Obstetrics and Gynecology, San Gerardo Hospital, University of Milan-Bicocca, Department of Medicine and Surgery, Milan, Italy
5Unit of Gynecological Oncology Research, European Institute of Oncology, Milan, Italy
6Breast Cancer Unit and Translational Research Unit, ASST Cremona, Cremona, Italy
7Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy
Giovanna Damia, email: firstname.lastname@example.org
Keywords: ovarian cancer; patients-derived xenografts; cisplatin; drug resistance; DNA repair
Received: January 29, 2018 Accepted: April 05, 2018 Published: May 15, 2018
A xenobank of patient-derived (PDX) ovarian tumor samples has been established consisting of tumors with different sensitivity to cisplatin (DDP), from very responsive to resistant. As the DNA repair pathway is an important driver in tumor response to DDP, we analyzed the mRNA expression of 20 genes involved in the nucleotide excision repair, fanconi anemia, homologous recombination, base excision repair, mismatch repair and translesion repair pathways and the methylation patterns of some of these genes. We also investigated the correlation with the response to platinum-based therapy. The mRNA levels of the selected genes were evaluated by Real Time-PCR (RT-PCR) with ad hoc validated primers and gene promoter methylation by pyrosequencing. All the DNA repair genes were variably expressed in all 42 PDX samples analyzed, with no particular histotype-specific pattern of expression. In high-grade serous/endometrioid PDXs, the CDK12 mRNA expression levels positively correlated with the expression of TP53BP1, PALB2, XPF and POLB. High-grade serous/endometrioid PDXs with TP53 mutations had significantly higher levels of POLQ, FANCD2, RAD51 and POLB than high-grade TP53 wild type PDXs. The mRNA levels of CDK12, PALB2 and XPF inversely associated with the in vivo DDP antitumor activity; higher CDK12 mRNA levels were associated with a higher recurrence rate in ovarian patients with low residual tumor. These data support the important role of CDK12 in the response to a platinum based therapy in ovarian patients.
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