Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts

Federica Guffanti, Maddalena Fratelli, Monica Ganzinelli, Marco Bolis, Francesca Ricci, Francesca Bizzaro, Rosaria Chilà, Federica Paola Sina, Robert Fruscio, Michela Lupia, Ugo Cavallaro, Maria Rosa Cappelletti, Daniele Generali, Raffaella Giavazzi, Giovanna Damia

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)24707-24717
Number of pages11
JournalOncotarget
Volume9
Issue number37
DOIs
Publication statusPublished - May 15 2018

Fingerprint

Platinum
Heterografts
DNA Repair
Carcinoma
Messenger RNA
Methylation
Genes
Fanconi Anemia
Neoplasms
DNA Mismatch Repair
Homologous Recombination
Residual Neoplasm
Cisplatin
Real-Time Polymerase Chain Reaction
Gene Expression
Recurrence
Mutation
Therapeutics

Keywords

  • Cisplatin
  • DNA repair
  • Drug resistance
  • Ovarian cancer
  • Patients-derived xenografts

ASJC Scopus subject areas

  • Oncology

Cite this

Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts. / Guffanti, Federica; Fratelli, Maddalena; Ganzinelli, Monica; Bolis, Marco; Ricci, Francesca; Bizzaro, Francesca; Chilà, Rosaria; Sina, Federica Paola; Fruscio, Robert; Lupia, Michela; Cavallaro, Ugo; Cappelletti, Maria Rosa; Generali, Daniele; Giavazzi, Raffaella; Damia, Giovanna.

In: Oncotarget, Vol. 9, No. 37, 15.05.2018, p. 24707-24717.

Research output: Contribution to journalArticle

Guffanti, Federica ; Fratelli, Maddalena ; Ganzinelli, Monica ; Bolis, Marco ; Ricci, Francesca ; Bizzaro, Francesca ; Chilà, Rosaria ; Sina, Federica Paola ; Fruscio, Robert ; Lupia, Michela ; Cavallaro, Ugo ; Cappelletti, Maria Rosa ; Generali, Daniele ; Giavazzi, Raffaella ; Damia, Giovanna. / Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts. In: Oncotarget. 2018 ; Vol. 9, No. 37. pp. 24707-24717.
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AU - Guffanti, Federica

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AU - Ricci, Francesca

AU - Bizzaro, Francesca

AU - Chilà, Rosaria

AU - Sina, Federica Paola

AU - Fruscio, Robert

AU - Lupia, Michela

AU - Cavallaro, Ugo

AU - Cappelletti, Maria Rosa

AU - Generali, Daniele

AU - Giavazzi, Raffaella

AU - Damia, Giovanna

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