Abstract 508: DNA repair status in a patient derived ovarian cancer xenobank
Authors: Federica Guffanti, Maddalena Fratelli, Monica Ganzinelli, Francesca Ricci, Roberta Affatato, Maria Rosa Cappelletti, Daniele Generali, Francesca Bizzaro, Massimo Broggini, Raffaella Giavazzi, Giovanna Damia
Journal: Cancer Research (2017)

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy with a 5-year relative survival rate of 45%. The high mortality rate is in part due to the development of platinum chemoresistance occurring in more than 70% of patients after the first-line therapy. DNA repair capacity has been reported to be a key determinant for the cellular response to platinum agents. Since half of the high grade serous EOCs lacks Homologous Recombination repair, we aimed to profile the DNA repair status in a panel of well characterized 42 ovarian patient derived xenografts (PDXs) recently established in our laboratory and to correlate it with the in vivo response to a platinum based therapy. We evaluated by real time PCR (ABI-7900, Applied Biosystems) the mRNA levels of genes with a key role in Base Excision Repair (OGG1, POLB and PARP1), Homologous Recombination (BRCA1, PALB2, TP53BP1 and RAD51), Nucleotide Excision Repair (ERCC1, XPA, XPF, XPD and XPG), Fanconi Anemia pathway (FANCA, FANCC, FANCD2 and FANCF), Translesion Repair (POLEta), Mismatch Repair (MLH1), Microhomology End Joining (POLQ), Non Homologous End Joining (XRCC4, XRCC5, XRCC6 and XRCC7) and CDK12, a kinase regulating the transcription of some DNA repair genes. The methylation status of BRCA1, ERCC1, MLH1, XPA, XPG and FANCF was investigated by standard techniques. Our results show that the DNA repair genes considered were variably expressed in all the 42 PDXs analyzed, with no specific histotype-specific cluster of expression. The expression of PALB2, FANCC, FANCD2, OGG1, POLQ and RAD51 was found to correlate with the expression of at least six other genes. In high grade serous/endometrioid PDXs, the CDK12 mRNA expression levels positively correlated with the expression of TP53BP1, PALB2, XPF and POLB. BRCA1 was found to be hypermethylated in 51% of the xenografts. TP53 mutated PDXs showed statistically significant higher levels of POLQ, FANCD2, RAD51, and POLB genes. The expression of CDK12 [p=0.017], PALB2 [p=0.019] and XPF [p= 0.016] was negatively associated with the in vivo response to DDP, with resistant PDXs showing higher mRNA levels than responsive ones. We looked for association with overall survival in the TCGA data set and we found that high levels of CDK12 were associated with a worse overall survival in patients with a residual tumor after surgery minus than 2cm. These data suggest that some DNA repair genes can have a role in EOC patients’ response to DDP therapy. Particularly, CDK12 was significantly able to predict worse survival in patients undergoing optimal debulking surgery. Our xenobank will be a valid instrument to set up functional DNA repair assays, as suggested by preliminary data on primary cultures. Citation Format: Federica Guffanti, Maddalena Fratelli, Monica Ganzinelli, Francesca Ricci, Roberta Affatato, Maria Rosa Cappelletti, Daniele Generali, Francesca Bizzaro, Massimo Broggini, Raffaella Giavazzi, Giovanna Damia. DNA repair status in a patient derived ovarian cancer xenobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 508. doi:10.1158/1538-7445.AM2017-508