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Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973859/ https://www.ncbi.nlm.nih.gov/pubmed/29872499 http://dx.doi.org/10.18632/oncotarget.25185 |
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author | 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 |
author_facet | 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 |
author_sort | Guffanti, Federica |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5973859 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-59738592018-06-05 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 Oncotarget Research Paper 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. Impact Journals LLC 2018-05-15 /pmc/articles/PMC5973859/ /pubmed/29872499 http://dx.doi.org/10.18632/oncotarget.25185 Text en Copyright: © 2018 Guffanti et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper 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 |
title | Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts |
title_full | Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts |
title_fullStr | Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts |
title_full_unstemmed | Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts |
title_short | Platinum sensitivity and DNA repair in a recently established panel of patient-derived ovarian carcinoma xenografts |
title_sort | platinum sensitivity and dna repair in a recently established panel of patient-derived ovarian carcinoma xenografts |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973859/ https://www.ncbi.nlm.nih.gov/pubmed/29872499 http://dx.doi.org/10.18632/oncotarget.25185 |
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