Ovarian carcinoma patient derived xenografts reproduce their tumor of origin and preserve an oligoclonal structure
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Pierre-Emmanuel Colombo1,2, Stanislas du Manoir2,3, Béatrice Orsett2,3,4, Rui Bras-Gonçalves2,3,4, Mario B. Lambros5, Alan MacKay5, Tien-Tuan Nguyen2,3, Florence Boissière6, Didier Pourquier7, Frédéric Bibeau7, Jorge S. Reis-Filho8 and Charles Theillet2,3
1 Department of Surgical Oncology, Institut de Cancérologie de Montpellier, Montpellier, France
2 Institut de Recherche en Cancérologie de Montpellier, Université Montpellier, Montpellier, France
3 INSERM U1194, Montpellier, France
4 Institut de Cancérologie de Montpellier, Montpellier, France
5 Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK
6 Unité de Recherche Translationnelle, Institut de Cancérologie de Montpellier, Montpellier, France
7 Department of Pathology, Institut de Cancérologie de Montpellier, Montpellier, France
8 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Charles Theillet, email:
Jorge Reis-Filho, email:
Keywords: ovarian cancer, PDX, CNC, mutations, oligoclonality
Received: April 10, 2015 Accepted: July 02, 2015 Published: July 31, 2015
Advanced Epithelial Ovarian Cancer (EOC) patients frequently relapse by 24 months and develop resistant disease. Research on EOC therapies relies on cancer cell lines established decades ago making Patient Derived Xenografts (PDX) attractive models, because they are faithful representations of the original tumor. We established 35 ovarian cancer PDXs resulting from the original graft of 77 EOC samples onto immuno-compromised mice. PDXs covered the diversity of EOC histotypes and graft take was correlated with early patient death. Fourteen PDXs were characterized at the genetic and histological levels. PDXs reproduced phenotypic features of the ovarian tumors of origin and conserved the principal characteristics of the original copy number change (CNC) profiles over several passages. However, CNC fluctuations in specific subregions comparing the original tumor and the PDXs indicated the oligoclonal nature of the original tumors. Detailed analysis by CGH, FISH and exome sequencing of one case, for which several tumor nodules were sampled and grafted, revealed that PDXs globally maintained an oligoclonal structure. No overgrowth of a particular subclone present in the original tumor was observed in the PDXs. This suggested that xenotransplantation of ovarian tumors and growth as PDX preserved at least in part the clonal diversity of the original tumor. We believe our data reinforce the potential of PDX as exquisite tools in pre-clinical assays.
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