Abstract 1470: Ovarian cancer PDXs preserve preexisting genetic oligoclonality

Abstract

Abstract Advanced Epithelial Ovarian Cancer (EOC) is the leading cause of female cancer casualties and its prognosis remains grim, with about 30% of 5-year overall survival. Classically EOCs have been stratified according to 5 histotypes, tumor grading and disease stages. However, worst prognosis is associated to high grade EOCs, which mostly comprise serous ovarian carcinomas (SOC). A large majority of the patients relapse by 18 to 24 months after end of chemotherapy (CT) and eventually develop resistant disease. Research aiming at proposing more effective therapies relies on a limited set of cancer cell lines established several decades ago and whose representativeness of the actual disease has been put in doubt (Domcke et al., 2013; Nature Comm). This strongly calls for the production of novel EOC models to support experimental and preclinical work. In the last decade patient derived xenografts (PDX) have gained considerable interest, because they faithfully reproduce the characteristics of the tumor of origin. We, here, report the establishment of a collection of 35 ovarian cancer PDXs resulting from the original graft of 77 ovarian tumor samples onto immuno-compromised mice. Interestingly, established PDXs covered the diversity of EOC histotypes. We characterized a subset of 14 EOC PDXs at the genetic (array-CGH and transcriptome) and histological levels. This revealed that PDXs perfectly reproduce the original genetic and morphological features of the ovarian tumors they stemmed from. It was of note that PDXs conserved the principal characteristics of the original CNC profiles over several passages. However, a detailed comparison revealed fluctuation of CNC patterns in a fraction of chromosomal regions between the original tumor and the PDXs, that could be attributed to the oligoclonal nature of the original tumor. The analysis by CGH, FISH and exome sequencing of one case, for which several tumor nodules were sampled and grafted, revealed that PDX globally maintained an oligoclonal structure. Despite fluctuations in the relative prevalence of some mutations according to the sample, we did not observe any overgrowth of a particular subclone present in the original tumor. This suggests that xenotransplantation of ovarian tumors and growth as PDX is not associated to a drastic change in selective pressure. We believe these findings are of interest to determine the impact of different therapy regimen on the clonality of EOC. Citation Format: Pierre-Emmanuel Colombo, Stanislas du Manoir, Beatrice Orsetti, Rui Bras-Goncalves, Alan MacKay, Maryou Lambros, Tuan T. Nguyen, Florence Boissiere, Didier Pourquier, Jorge Reis-Filho, Charles G. Theillet. Ovarian cancer PDXs preserve preexisting genetic oligoclonality. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1470. doi:10.1158/1538-7445.AM2015-1470