Abstract 5605: Spectral karyotyping characterization of ovarian adenocarcinomas and corresponding cell lines and xenografts

Abstract

Abstract Ovarian cancer is the 9th leading cancer and the 5th cause of cancer deaths in women in the USA. To understand tumor biology, identify oncogenic driver pathways and verify response to drugs, numerous in vitro (cell lines) and in vivo (xenograft in mouse) models have been developed and extensively used. In this study, we aimed to cytogenetically characterize ovarian carcinomas and their respective in vitro and in vivo models to investigate how representative the models are of their originating source. Ascitic fluid was collected from 10 women with previously untreated high grade serous papillary adenocarcinomas of the ovary that presented with malignant ascites (stage 3). Ascitic fluid was subjected to differential centrifugation and plating to enrich for the tumor cell population (TCP). The TCP cells were cultured and considered permanent cell lines (CLP) when grew continuously without evidence of a non-malignant component and could be recovered from cryopreservation. TCP cells were also inoculated intraperitoneally into athymic nude mice and tumors harvested and cryopreserved (XCP). Eight pairs of TCP and CLP and two triplets of TCP, CLP and XCP specimens were characterized by spectral karyotyping (SKY), for a total of 22 specimens. Highly rearranged karyotypes were detected in all specimens. All matched pairs and triplets were obviously related, sharing most of the structural (SA) and numerical (NA) abnormalities identified. Numerous examples of evolution from simple to complex chromosomal rearrangements and of multiple rearrangements originating from a single breakpoint were detected. For 9 patients, TCP and CLP specimens had the same ploidy level (near-2n in 4, near-3n in 3 and near 4n in 2); for one patient, the ploidy changed from near-2n (TCP) to near-4n (CLP). The 2 xenografts had same ploidy as their matched TCP and CLP specimens. In individual analyses, specific SA accounted for <10% of total SA in 8 specimens, for 10-30% in 8 and for >30% in 6. Specific NA accounted for <10% of total NA in 13 specimens, for 10-30% in 6 and for >30% in 3. In the TCP-CLP analyses, 3 pairs were very similar, differing by <10% of specific abnormalities; 5 pairs differed by 10-30% and 2 pairs by >30%. Higher frequency of abnormalities was detected in the TCP specimen for 4 pairs, and in the CLP for 3 pairs. One xenograft was very similar to both TCP and CLP, while the other was closer to the CLP. In conclusion, the ovarian adenocarcinomas were highly rearranged chromosomally and highly heterogeneous. In vitro (CLP) and in vivo (XCP) models maintained a core of the TCP's SA and NA but also displayed unique events, quantitatively and qualitatively variable in distinct tumors, indicating evidence of ex vivo tumor cell selection or progression events. These findings have implications for using established tumor models in research, as well as for potentially identifying the driver rearrangements in specific tumors. Citation Format: Marileila Varella-Garcia, Isabel M. Bernal, Sakshi Mahale, Evelyn M. Musselwhite, Victor Stastny, Mahboubeh Papari-Zareei, Jayanthi Lea, Tito Woodburn, Patrick Reynolds, Adi F. Gazdar. Spectral karyotyping characterization of ovarian adenocarcinomas and corresponding cell lines and xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5605. doi:10.1158/1538-7445.AM2014-5605