Abstract 4238: Unique ovarian cancer cell line panel: Molecular subtypes and therapy response
Authors: Beaufort Corine M. , Helmijr Jean , Ruigrok-Ritstier Kirsten , Smid Marcel , Heine Anouk , Jansen Maurice PHM , Berns Els MJJ , Helleman Jozien 
Published: August 2012

Abstract
Epithelial ovarian cancer is the most lethal gynecological malignancy in the Western world. Up to 70% of the patients do not survive the first 5 years after diagnosis, mostly due to acquired chemotherapy resistance. With the goal to stratify a heterogeneous group of patients, recently, a number of studies have identified molecular subtypes within ovarian carcinomas. However, the relation with response to chemotherapeutics is unknown. An extensive model system in which the response to different chemotherapeutics can be related to molecular subtypes is therefore imperative to know how to individualize treatment based on these molecular subtypes. We have an (increasing) collection of so far 40 ovarian cancer cell lines. The large number and extensive characterization of the cell lines makes this a unique model. We have data of the growth and morphological properties, exon-based gene expression (22.000 genes), microRNA expression (400 miRNAs), mutation analysis (PIK3CA, RAF & RAS genes), microsatellite instability status (MSI) and response curves for eight chemotherapeutics used in first- and second-line treatment. Unsupervised absolute clustering using the most variable expressed genes and microRNAs revealed two even clusters of cell lines with significantly different characteristics. The cell lines in the first cluster compared to the second: -show more often a round and less often an epithelial morphology (cell lines with spindle morphology are divided over both clusters), -show more often no Epithelial Cell Adhesion Molecule (EpCAM) and high CD44 membrane expression -are highly proliferative -are more often PI3K/Ras mutated and MSI Interestingly, the cell lines within the first cluster are significantly more sensitive to six of the eight tested chemotherapeutics compared to the second cluster BRB class comparison analysis revealed that 287 genes were differentially expressed between the two clusters (permutation p&lt;0.01, FDR&lt;5%, 10.000 permutations). Pathway analysis of these genes revealed the significantly overrepresented canonical pathways and molecular & cellular functions including Interferon Signaling (p=0.007), Arachidonic Acid Metabolism (p=0.030) and Cell-To-Cell Signaling and Interaction (p&lt;0.03). We are currently identifying the published clinical molecular subtypes in our cell lines and relating it with response to treatment. This will give information on which of the commonly used therapeutics are expected to be most effective in the different molecular subtype. In the future, the response to targeted therapeutics can be tested in our cell line panel which may give additional information on how to treat each subtype. In conclusion, this large panel of extremely well characterized ovarian cancer cell lines is a unique model system that can be used in many future translational and functional studies and we are happy to collaborate (j.helleman@erasmusmc.nl).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4238. doi:1538-7445.AM2012-4238