Abstract 3146: Oncogene signatures and oncogene interaction networks in SUM breast cancer cell lines.
Authors: Guest Stephen 
Published: August 2014

During the course of tumorigenesis, cancer cells acquire a large number of genetic and epigenetic alterations. A subset of these alterations result in the generation of driver oncogenes that play critical roles in initiating and maintaining the transformed phenotype. Identification and therapeutic targeting of driver oncogenes has revolutionized cancer treatment however, responses to therapies that target a single oncogene are rarely durable. We hypothesize that most solid tumors are simultaneously driven by multiple driver oncogenes that together form an oncogene network and that durable therapies will need to target multiple oncogenes. Identifying multiple driver oncogenes among the large number of mutated/amplified genes that are present in most solid tumors is a nontrivial task that will require novel approaches. In this work we have combined RNAi-based dropout screens with copy number, expression and exome mutation analysis to identify the full complement of driver oncogenes that function in a panel of breast cancer cell lines. Our initial analysis has focused on four cell lines that each contain a known activated receptor tyrosine kinase (RTK) driver oncogene (SUM-52/FGFR2, SUM-185/FGFR3, SUM-190/HER2, and SUM-225/HER2). Using the SUM-52 cell line data as an example, we identified 956 copy number amplified genes and RNAi-based screening showed that 13 are amplified/over expressed and are necessary for growth/survival of this cell line. Similarly, of the 615 mutated genes in this cell line, 23 scored in the screen. Three specific gene mutations were previously identified in other cancer types. Together these genes comprise a first draft of the complete oncogene signature for this cell line. This oncogene signature contains the known driver oncogene, FGFR2, as well as a novel oncogene, MYST3, that is of particular interest because it is found to be focally amplified in 5 different cancer subtypes in the TCGA database. Additionally, one of the mutated genes, RASGRF3 is of particular interest due to the presence of this mutation in the COSMIC database and its role is ras/MAPK signaling. In an effort to identify oncogenes that cooperate with activated RTKs, we performed time-series expression analysis following treatment of cells with RTK inhibitors. In the SUM-52 cell line we identified a suite of genes that are regulated by FGFR2 in these cells and some of these genes are themselves amplified and necessary for growth/survival. Amplified genes regulated by an upstream driver oncogene represent candidate cooperating oncogenes that function as part of an FGFR2 driver oncogene network in these cells. Similar results have been obtained in additional cell lines from our panel including SUM-190 and SUM-225. Future work will focus on validation of oncogene signatures and identification of oncogenes that can be targeted to elicit a synthetic lethal response in the presence of specific, activated driver oncogenes.

Citation Format: Stephen Guest. Oncogene signatures and oncogene interaction networks in SUM breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3146. doi:10.1158/1538-7445.AM2013-3146