Abstract 5099: Identification of complex oncogene signatures in human cancer specimens and cell lines

Abstract

Abstract Activated oncogenes are the genetic drivers of human cancer progression. Oncogenes become activated by structural DNA alterations including gene amplification and over expression, point mutations, and gene translocations/rearrangements. Data from existing targeted cancer treatments clearly show that the best response is observed when the activated oncogene is targeted. On the other hand, among the patients with activated oncogene who respond to a targeted treatment, the level and duration of response is highly variable. This could be explained by the genomic context of an activated oncogene that is unique to any given patient. Therefore, the ability to detect complex oncogene signatures in human cancer specimens is vital for better predictions of the efficacy of targeted agents, and to design therapeutic strategies with multiple targeted agents. In our laboratory, we have been working to identify candidate amplified and point mutated oncogenes in multiple human cancer specimens and cell lines. To obtain individual oncogene signatures, we have used high resolution aCGH coupled with a novel gene expression algorithm that allows for the identification of genes that are over expressed within amplicons in individual specimens. We have also used a high-throughput, mass spectrometry based method for detection of point mutations in oncogenes using the same specimens. These approaches have allowed us to identify tens to hundreds of candidate oncogenes in each specimen which were then refined by on-line computational tools such as Gene Tracker. Using this approach, we have elucidated complex oncogene signatures for over 50 cancer cell lines and specimens. Analysis of these data sets points to highly variable oncogene combinations in individual specimens. In other studies using a subset of breast cancers selected for the presence of the 8p11 amplicon, we found that even in these highly selected specimens, the oncogene signatures were unique to each patient. These signatures make clear predictions about combinations of targeted agents that could be considered. For example, we have observed activation of oncogenes in the 8p11 amplicon to be associated with other oncogenes such the EGFR, cdk4, MYST3, CRKL, and others. Additionally, the presence of PIK3CA mutations occurs variably in these specimens as well. Most of the breast cancer specimens and cell lines in our study have a well-defined signature of oncogenes, and understanding these signatures is important not only for the design of strategies using multiple targeted agents, but also for the proper interpretation of clinical trial results using single targeted agents. Thus, we have developed a high-throughput, cost effective molecular diagnostic platform that can accurately and rapidly identify the causal driving oncogenes in an individual cancer biopsy specimens and therefore can be adapted to analysis of large numbers of patient's specimens. 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 5099. doi:1538-7445.AM2012-5099