Identification Of Complex Oncogene Signatures In Human Cancer Specimens And Cell Lines

Activated oncogenes are the genetic drivers of human cancer progression. Oncogenes become activated by structural DNA alterations including gene amplification accompanied by gene over expression, point mutations, and gene translocations/rearrangements. Data from recent clinical trials using targeted agents strongly suggest that clinical efficacy of these drugs is optimal when the target is an activated oncogene. However, it is also clear that even among patients that respond to drugs that target activated oncogenes, the level and duration of response is highly variable. One possible reason for heterogeneity in response to oncogene-targeted agents is the genomic context of a particular activated oncogene is not the same in all patients. Thus, the genomic context of an oncogene-target can have a dramatic influence on drug efficacy. Therefore, the ability to detect and diagnose complex oncogene signatures in human cancer specimens is vital for better predictions of the efficacy of targeted agents, and to design personalized therapeutic strategies. In our Oncogenomics laboratory, we have been working to identify candidate amplified and point mutated oncogenes in human breast, ovarian and lung cancer specimens and cell lines. To obtain individual oncogene signatures, we have used high resolution array comparative genomic hybridization coupled with a novel gene expression algorithm that allows for the identification of genes that are over expressed within amplicons in individual specimens, and Sequenom analysis for identification of point mutated oncogenes. These approaches have allowed us to elucidate complex oncogene signatures for over 50 cancer cell lines and specimens. Analysis of these data sets suggests that oncogene combinations across specimens is nearly random. Thus, knowing the status of one oncogene such as HER-2 does not predict what other oncogenes may be activated in the specimen or cell line. Indeed, we have observed HER-2 amplifications in the context of amplifications of oncogenes in the 11q12 or 8p11 amplicons, among others, and in the presence of absence of PIK3CA mutations. Furthermore, analysis of the effects of small molecule inhibitors of HER-2 at the level of cell survival/proliferation and gene expression demonstrated a dramatic effect of oncogene context on response to a targeted agent. In particular, PIK3CA mutations in the presence of HER-2 amplification and over expression was associated with a greatly attenuated response of the cells to the HER-2 targeted agent. Collectively, these results point to a need for a molecular diagnostic platform that can accurately identify the causal driving oncogenes in an individual cancer biopsy specimen in order to optimize clinical trial design, and develop personalized therapeutic strategies.