Decades of cancer research including comprehensive molecular profiling combined with the development of a broad array of targeted therapies have created the opportunity to transform cancer care by implementing precision oncology based approaches. An important element of this system is the widespread availability of robust and cost-effective multi-variate profiling methods to characterize relevant cancer associated molecular alterations in the future. Current commercially available multi-variate profiling methods vary dramatically with regard to the number of cancer genes that are interrogated. Given that many large scale and detailed molecular profiling studies have been completed, the landscape of somatic alterations in solid tumors is reasonably well-known. Furthermore, the specific gene variants that are relevant to application of targeted therapies are also a matter of record. Therefore, we set out to define the number of relevant cancer genes for precision oncology research based on the currently available empirical evidence. To define recurrent somatic alterations in solid tumors, we created a compendium of variant calls from > 15,000 exomes, defined focal amplifications and deletions from > 30,000 arrays, and defined recurrent fusions from several thousand RNAseq profiles. Statistical approaches were implemented to define genes containing recurrent missense mutations (i.e., hotspots), enriched in truncating mutations or subject to recurrent copy number gain/loss or translocation. This gene set was then used to comprehensively search approved cancer drug labels, clinical practice guidelines, and clinical trials to identify records containing published evidence that specific recurrent somatic gene variants were used as part of the indication statement of an approved targeted therapy, were recommended for testing as part of clinical practice for therapeutic decisions, or were used as enrollment criteria in clinical trials. The relevant cancer genome thus defined consists of < 100 genes. These results suggest that targeted multi-variate profiling approaches may be sufficient to support precision oncology goals in the future.

Citation Format: Habib R. Hamidi, Santoshi Bandla, Nick Khazanov, Paul William, Nikki Bonevich, Chris Zurenko, Sarah Anstead, Chris Taylor, Reuban Richmonds, David Galimberti, Ken Kopp, Dinesh Cyanam, Michael Hogan, Vinay Mittal, Seth Sadis. Defining the relevant genome in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3811. doi:10.1158/1538-7445.AM2017-3811