PROJECT SUMMARY Genomic sequencing and molecular profiling of tumor samples is becoming routine at many cancer centers, and the scientific community is poised to sequence hundreds of thousands of tumor samples over the next five years, providing unprecedented insight into cancer initiation, progression, and treatment effects. Ensuring that these data sets are easily accessible and interpretable to scientists and clinicians is of vital importance. Towards this end, we seek to continually evolve and expand the capabilities of the cBioPortal for Cancer Genomics, a unique and vital platform that enables interactive exploratory data analysis of large-scale cancer genomic data sets. The cBioPortal has become the most widely used tool within the cancer genomics community and is the most highly cited. The public site (cbioportal.org) contains data from more than 20,000 tumor samples, including all data from The Cancer Genome Atlas, and is accessed by more than 25,000 unique users each month. Since the software is available under an open source license, there are >40 local installations of the software system at cancer centers and drug companies, and multiple institutions are making contributions to the software, including the four that are part of this application (Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Princess Margaret Cancer Centre, and Children?s Hospital of Philadelphia). To ensure that this vital resource continues to aid the cancer research community and to keep pace with the rapidly advancing fields of cancer genomics and precision cancer medicine, and the imminent steep increase in the number of profiled tumor samples, we propose to actively sustain and evolve the cBioPortal platform. Specifically, we will implement major architectural changes to the cBioPortal software to ensure future scalability and performance, and accelerate new feature development (Aim 1). We will also develop novel analysis tools for drug target discovery in large cancer genomics cohorts, as well as new features for precision cancer medicine, including for clinical trial design and the budding field of immunogenomics (Aim 2). We also plan to build and leverage a vibrant open source software development community to maintain and adapt the software and develop essential new features (Aim 3). Finally, to maximize use in the scientific community, we plan to expand community outreach and education, and create mechanisms for community engagement and feedback (Aim 4). With these improvements, the cBioPortal has the potential to significantly accelerate cancer research and development of new biomarkers and drugs. Several cancer centers are already using the cBioPortal as part of their precision medicine programs to guide interpretation of genomic variants. We expect that, over the next few years, the cBioPortal will have a tremendous impact on all areas of basic cancer research and patient care.