PROJECT SUMMARY/ABSTRACT Most applications of genomics in modern oncology focus on somatic mutations acquired during tumor evolution and selecting drugs to target these tumor-specific mutations. While effective, these approaches usually do not consider the broader context of a patient’s inherited (i.e., germline) genetics, which is a major source of cancer risk that can modify the effects of somatic mutations and alter therapeutic responses. This focus on somatic mutations is also a major limitation for cancers driven by the RAS oncogene family, which are recalcitrant to virtually all targeted therapies. Somatic RAS alterations are common in many cancers—especially pancreatic, colorectal, skin, and lung tumors (hereafter: “RAS-driven cancers”)—but are difficult to inhibit pharmacologically. These cancers comprise 39% of all cancer-related deaths in the USA each year, many of which could be prevented if their cancers were intercepted at earlier stages. This reflects an urgent opportunity to reduce cancer- related mortality by unifying germline and somatic genetics to prioritize high-risk individuals for screening or early intervention and to identify novel targets for therapeutic development. In this proposal, I outline a strategy to dissect the impact of germline genetics in RAS-driven cancers. During the K99 phase, I will discover germline factors that modify RAS oncogenicity in a unique collection of somatic, germline, clinical, and/or transcriptomic data for >35,000 individuals. During the R00 phase, I will nucleate an independent research program around a comprehensive computational framework for the genome-wide detection of germline risk factors for cancer spanning the full spectrum of variation accessible to genome sequencing, with an emphasis on understudied classes of variation like structural and rare noncoding variants. I will apply this method to systematically map genetic risk factors for RAS-driven cancers in a diverse set of >10,200 patients and >17,100 cancer-free controls. My long-term career goal is to usher in a new era of preventative precision oncology by unlocking the potential of human genomics to illuminate the heritable causes of cancer initiation and progression. My mentors and I have developed a comprehensive training plan in cancer biology and medical oncology for my K99 phase that will prepare me to launch a successful independent career at the intersection of genomics, cancer, and data science in the R00 phase. My postdoctoral training will be supervised Dr. Eliezer Van Allen, who is a world- leader in computational oncology. I will also benefit from the complementary expertise of two co-mentors in Drs. Alexander Gusev (statistics) and Kevin Haigis (RAS biology), who will buttress Dr. Van Allen’s mentorship and ensure I build a well-rounded skillset during the mentored K99 phase to lay the foundation for a highly productive independent R00 phase. Finally, my proposed research plan will be facilitated by the outstanding scientific environment at Dana-Farber Cancer Institute, which is the ideal ecosystem to support my postdoctoral phase.

PROJECT NARRATIVE The RAS gene family encodes the central components of the RAS signaling pathway, which is the most frequently altered oncogenic pathway across all cancers but is especially prominent in pancreatic, colorectal, lung, and skin malignancies. These RAS-driven cancers collectively account for the largest single source of cancer-related mortality in the United States but are often treatable if intercepted at an early stage, meaning that new strategies are desperately needed to anticipate and prevent RAS-driven cancers. In this proposal, I outline an interdisciplinary research project grounded in my 12 years of experience in genomic data science to systematically discover new inherited genetic factors that influence the onset, progression, and dynamics of RAS-driven cancer, which has the potential to uncover previously unknown facets of cancer biology, enable preventative screening tailored to an individual’s inherited genetic risk, improve equity in clinical oncology, and nominate new targets for the prevention or treatment of these devastating malignancies.