PROJECT SUMMARY This Mentored Clinical Scientist Career Development Award (K08) details a five-year plan to promote Dr. Heather Wachtel’s transition to an independent career as a physician-scientist studying neuroendocrine tumors. Bioinformatics and genomics are rapidly evolving fields which offer novel approaches to the study of human disease. This career development plan includes formal training in bioinformatics and computational genomics, as an in-depth understanding of these fields is critical for successful completion of the proposed research, and for Dr. Wachtel’s development as an independent investigator. Dr. Wachtel is mentored by Dr. Katherine Nathanson, a cancer geneticist, and her current work with Dr. Nathanson utilizes translational approaches to study tumorigenesis and the spectrum of disease associated with hereditary cancer predisposition genes. Dr. Wachtel’s focus is on succinate dehydrogenase (SDHx) pathogenic variants and neuroendocrine tumors. Succinate dehydrogenase is a highly conserved mitochondrial complex with critical roles in metabolism and cancer. Inherited loss-of-function mutations in the SDHx genes are causative in several human cancers. Recent data suggests that tumors associated with germline pathogenic variants in SDHx, including pheochromocytoma, paraganglioma and renal cell carcinoma, are linked to DNA damage. However, DNA damage repair has not been studied on a gene-specific level, and the gene and allele-specific risks of SDHx germline pathogenic variants remain incompletely characterized. This proposal aims to accurately characterize the phenotypes and tumor biology associated with SDHx germline variants, to develop improved risk estimates and identify targeted therapies for patients who progress to disease. In AIM 1, Dr. Wachtel proposes to perform a Phenome-Wide Association study (PheWAS) of SDHx in the UK Biobank to accurately characterize the gene-specific oncologic associations of SDHx and quantify phenotypic associations with inflammatory and metabolic disease at the gene level. Findings will be replicated in an independent cohort from the Penn Medicine BioBank. In AIM 2, Dr. Wachtel will utilize the unique resources of the Penn Neuroendocrine Tumor Center and expertise in collaborative studies to quantify genomic signatures of DNA damage response pathways in pheochromocytoma and paraganglioma associated with SDHx germline pathogenic variants. Finally, she will evaluate the evidence for potential poly(ADP-ribose) polymerase (PARP) inhibitor susceptibility in patient-derived tumor specimens. Dr. Wachtel will supplement these studies with a career development program which takes full advantage of the depth and breadth of resources at the University of Pennsylvania. Dr. Wachtel has assembled a mentoring and advisory team of accomplished and successful physician-scientists and geneticists to guide her career development. She will engage in both formal didactic and hands-on training to hone her skills in ...