A genotype-phenotype study of germline succinate dehydrogenase pathogenic variants

项目摘要 这个指导临床科学家职业发展奖（K 08）详细介绍了一个五年计划，以促进博士石楠 Wachtel的过渡到一个独立的职业生涯作为一个医生，科学家研究神经内分泌肿瘤。 生物信息学和基因组学是快速发展的领域，为人类的研究提供了新的方法。 疾病该职业发展计划包括生物信息学和计算基因组学方面的正式培训， 因为深入了解这些领域对于成功完成拟议的研究至关重要， 支持Wachtel博士发展为独立调查员。Wachtel博士由凯瑟琳博士指导 Nathanson是一位癌症遗传学家，她目前与Nathanson博士的工作利用翻译方法， 研究肿瘤发生和与遗传性癌症易感基因相关的疾病谱。博士 Wachtel的重点是琥珀酸脱氢酶（SDHx）致病性变体和神经内分泌肿瘤。 琥珀酸脱氢酶是一种高度保守的线粒体复合物，在代谢中起关键作用， 癌SDHx基因中的遗传性功能丧失突变是几种人类癌症的病因。最近 数据表明与SDHx的生殖系致病性变体相关的肿瘤，包括嗜铬细胞瘤， 副神经节瘤和肾细胞癌与DNA损伤有关。然而，DNA损伤修复并没有 在基因特异性水平上进行了研究，SDHx生殖系致病性的基因和等位基因特异性风险 变体的特征仍然不完全。该提案旨在准确表征表型， 与SDHx生殖系变异相关的肿瘤生物学，以开发改进的风险估计并确定靶向 治疗进展为疾病的患者。在AIM 1中，Wachtel博士建议进行全表型组 英国生物库中SDHx的关联研究（PheWAS），以准确表征基因特异性肿瘤 SDHx的相关性，并量化该基因与炎症和代谢性疾病的表型相关性， 水平研究结果将在Penn Medicine BioBank的一个独立队列中复制。在AIM 2中，Wachtel博士 将利用宾夕法尼亚神经内分泌肿瘤中心的独特资源和合作研究的专业知识 量化嗜铬细胞瘤和副神经节瘤中DNA损伤反应途径的基因组特征 与SDHx生殖系致病性变异相关。最后，她将评估证据， 患者来源的肿瘤标本中聚（ADP-核糖）聚合酶（PARP）抑制剂的敏感性。瓦赫特尔博士 将补充这些研究与职业发展计划，充分利用深度， 在宾夕法尼亚大学的资源广度。瓦赫特尔博士召集了一个辅导和咨询小组 一个由成功的医学科学家和遗传学家组成的团队，指导她的职业发展。她 她将参加正式的教学和实践培训，以磨练她在生物信息学和基因组学方面的技能。这 职业发展计划和研究策略中详细介绍的实验将为Wachtel博士提供 必要的工具，以实现她的长期目标，一个独立的调查职业生涯作为一个医生，科学家。

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 bioinformatics and genomics. This career development plan and the experiments detailed in the Research Strategy will provide Dr. Wachtel with the tools necessary to achieve her long-term goal of an independent investigative career as a physician-scientist.