# A genotype-phenotype study of germline succinate dehydrogenase pathogenic variants

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2024 · $193,371

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10904019
- **Project number:** 5K08CA270385-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Heather Wachtel
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $193,371
- **Award type:** 5
- **Project period:** 2022-08-17 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904019

## Citation

> US National Institutes of Health, RePORTER application 10904019, A genotype-phenotype study of germline succinate dehydrogenase pathogenic variants (5K08CA270385-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10904019. Licensed CC0.

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