SUN-465 A Rare Germline Loss-of-Function Variant in the Pyruvate Dehydrogenase Phosphatase Catalytic Subunit 2 Gene in a Patient with Abdominal Paraganglioma

Abstract Disclosure: F. Freitas-Castro: None. G.F. Fagundes: None. L.S. Santana: None. A.F. Afonso: None. F.L. Ledesma: None. I.C. Soares: None. B.B. Mendonca: None. A. Latronico: None. M.Q. Almeida: None. Background: Pheochromocytomas and paragangliomas (PPGLs) are associated with germline genetic defects in 30-50% of cases and are categorized into three transcriptional clusters. Cluster 1, subdivided into Clusters 1A and 1B, involves genes associated with cellular pseudohypoxia. Cluster 1A encompasses mutations in genes encoding Krebs cycle enzymes (e.g., succinate dehydrogenase complex subunits SDHA, SDHB, SDHC, and SDHD), leading to the accumulation of oncometabolites such as succinate and pyruvate, which increase the stabilization of hypoxia-inducible factor 2-alpha (HIF-2α). Aim: To investigate novel genetic etiologies in patients with PPGLs. Methods: Whole-exome sequencing (WES) of paired germline and tumor DNA was performed on 50 patients with PPGLs who lacked germline defects in previously known susceptibility genes. A targeted analysis enriched for 3,485 genes involved in cellular responses to hypoxia, mitochondrial function, the Krebs cycle, and tumorigenesis was conducted. Results: A germline c.280A>T (p.Lys94*) variant in the Pyruvate Dehydrogenase Phosphatase Catalytic Subunit 2 (PDP2) gene was identified in a 43-year-old female diagnosed with a 10.5 cm abdominal PGL. This stop-codon variant is absent from population databases and has been classified as a variant of uncertain significance. Tumor WES revealed no oncogenic variants. Additionally, immunohistochemistry for SDHB was positive in the tumor. The patient had no family history of cancer. Among her six siblings, one was tested for the variant, with a negative result. She has no children, and her parents are deceased. PDP2 gene encodes an enzyme responsible for dephosphorylating and reactivating the E1 alpha subunit of the pyruvate dehydrogenase complex (PDC), a critical regulator of mitochondrial metabolism. While the PDC has been implicated in glucose metabolism and tumor aggression in other cancers, such as neuroblastoma, it has not been previously associated with PPGLs. No specific phenotype has been associated with this gene. Conclusion: We report, for the first time, a rare loss-of-function PDP2 variant in a patient with abdominal PGL, which may contribute to HIF-2α stabilization and the pathogenesis of PPGL. Ongoing functional studies aim to further investigate this hypothesis. Support: Sao Paulo Research Foundation (FAPESP) grant 2019/15873-6 (to M.Q.A.), and FAPESP post-doctoral fellowship 2021/11240-9 (to F.F-C.). Presentation: Sunday, July 13, 2025