Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Area of Science:

• Endocrinology
• Oncology
• Metabolic Research

Background:

• Pheochromocytomas and paragangliomas (PPGLs) are tumors linked to metabolic dysregulation.
• Genetic mutations in tricarboxylic acid (TCA) cycle genes are implicated in PPGL development, accounting for a significant portion of cases.

Purpose of the Study:

• To identify novel mutations in TCA cycle-related genes in individuals with PPGLs who lack mutations in known susceptibility genes.
• To investigate the role of these mutations in tumor formation and metabolic pathways.

Main Methods:

• Targeted sequencing of 37 TCA cycle-related genes in 104 PPGL patients.
• Omics-based analyses, metabolite determination, and 13C5-glutamate labeling assays.
• Functional evaluation of identified variants in cell-based assays.

Main Results:

• Five germline variants in DLST were identified in 8 unrelated individuals (approx. 7%), with most diagnosed with multiple PPGLs.
• A recurrent DLST variant (p.Gly374Glu) caused 2-hydroxyglutarate accumulation and showed similarities to EPAS1-mutated PPGLs, suggesting a link to pseudohypoxia.
• DLST was found to be expressed in tumors with TCA cycle or EPAS1 mutations.

Conclusions:

• DLST is identified as a novel PPGL susceptibility gene.
• Disruption of the TCA cycle, particularly through DLST mutations, plays a critical role in PPGL tumorigenesis.
• These findings reinforce the importance of metabolic pathways in the development of PPGLs.