SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Succinate dehydrogenase-complex II (SDH) gene variants traditionally correlate with specific tumor types.
• SDHB variants are linked to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL), while SDHD variants are associated with head and neck paraganglioma (HNPGL).
• This study focuses on SDHB genotype-phenotype associations, examining individual variant impacts on disease risk and malignancy.

Purpose of the Study:

• To investigate the genotype-phenotype associations of SDHB gene variants.
• To determine the impact of missense versus truncating SDHB variants on tumor incidence, age of onset, and malignancy risk.
• To understand how different SDHB variant types influence disease progression and tissue sensitivity.

Main Methods:

• Analysis of two independent datasets comprising 448 patients with PPGL and HNPGL.
• Association studies of missense or truncating SDHB variants with tumor incidence, age of onset, and malignancy risk.
• Utilized binomial testing and Kaplan-Meier analysis for statistical evaluation.

Main Results:

• Truncating SDHB variants were significantly more common in PPGL patients (20% margin) compared to missense variants.
• Malignancy risk was significantly higher in carriers of truncating SDHB variants versus missense variants.
• No significant overall difference in age of PPGL onset was observed between variant types, though individual variants may show variations.

Conclusions:

• Truncating SDHB variants confer an elevated risk for PPGL and malignancy compared to missense variants.
• These findings support previous associations between truncating variants and PPGL.
• Differences in complex II function and tissue sensitivity likely explain the varying impact of SDHB variant types.