Elevated plasma succinate in PTEN, SDHB, and SDHD mutation-positive individuals

Area of Science:

• Biochemistry
• Genetics
• Oncology

Background:

• Cowden syndrome is linked to mutations in PTEN, SDHB, and SDHD genes.
• PTEN mutations are associated with Cowden syndrome, while SDH variants are linked to paraganglioma.
• A common biochemical alteration, succinate accumulation, was hypothesized for both PTEN and SDH mutation carriers.

Purpose of the Study:

• To investigate the hypothesis that succinate accumulation is a common feature in individuals with PTEN mutations and SDH variants.
• To identify a shared biochemical marker for individuals with Cowden syndrome and paraganglioma-associated gene mutations.

Main Methods:

• Collected urine and blood samples from individuals meeting diagnostic criteria for Cowden syndrome or paraganglioma, or those with known susceptibility gene mutations.
• Measured succinate levels in plasma and urine.
• Sequenced PTEN, SDHB, SDHC, and SDHD genes from genomic DNA.

Main Results:

• Elevated plasma succinate was observed in 62% of individuals with PTEN, SDHB, or SDHD mutations compared to 16% of controls (P < 0.001).
• Pathogenic PTEN mutations were associated with elevated succinate in 67% of cases.
• SDHB and SDHD mutations also showed elevated succinate levels in 100% and 40% of cases, respectively.

Conclusions:

• Mutations in PTEN, SDHB, and SDHD impair succinate dehydrogenase activity, leading to succinate accumulation.
• This identifies a common biochemical alteration in PTEN and SDHx mutation-positive individuals.
• Plasma organic acid analysis can serve as a cost-effective screening tool for PTEN and SDH gene sequencing.