Identification of Succinate Dehydrogenase Gene Variant Carriers by Blood Biomarkers.

BACKGROUND

Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase genes () are at risk of developing tumors, including paragangliomas, gastrointestinal stromal tumors, and renal cell carcinomas. Early tumor detection is paramount for improved clinical outcome. Blood-based biomarkers could aid in identifying individuals with PVs early and provide functional evidence in patients with variants of unknown significance.

METHODS

Blood plasma, urine, peripheral blood mononuclear cells, and erythrocytes from patients with and without PVs were investigated for central carbon metabolites. These were measured by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy and included among others, succinate, fumarate, α-ketoglutarate, and lactate.

RESULTS

Plasma succinate to fumarate ratios effectively distinguished tumor-bearing and asymptomatic patients with and without PV with promising diagnostic performance (areas under the receiver operating characteristic curve 0.86-0.95), although higher levels were noted in individuals with PV. Metabolites in urine and in peripheral blood mononuclear cell extracts were largely similar between groups. Erythrocytes showed strong metabolic alterations in patients with PV compared to controls, with 8 of 13 low-molecular organic acids being significantly different ( < .05). The lactate-α-ketoglutarate-ratio of erythrocytes identified individuals with PV equally well as plasma, with a sensitivity and specificity of 92% (AUC 0.97).

CONCLUSION

Blood biomarkers have been underutilized for identifying carriers of PV or to validate variants of unknown significance. Our findings advocate for further investigation into a combined approach involving plasma and erythrocytes for future diagnostic strategies.