PDF(Pubmed)
Abstract：
UNASSIGNED: Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx) 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.
UNASSIGNED: Blood plasma, urine, peripheral blood mononuclear cells, and erythrocytes from patients with and without SDHx 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.
UNASSIGNED: Plasma succinate to fumarate ratios effectively distinguished tumor-bearing and asymptomatic patients with and without SDHx PV with promising diagnostic performance (areas under the receiver operating characteristic curve 0.86-0.95), although higher levels were noted in individuals with SDHB PV. Metabolites in urine and in peripheral blood mononuclear cell extracts were largely similar between groups. Erythrocytes showed strong metabolic alterations in patients with SDHx PV compared to controls, with 8 of 13 low-molecular organic acids being significantly different (P < .05). The lactate-α-ketoglutarate-ratio of erythrocytes identified individuals with SDHx PV equally well as plasma, with a sensitivity and specificity of 92% (AUC 0.97).
UNASSIGNED: Blood biomarkers have been underutilized for identifying carriers of SDHx 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.
UNASSIGNED: Blood plasma, urine, peripheral blood mononuclear cells, and erythrocytes from patients with and without SDHx 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.
UNASSIGNED: Plasma succinate to fumarate ratios effectively distinguished tumor-bearing and asymptomatic patients with and without SDHx PV with promising diagnostic performance (areas under the receiver operating characteristic curve 0.86-0.95), although higher levels were noted in individuals with SDHB PV. Metabolites in urine and in peripheral blood mononuclear cell extracts were largely similar between groups. Erythrocytes showed strong metabolic alterations in patients with SDHx PV compared to controls, with 8 of 13 low-molecular organic acids being significantly different (P < .05). The lactate-α-ketoglutarate-ratio of erythrocytes identified individuals with SDHx PV equally well as plasma, with a sensitivity and specificity of 92% (AUC 0.97).
UNASSIGNED: Blood biomarkers have been underutilized for identifying carriers of SDHx 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.
摘要：
■琥珀酸脱氢酶基因（SDHx）中种系致病变异（PV）的携带者有发展为肿瘤的风险，包括副神经节瘤,胃肠道间质瘤,和肾细胞癌。早期肿瘤检测对于改善临床结果至关重要。基于血液的生物标志物可以帮助早期识别患有PV的个体，并为具有未知意义的变异的患者提供功能证据。
■血浆，尿液,外周血单核细胞，研究了患有和不患有SDHxPV的患者的红细胞中的中央碳代谢产物。这些是通过液相色谱-串联质谱和核磁共振波谱测量的，其中包括，琥珀酸盐,富马酸盐,α-酮戊二酸，和乳酸。
■血浆琥珀酸盐与富马酸盐的比率可有效区分患有和不患有SDHxPV的荷瘤患者和无症状患者，具有良好的诊断性能（受试者工作特征曲线下的面积为0.86-0.95），尽管SDHBPV患者的水平较高。两组之间尿液和外周血单核细胞提取物中的代谢物在很大程度上相似。与对照组相比，SDHxPV患者的红细胞表现出强烈的代谢改变，13种低分子有机酸中有8种差异显著(P<.05)。红细胞的乳酸-α-酮戊二酸比率确定SDHxPV的个体与血浆相同，敏感性和特异性为92%(AUC0.97)。
■血液生物标志物未被充分用于鉴定SDHxPV的携带者或验证未知意义的变体。我们的发现主张进一步研究涉及血浆和红细胞的组合方法，以用于未来的诊断策略。
■血浆，尿液,外周血单核细胞，研究了患有和不患有SDHxPV的患者的红细胞中的中央碳代谢产物。这些是通过液相色谱-串联质谱和核磁共振波谱测量的，其中包括，琥珀酸盐,富马酸盐,α-酮戊二酸，和乳酸。
■血浆琥珀酸盐与富马酸盐的比率可有效区分患有和不患有SDHxPV的荷瘤患者和无症状患者，具有良好的诊断性能（受试者工作特征曲线下的面积为0.86-0.95），尽管SDHBPV患者的水平较高。两组之间尿液和外周血单核细胞提取物中的代谢物在很大程度上相似。与对照组相比，SDHxPV患者的红细胞表现出强烈的代谢改变，13种低分子有机酸中有8种差异显著(P<.05)。红细胞的乳酸-α-酮戊二酸比率确定SDHxPV的个体与血浆相同，敏感性和特异性为92%(AUC0.97)。
■血液生物标志物未被充分用于鉴定SDHxPV的携带者或验证未知意义的变体。我们的发现主张进一步研究涉及血浆和红细胞的组合方法，以用于未来的诊断策略。
