De Fabritiis Simone, Valentinuzzi Silvia, Piras Gianluca, Cicalini Ilaria, Pieragostino Damiana, Pagotto Sara, Perconti Silvia, Zucchelli Mirco, Schena Alberto, Taschin Elisa, Berteşteanu Gloria Simona, Esposito Diana Liberata, Stigliano Antonio, De Laurenzi Vincenzo, Schiavi Francesca, Sanna Mario, Del Boccio Piero, Verginelli Fabio, Mariani-Costantini Renato
Department of Medicine and Aging Sciences, "G. d'Annunzio" University of Chieti-Pescara, 66100, Chieti, Italy.
Center for Advanced Studies and Technology (CAST), 66100, Chieti, Italy.
Oncogenesis. 2023 Feb 25;12(1):10. doi: 10.1038/s41389-023-00456-4.
Head and neck paragangliomas (HNPGLs), rare chemoresistant tumors curable only with surgery, are strongly influenced by genetic predisposition, hence patients and relatives require lifetime follow-up with MRI and/or PET-CT because of de novo disease risk. This entails exposure to electromagnetic/ionizing radiation, costs, and organizational challenges, because patients and relatives are scattered far from reference centers. Simplified first-line screening strategies are needed. We employed flow injection analysis tandem mass spectrometry, as used in newborn metabolic screening, to compare the plasma metabolic profile of HNPGL patients (59 samples, 56 cases) and healthy controls (24 samples, 24 cases). Principal Component Analysis (PCA) and Partial Least Discriminant Analysis (PLS-DA) highlighted a distinctive HNPGL signature, likely reflecting the anaplerotic conversion of the TCA cycle to glutaminolysis and catabolism of branched amino acids, DNA damage and deoxyadenosine (dAdo) accumulation, impairment of fatty acid oxidation, switch towards the Warburg effect and proinflammatory lysophosphatidylcholines (LPCs) signaling. Statistical analysis of the metabolites that most impacted on PLS-DA was extended to 10 acoustic neuroma and 2 cholesteatoma patients, confirming significant differences relative to the HNPGL plasma metabolomic profile. The best confusion matrix from the ROC curve built on 2 metabolites, dAdo and C26:0-LPC, provided specificity of 94.29% and sensitivity of 89.29%, with positive and negative predictive values of 96.2% and 84.6%, respectively. Analysis of dAdo and C26:0-LPC levels in dried venous and capillary blood confirmed that dAdo, likely deriving from 2'-deoxy-ATP accumulated in HNPGL cells following endogenous genotoxic damage, efficiently discriminated HNPGL patients from healthy controls and acoustic neuroma/cholesteatoma patients on easily manageable dried blood spots.
头颈部副神经节瘤（HNPGLs）是一种罕见的化疗耐药性肿瘤，只能通过手术治愈，其发病受遗传易感性的强烈影响。因此，由于存在新发疾病的风险，患者及其亲属需要通过MRI和/或PET-CT进行终身随访。这带来了电磁/电离辐射暴露、成本以及组织方面的挑战，因为患者及其亲属分布在远离参考中心的地方。需要简化的一线筛查策略。我们采用了新生儿代谢筛查中使用的流动注射分析串联质谱法，比较HNPGL患者（59份样本，56例）和健康对照者（24份样本，24例）的血浆代谢谱。主成分分析（PCA）和偏最小二乘判别分析（PLS-DA）突出了一种独特的HNPGL特征，可能反映了三羧酸循环向谷氨酰胺分解代谢的回补反应以及支链氨基酸的分解代谢、DNA损伤和脱氧腺苷（dAdo）积累、脂肪酸氧化受损、向瓦氏效应的转变以及促炎溶血磷脂酰胆碱（LPCs）信号传导。对PLS-DA影响最大的代谢物的统计分析扩展到了10例听神经瘤患者和2例胆脂瘤患者，证实与HNPGL血浆代谢组学谱存在显著差异。基于2种代谢物dAdo和C26:0-LPC构建的ROC曲线得出的最佳混淆矩阵，特异性为94.29%，敏感性为89.29%，阳性预测值和阴性预测值分别为96.2%和84.6%。对干燥静脉血和毛细血管血中dAdo和C26:0-LPC水平的分析证实，dAdo可能源自内源性基因毒性损伤后HNPGL细胞中积累的2'-脱氧-ATP，它能在易于处理的干血斑上有效地区分HNPGL患者与健康对照者以及听神经瘤/胆脂瘤患者。
