生物标志物改善副神经节瘤的遗传和转移性疾病预测：一项前瞻性研究的见解
Biomarkers Improving Genetic and Metastatic Disease Prediction in Paraganglioma: Insights From a Prospective Study.
作者信息
Drossart Tom, Buffet Alexandre, Janbain Ali, Ottolenghi Chris, Amar Laurence, Libé Rossella, Drui Delphine, Lussey-Lepoutre Charlotte, Mancini Maxence, Lounis Timgad, Guénégou-Arnoux Armelle, Méatchi Tchao, Bertherat Jérôme, Burnichon Nelly, Favier Judith, Gimenez-Roqueplo Anne-Paule
机构信息
Université Paris Cité, Inserm, PARCC, Équipe Labellisée Ligue contre le Cancer, Paris F-75015 France.
Département de Médecine Génomique des Tumeurs et des Cancers, Fédération de Génétique et de Médecine Génomique, Assistance Publique-Hôpitaux de Paris Centre, Hôpital Européen Georges Pompidou, Paris F-75015 France.
出版信息
J Clin Endocrinol Metab. 2025 Jul 15;110(8):2193-2204. doi: 10.1210/clinem/dgae797.
CONTEXT AND OBJECTIVE
Identifying the risk of malignancy and genetic status in primary paraganglioma or pheochromocytoma (PPGL) is a key challenge. The aim was to assess the diagnostic accuracy of genomic, metabolomic and histopathological biomarkers for predicting metastatic and genetic status.
DESIGN, SETTING, AND PATIENTS: COMETE-TACTIC is a prospective study (NCT02672020) conducted from November 2015 to March 2019 across 16 referral centers. Tumor samples and liquid biopsies from 231 consecutive patients with PPGL were collected.
MAIN OUTCOME MEASURES
Germline and somatic genetic status were determined by next-generation sequencing, SDHB, SDHA and CA9 immunohistochemistries were performed on tumor tissues. TERT promoter methylation was assessed by pyrosequencing. Metabolomic profile and circulating miRNAs were measured in liquid biopsies by gas chromatography MS/MS and TaqMan assay quantified by droplet digital PCR, respectively.
RESULTS
Tumor analysis outperformed germline analysis for determining genetic status. Positive SDHA and SDHB staining combined with negative CA9 labeling indicated the absence of SDHx and VHL variants. Plasma succinate levels above 4.94 µM identified SDHx mutation carriers with 65% sensitivity and 92% specificity [area under the receiver operating characteristic curve (AUC-ROC) 0.82, 95% confidence interval (CI) 0.70-0.93]. Among circulating miRNAs, miR-483-5p was the best classifier of metastatic status (AUC-ROC 0.64, 95%CI 0.52-0.77). A sum of dinucleotide methylation rate of TERT promoter CpGs above 42% predicted metastatic status (AUC-ROC 0.75, 95% CI 0.65-0.85). Multivariate analyses showed that biomarker combinations significantly predicted SDHx status (AUC-ROC 0.99, 95% CI 0.98-1.00) and metastatic potential (AUC-ROC 0.93, 95% CI 0.84-1).
CONCLUSION
Circulating miR-483-5p, plasma succinate, TERT promoter methylation, and SDHB immunostaining are valuable for PPGL risk stratification. Combining biomarkers with clinical data provides excellent diagnostic accuracy for metastatic patients (AUC-ROC 0.97, 95%CI 0.93-1).
背景与目的
确定原发性副神经节瘤或嗜铬细胞瘤（PPGL）的恶性风险和基因状态是一项关键挑战。本研究旨在评估基因组、代谢组和组织病理学生物标志物在预测转移和基因状态方面的诊断准确性。
设计、研究地点与患者：COMETE-TACTIC是一项前瞻性研究（NCT02672020），于2015年11月至2019年3月在16个转诊中心开展。收集了231例连续的PPGL患者的肿瘤样本和液体活检样本。
主要观察指标
通过下一代测序确定胚系和体细胞基因状态，对肿瘤组织进行SDHB、SDHA和CA9免疫组织化学检测。通过焦磷酸测序评估TERT启动子甲基化。分别采用气相色谱-质谱联用技术和液滴数字PCR定量的TaqMan分析方法检测液体活检样本中的代谢组学特征和循环miRNA。
结果
在确定基因状态方面，肿瘤分析优于胚系分析。SDHA和SDHB染色阳性且CA9标记阴性表明不存在SDHx和VHL变异。血浆琥珀酸水平高于4.94µM可识别SDHx突变携带者，灵敏度为65%，特异性为92%[受试者操作特征曲线下面积（AUC-ROC）为0.82，95%置信区间（CI）为0.70-0.93]。在循环miRNA中，miR-483-5p是转移状态的最佳分类指标（AUC-ROC为0.64，95%CI为0.52-0.77）。TERT启动子CpG二核苷酸甲基化率总和高于42%可预测转移状态（AUC-ROC为0.75，95%CI为0.65-0.85）。多变量分析显示，生物标志物组合可显著预测SDHx状态（AUC-ROC为0.99，95%CI为0.98-1.00）和转移潜能（AUC-ROC为0.93，95%CI为0.84-1）。
结论
循环miR-483-5p、血浆琥珀酸、TERT启动子甲基化和SDHB免疫染色对PPGL风险分层具有重要价值。将生物标志物与临床数据相结合可为转移患者提供出色的诊断准确性（AUC-ROC为0.97，95%CI为0.93-1）。
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