定量靶向蛋白质组学用于无端静脉血栓栓塞患者隐匿性癌筛查：来自前瞻性PLATO-VTE研究的结果

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2025-08-01 DOI:10.1016/j.rpth.2025.103018

Noori A.M. Guman , Noémie Kraaijpoel , Frits I. Mulder , Marc Carrier , Luis Jara-Palomares , Marcello Di Nisio , Walter Ageno , Jan Beyer-Westendorf , Frederikus A. Klok , Thomas Vanassche , Johannes M.M.B. Otten , Benilde Cosmi , Mike J.L. Peters , Marije ten Wolde , Aurélien Delluc , Pieter W. Kamphuisen , Verónica Sánchez-López , Ettore Porreca , Jip Ramaker , Patrick M.M. Bossuyt , Yassene Mohammed

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引用次数: 0

摘要

背景：大约5%的非诱发性静脉血栓栓塞（VTE）患者有隐匿性癌症。尽管进行了标准的癌症筛查，但仍有50%的癌症未被发现。目的：我们使用定量靶向蛋白质组学技术在非诱发性静脉血栓栓塞患者中鉴定新的癌症生物标志物。方法：年龄≥40岁、首次无诱发性静脉血栓栓塞且前5年无恶性肿瘤的患者被邀请参加一项国际前瞻性队列研究。静脉血栓栓塞后10天内采集血浆样本。主要结果是在12个月的随访中确诊癌症。使用基于定量质谱的靶向蛋白质组学测量了269种血浆蛋白的浓度，这些蛋白覆盖凝血、补体和癌症相关途径。在巢式病例对照研究中，将癌症患者的蛋白质谱与随机抽样的独特对照患者的蛋白质谱进行比较（比例为3:1）。未校正P值<； 0.05和折叠变化≥15%的蛋白质合并在多变量logistic回归模型中。为了解决所获得模型的可变性，在250个bootstrap样本中重复了蛋白质选择和模型构建方法，并计算了乐观调整的c统计量。结果在476名参与者中，28名（5.9%）是新诊断出的癌症。24例患者可获得血浆样本，并与75例对照患者进行比较。p -选择素、β-2微球蛋白、补体成分7、细胞内粘附分子1和lumican的浓度高于对照组，而凝血因子(F)VII、FX和FXII、β-Ala-His二肽酶和kalistatin的浓度低于对照组。包含这些蛋白的多变量logistic回归模型的乐观校正c统计量为0.78 （95% CI, 0.70-0.87）。结论在隐匿性癌患者中发现了10种差异丰富的蛋白，提示血浆蛋白质组学检测可能成为隐匿性癌非诱发性静脉血栓栓塞患者的新生物标志物。

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Quantitative targeted proteomics for occult cancer screening in patients with unprovoked venous thromboembolism: results from the prospective PLATO-VTE study

Background

About 5% of patients with unprovoked venous thromboembolism (VTE) have occult cancer. Despite standard cancer screening, 50% of cancers remain undetected.

Objectives

We used quantitative targeted proteomics to identify novel cancer biomarkers among patients with unprovoked VTE.

Methods

Patients aged ≥40 years with a first unprovoked VTE and without a malignancy in the preceding 5 years were invited to an international prospective cohort study. Plasma samples were collected within 10 days after VTE. The primary outcome was an adjudicated cancer diagnosis during 12-month follow-up. Concentrations of 269 plasma proteins covering coagulation, complement, and cancer-associated pathways were measured using quantitative mass spectrometry-based targeted proteomics. In a nested case-control study, protein profiles of patients with cancer were compared with those of randomly sampled unique control patients (ratio 3:1). Proteins with an unadjusted P value < .05 and fold change ≥15% were combined in a multivariable logistic regression model. To address the variability in the obtained model, the protein selection and model-building approach were replicated in 250 bootstrap samples, and an optimism-adjusted c-statistic was calculated.

Results

Of the 476 included participants, 28 (5.9%) were newly diagnosed with cancer. Plasma samples were available for 24 cases, which were compared with those of 75 control patients. Concentrations of P-selectin, β-2 microglobulin, complement component 7, intracellular adhesion molecule 1, and lumican were higher in cases than in controls, whereas coagulation factor (F)VII, FX, and FXII, β-Ala-His dipeptidase, and kalistatin were lower. The optimism-adjusted c-statistic of the multivariable logistic regression model including these proteins was 0.78 (95% CI, 0.70-0.87).

Conclusion

Ten differentially abundant proteins were identified in patients with occult cancer, suggesting potential of plasma proteomic tests as novel biomarker for occult cancer in patients with unprovoked VTE.

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