Mettler Esther, Fottner Christian, Bakhshandeh Neda, Trenkler Anja, Kuchen Robert, Weber Matthias M
Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany.
Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany.
Cancers (Basel). 2022 Feb 17;14(4):1025. doi: 10.3390/cancers14041025.
Neuroendocrine neoplasia (NEN) encompasses a diverse group of malignancies marked by histological heterogeneity and highly variable clinical outcomes. Apart from Chromogranin A, specific biomarkers predicting residual tumor disease, tumor burden, and disease progression in NEN are scant. Thus, there is a strong clinical need for new and minimally invasive biomarkers that allow for an evaluation of the prognosis, clinical course, and response to treatment of NEN patients, thereby helping implement individualized treatment decisions in this heterogeneous group of patients. In the current prospective study, we evaluated the role of plasma cell-free DNA concentration and its global hypomethylation and fragmentation as possible diagnostic and prognostic biomarkers in patients with neuroendocrine neoplasias.
The plasma cfDNA concentration, cfDNA hypomethylation, and cfDNA integrity were evaluated prospectively in 63 NEN patients with presumably cured or advanced metastatic disease. The cfDNA characteristics in NEN patients were compared to the results of a group of 29 healthy controls and correlated with clinical and histopathological data of the patients.
Patients with advanced NEN showed a significantly higher cfDNA concentration and percentage of hypomethylation and a reduced cfDNA integrity as compared to the surgically cured NET patients and the healthy control group. The increased hypomethylation and concentration of cfDNA and the reduced cfDNA integrity in NEN patients were strongly associated with tumor burden and poor prognosis, while no correlation with tumor grading, differentiation, localization, or hormonal activity could be found. Multiparametric ROC analysis of plasma cfDNA characteristics was able to distinguish NEN patients with metastatic disease from the control group and the cured NEN patients with AUC values of 0.694 and 0.908, respectively. This was significant even for the group with only a low tumor burden.
The present study, for the first time, demonstrates that the combination of plasma cfDNA concentration, global hypomethylation, and fragment length pattern has the potential to serve as a potent and sensitive prognostic and therapeutic "liquid biopsy" biomarker for tumor burden and disease progression in patients with neuroendocrine neoplasias.
神经内分泌肿瘤（NEN）是一组异质性恶性肿瘤，具有组织学异质性和高度可变的临床结局。除嗜铬粒蛋白A外，预测NEN患者残留肿瘤疾病、肿瘤负荷和疾病进展的特异性生物标志物很少。因此，临床上迫切需要新的微创生物标志物，以评估NEN患者的预后、临床病程和对治疗的反应，从而有助于在这一异质性患者群体中实施个体化治疗决策。在当前的前瞻性研究中，我们评估了血浆游离DNA浓度及其整体低甲基化和片段化作为神经内分泌肿瘤患者可能的诊断和预后生物标志物的作用。
前瞻性评估63例可能已治愈或患有晚期转移性疾病的NEN患者的血浆游离DNA浓度、游离DNA低甲基化和游离DNA完整性。将NEN患者的游离DNA特征与29名健康对照者的结果进行比较，并与患者的临床和组织病理学数据相关联。
与手术治愈的神经内分泌肿瘤（NET）患者和健康对照组相比，晚期NEN患者的游离DNA浓度、低甲基化百分比显著更高，游离DNA完整性降低。NEN患者游离DNA低甲基化和浓度增加以及游离DNA完整性降低与肿瘤负荷和不良预后密切相关，而与肿瘤分级、分化、定位或激素活性无相关性。血浆游离DNA特征的多参数ROC分析能够将转移性疾病的NEN患者与对照组和治愈的NEN患者区分开来，AUC值分别为0.694和0.908。即使对于肿瘤负荷较低的组，这一结果也具有显著性。
本研究首次表明，血浆游离DNA浓度、整体低甲基化和片段长度模式的组合有可能作为一种强大而敏感的预后和治疗“液体活检”生物标志物，用于评估神经内分泌肿瘤患者的肿瘤负荷和疾病进展。
