van Wezel Esther M, van Zogchel Lieke M J, van Wijk Jalenka, Timmerman Ilse, Vo Ngoc-Kim, Zappeij-Kannegieter Lily, deCarolis Boris, Simon Thorsten, van Noesel Max M, Molenaar Jan J, van Groningen Tim, Versteeg Rogier, Caron Huib N, van der Schoot C Ellen, Koster Jan, van Nes Johan, Tytgat Godelieve A M
Sanquin Research Amsterdam, the Netherlands.
Amsterdam University Medical Center, Amsterdam, the Netherlands.
JCO Precis Oncol. 2019 Oct 3;3. doi: 10.1200/PO.18.00413. eCollection 2019.
Patients with neuroblastoma in molecular remission remain at considerable risk for disease recurrence. Studies have found that neuroblastoma tissue contains adrenergic (ADRN) and mesenchymal (MES) cells; the latter express low levels of commonly used markers for minimal residual disease (MRD). We identified MES-specific MRD markers and studied the dynamics of these markers during treatment.
Microarray data were used to identify genes differentially expressed between ADRN and MES cell lines. Candidate genes were then studied using real-time quantitative polymerase chain reaction in cell lines and control bone marrow and peripheral blood samples. After selecting a panel of markers, serial bone marrow, peripheral blood, and peripheral blood stem cell samples were obtained from patients with high-risk neuroblastoma and tested for marker expression; survival analyses were also performed.
, , and mRNAs were used as a panel for specifically detecting MES mRNA in patient samples. MES mRNA was detected only rarely in peripheral blood; moreover, the presence of MES mRNA in peripheral blood stem cell samples was associated with low event-free survival and overall survival. Of note, during treatment, serial bone marrow samples obtained from 29 patients revealed a difference in dynamics between MES mRNA markers and ADRN mRNA markers. Furthermore, MES mRNA was detected in a higher percentage of patients with recurrent disease than in those who remained disease free (53% 32%, respectively; = .03).
We propose that the markers and , in combination with , be used for real-time quantitative polymerase chain reaction-based detection of MES neuroblastoma mRNA in patient samples because these markers have a unique pattern during treatment and are more prevalent in patients with poor outcome. Together with existing markers of MRD, these new markers should be investigated further in large prospective studies.
处于分子缓解期的神经母细胞瘤患者疾病复发风险仍然很高。研究发现神经母细胞瘤组织含有肾上腺素能（ADRN）细胞和间充质（MES）细胞；后者表达的常用微小残留病（MRD）标志物水平较低。我们鉴定了MES特异性MRD标志物，并研究了这些标志物在治疗过程中的动态变化。
利用微阵列数据鉴定ADRN和MES细胞系之间差异表达的基因。然后使用实时定量聚合酶链反应在细胞系以及对照骨髓和外周血样本中研究候选基因。在选择一组标志物后，从高危神经母细胞瘤患者中获取系列骨髓、外周血和外周血干细胞样本，并检测标志物表达；还进行了生存分析。
、 和 mRNA被用作在患者样本中特异性检测MES mRNA的一组标志物。MES mRNA在外周血中很少被检测到；此外，外周血干细胞样本中MES mRNA的存在与无事件生存率和总生存率低相关。值得注意的是，在治疗期间，从29例患者获得的系列骨髓样本显示MES mRNA标志物和ADRN mRNA标志物在动态变化上存在差异。此外，与疾病无复发的患者相比，复发疾病患者中检测到MES mRNA的比例更高（分别为53%和32%；P = 0.03）。
我们建议将 、 和 标志物与 一起用于基于实时定量聚合酶链反应的患者样本中MES神经母细胞瘤mRNA的检测，因为这些标志物在治疗过程中具有独特模式，并且在预后不良的患者中更普遍。与现有的MRD标志物一起，这些新标志物应在大型前瞻性研究中进一步研究。
