Haber Michelle, Smith Janice, Bordow Sharon B, Flemming Claudia, Cohn Susan L, London Wendy B, Marshall Glenn M, Norris Murray D
Children's Cancer Institute Australia for Medical Research, Sydney, Australia.
J Clin Oncol. 2006 Apr 1;24(10):1546-53. doi: 10.1200/JCO.2005.01.6196.
We have previously shown in a retrospective study that expression of the multidrug transporter gene MRP1 (ABCC1) is associated with outcome in neuroblastoma. We have now undertaken a prospective analysis to examine the independent prognostic significance of MRP1 expression in a large cohort of primary untreated neuroblastomas.
Two hundred nine diagnostic neuroblastoma samples from patients prospectively enrolled onto the Pediatric Oncology Group biology protocol 9047 were analyzed for expression of the MRP1, MDR1, MYCN, and TRKA genes using real-time polymerase chain reaction. Expression levels were correlated with established prognostic indicators and disease outcome.
MRP1 expression was detected in all tumors analyzed, and levels were significantly higher in tumors with versus without MYCN amplification (P < .0001). High levels of MRP1 were highly predictive of both event-free survival (EFS; P < .001) and overall survival (OS; P < .001). High-level MYCN and low-level TRKA were also predictive of poor outcome. MDR1 expression demonstrated no prognostic significance. After adjustment for the effect of statistically significant prognostic indicators in multivariate models, MRP1 expression retained significant prognostic value for both EFS (hazard ratio = 3.0; P = .0011) and OS (hazard ratio = 2.5; P = .0095), whereas MYCN amplification did not have prognostic significance.
The results of this prospective study confirm our earlier findings and support a clinically relevant role for MRP1 gene expression in neuroblastoma. These findings have implications for the biology, prognosis, and treatment of this disease and provide evidence that MRP1 is a bone fide molecular target for reversing chemotherapy resistance in aggressive drug-refractory neuroblastoma.
我们先前在一项回顾性研究中表明，多药转运蛋白基因MRP1（ABCC1）的表达与神经母细胞瘤的预后相关。我们现在进行了一项前瞻性分析，以检验MRP1表达在一大群未经治疗的原发性神经母细胞瘤中的独立预后意义。
对前瞻性纳入儿童肿瘤学组生物学方案9047的209例诊断为神经母细胞瘤的患者样本，使用实时聚合酶链反应分析MRP1、MDR1、MYCN和TRKA基因的表达。表达水平与既定的预后指标和疾病结局相关。
在所有分析的肿瘤中均检测到MRP1表达，有MYCN扩增的肿瘤中其水平显著高于无MYCN扩增的肿瘤（P <.0001）。高水平的MRP1对无事件生存期（EFS；P <.001）和总生存期（OS；P <.001）均具有高度预测性。高水平的MYCN和低水平的TRKA也预示着预后不良。MDR1表达无预后意义。在多变量模型中对具有统计学意义的预后指标的影响进行校正后，MRP1表达对EFS（风险比 = 3.0；P =.0011）和OS（风险比 = 2.5；P =.0095）仍具有显著的预后价值，而MYCN扩增无预后意义。
这项前瞻性研究的结果证实了我们早期的发现，并支持MRP1基因表达在神经母细胞瘤中具有临床相关作用这一观点。这些发现对该疾病的生物学、预后和治疗具有重要意义，并提供了证据表明MRP1是逆转侵袭性耐药神经母细胞瘤化疗耐药性的真正分子靶点。
