Norris M D, Bordow S B, Marshall G M, Haber P S, Cohn S L, Haber M
Children's Leukaemia and Cancer Research Centre, University of New South Wales, Sydney, Australia.
N Engl J Med. 1996 Jan 25;334(4):231-8. doi: 10.1056/NEJM199601253340405.
Overexpression of the gene for the multidrug-resistance-associated protein (MRP) has been linked with resistance to chemotherapeutic agents (multidrug resistance) in vitro. The expression of MRP by neuroblastoma cells correlates with N-myc oncogene amplification, a well-established prognostic indicator in patients with neuroblastoma.
To relate MRP gene expression to established prognostic markers and the clinical outcome of neuroblastoma, we analyzed MRP expression in specimens of primary tumors from 60 patients with neuroblastoma.
Levels of MRP gene expression were significantly higher in tumors with N-myc amplification than in tumors without such amplification (P < 0.001). High levels of MRP expression were strongly associated with reductions in both survival and event-free survival (P < 0.001) in the overall study population and in subgroups of patients without N-myc amplification and patients with localized disease. For the overall study population, the five-year cumulative survival rates in the groups with high and low levels of MRP expression were 57 percent (95 percent confidence interval, 37 to 78 percent) and 94 percent (95 percent confidence interval, 86 to 100 percent), respectively. In contrast, expression of the MDR1 multi-drug-resistance gene was not predictive of survival or event-free survival. After adjustment by multivariate analysis for the effects of N-myc amplification and other prognostic indicators, high levels of MRP expression retained significant prognostic value for poor survival (relative hazard, 14.9; P = 0.01) and poor event-free survival (relative hazard, 9.7; P = 0.004), whereas N-myc amplification had no prognostic value.
High levels of MRP gene expression in patients with neuroblastoma correlate strongly with poor outcome. The findings suggest that expression of this multidrug-resistance gene accounts for the association between N-myc amplification and reduced survival.
多药耐药相关蛋白（MRP）基因的过表达在体外已与对化疗药物的耐药性（多药耐药）相关联。神经母细胞瘤细胞中MRP的表达与N - myc癌基因扩增相关，N - myc癌基因扩增是神经母细胞瘤患者中一个公认的预后指标。
为了将MRP基因表达与已确定的预后标志物及神经母细胞瘤的临床结局相关联，我们分析了60例神经母细胞瘤患者原发肿瘤标本中的MRP表达。
N - myc扩增的肿瘤中MRP基因表达水平显著高于无此类扩增的肿瘤（P < 0.001）。在整个研究人群以及无N - myc扩增的患者亚组和局限性疾病患者亚组中，高水平的MRP表达与生存率和无事件生存率的降低均密切相关（P < 0.001）。对于整个研究人群，MRP表达水平高和低的组中五年累积生存率分别为57%（95%置信区间，37%至78%）和94%（95%置信区间，86%至100%）。相比之下，MDR1多药耐药基因的表达不能预测生存率或无事件生存率。在对N - myc扩增和其他预后指标的影响进行多变量分析调整后，高水平的MRP表达对不良生存（相对风险，14.9；P = 0.01）和不良无事件生存（相对风险，9.7；P = 0.004）仍具有显著的预后价值，而N - myc扩增无预后价值。
神经母细胞瘤患者中高水平的MRP基因表达与不良结局密切相关。这些发现表明，这种多药耐药基因的表达解释了N - myc扩增与生存率降低之间的关联。
