EXPRESSION OF THE GENE FOR MULTIDRUG-RESISTANCE-ASSOCIATED PROTEIN AND OUTCOME IN PATIENTS WITH NEUROBLASTOMA

Background. Overexpression of the gene for the multidrug-resistance-as sociated protein (MRP) has been linked with resistance to chemotherape utic agents (multidrug resistance) in vitro. The expression of MRP by neuroblastoma cells correlates with N-myc oncogene amplification, a we ll-established prognostic indicator in patients with neuroblastoma. Me thods. 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. R esults. Levels of MRP gene expression were significantly higher in tum ors with N-myc amplification than in tumors without such amplification (P<0.001). High levels of MRP expression were strongly associated wit h reductions in both survival and event-free survival (P<0.001) in the overall study population and in subgroups of patients without N-myc a mplification and patients with localized disease. For the overall stud y population, the five-year cumulative survival rates in the groups wi th high and low levels of MRP expression were 57 percent (95 percent c onfidence interval, 37 to 78 percent) and 94 percent (95 percent confi dence interval, 86 to 100 percent), respectively. In contrast, express ion of the MDR1 multidrug-resistance gene was not predictive of surviv al or event-free survival. After adjustment by multivariate analysis f or the effects of N-myc amplification and other prognostic indicators, high levels of MRP expression retained significant prognostic value f or poor survival (relative hazard, 14.9; P=0.01) and poor event-free s urvival (relative hazard, 9.7; P=0.004), whereas N-myc amplification h ad no prognostic value. Conclusions. High levels of MRP gene expressio n in patients with neuroblastoma correlate strongly with poor outcome. The findings suggest that expression of this multidrug-resistance gen e accounts for the association between N-myc amplification and reduced survival. (C) 1996, Massachusetts Medical Society.