Association of high-level MRP1 expression with poor clinical outcome in a large prospective study of primary neuroblastoma.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Haber
Michelle
M
Children's Cancer Institute Australia for Medical Research, Sydney, Australia.
Smith
Janice
J
Bordow
Sharon B
SB
Flemming
Claudia
C
Cohn
Susan L
SL
London
Wendy B
WB
Marshall
Glenn M
GM
Norris
Murray D
MD
D000293:Adolescent; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005784:Gene Amplification; D019450:Genes, MDR; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000235:genetics*; D015999:Multivariate Analysis; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D009857:Oncogenes; D011446:Prospective Studies
D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C459801:MYCN protein, human; C421109:multidrug resistance-associated protein 1