This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haber, M. Articles by Norris, M. D. Search for Related Content PubMed PubMed Citation Articles by Haber, M. Articles by Norris, M. D. Social Bookmarking                            What's this?

Association of High-Level MRP1 Expression With Poor Clinical Outcome in a Large Prospective Study of Primary Neuroblastoma

Michelle Haber, Janice Smith, Sharon B. Bordow, Claudia Flemming, Susan L. Cohn, Wendy B. London, Glenn M. Marshall, Murray D. Norris

From the Children's Cancer Institute Australia for Medical Research, Sydney, Australia; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL; and Department of Statistics, University of Florida, and Children's Oncology Group Statistics Department, Gainesville, FL

Address reprint requests to Murray D. Norris, PhD, Children's Cancer Institute Australia for Medical Research, P.O. Box 81, Randwick, 2031, Sydney, Australia; e-mail: m.norris{at}unsw.edu.au

PURPOSE: 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.

PATIENTS AND 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.

CONCLUSION: 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.

This work was supported by grants from the National Health and Medical Research Council (Australia; M.H., G.M.M., and M.D.N.) and the Cancer Council New South Wales (Australia; M.H., G.M.M., and M.D.N.), Grant No. CA29139 from the National Cancer Institute, National Institutes of Health (S.L.C. and W.B.L.), and the Children's Oncology Group.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				T. Van Maerken, L. Ferdinande, J. Taildeman, I. Lambertz, N. Yigit, L. Vercruysse, A. Rihani, M. Michaelis, J. Cinatl Jr, C. A. Cuvelier, et al. Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53 J Natl Cancer Inst, November 18, 2009; 101(22): 1562 - 1574. [Abstract] [Full Text] [PDF]

				C. A. Burkhart, F. Watt, J. Murray, M. Pajic, A. Prokvolit, C. Xue, C. Flemming, J. Smith, A. Purmal, N. Isachenko, et al. Small-Molecule Multidrug Resistance-Associated Protein 1 Inhibitor Reversan Increases the Therapeutic Index of Chemotherapy in Mouse Models of Neuroblastoma Cancer Res., August 15, 2009; 69(16): 6573 - 6580. [Abstract] [Full Text] [PDF]

				M. D. Hogarty, M. D. Norris, K. Davis, X. Liu, N. F. Evageliou, C. S. Hayes, B. Pawel, R. Guo, H. Zhao, E. Sekyere, et al. ODC1 Is a Critical Determinant of MYCN Oncogenesis and a Therapeutic Target in Neuroblastoma Cancer Res., December 1, 2008; 68(23): 9735 - 9745. [Abstract] [Full Text] [PDF]

				V. Sagulenko, D. Muth, E. Sagulenko, T. Paffhausen, M. Schwab, and F. Westermann Cathepsin D protects human neuroblastoma cells from doxorubicin-induced cell death Carcinogenesis, October 1, 2008; 29(10): 1869 - 1877. [Abstract] [Full Text] [PDF]

				C. Xue, M. Haber, C. Flemming, G. M. Marshall, R. B. Lock, K. L. MacKenzie, K. V. Gurova, M. D. Norris, and A. V. Gudkov p53 Determines Multidrug Sensitivity of Childhood Neuroblastoma Cancer Res., November 1, 2007; 67(21): 10351 - 10360. [Abstract] [Full Text] [PDF]

				P. Jungsuwadee, M. P. Cole, R. Sultana, G. Joshi, J. Tangpong, D. A. Butterfield, D. K. St. Clair, and M. Vore Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice. Mol. Cancer Ther., November 1, 2006; 5(11): 2851 - 2860. [Abstract] [Full Text] [PDF]