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Does MYCN Amplification Manifested as Homogeneously Staining Regions at Diagnosis Predict a Worse Outcome in Children with Neuroblastoma? A Children's Oncology Group Study

Authors' Affiliations: ¹ The National Center for Pediatric Cancer Genetics, Children's Oncology Group and ² Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, Florida; ³ Children's Hospital Los Angeles, Los Angeles, California; ⁴ Northwestern University, Feinberg School of Medicine, Chicago, Illinois; ⁵ Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and ⁶ Dana-Farber Cancer Institute and Children's Hospital, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Rani E. George, Department of Pediatric Oncology, Dana 322, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-5281; Fax: 617-632-6989; E-mail: rani_george{at}dfci.harvard.edu.

Purpose: MYCN amplification in neuroblastoma tumor cells is manifested primarily as double minutes (dmins), whereas in cell lines it often appears in the form of homogeneously staining regions (HSR), suggesting that HSRs are associated with a more aggressive tumor phenotype and worse clinical outcome. The aim of this study was to determine whether children with neuroblastoma in which MYCN oncogene amplification is manifested as HSRs at diagnosis have a worse prognosis than those whose tumors exhibit dmins.

Experimental Design: A retrospective analysis of primary neuroblastomas analyzed for MYCN amplification by the Children's Oncology Group between 1993 and 2004 was done. Tumors with MYCN amplification were defined as having dmins, HSRs, or both (dmins + HSRs), and associations with currently used risk group stratification variables and patient outcome were assessed.

Results: Of the 4,102 tumor samples analyzed, 800 (19.5%) had MYCN amplification. Among the 677 tumors for which the pattern of amplification was known, 629 (92.9%) had dmins, 40 (5.9%) had HSRs, and 8 (0.1%) had dmins + HSRs. Although MYCN amplification is associated with older age, higher stage, and unfavorable histology, whether the amplification occurred as dmins or HSRs did not significantly affect these risk factors. There were no differences in the event-free survival (EFS) or overall survival in patients with MYCN amplification manifested as either dmins or HSRs (5-year EFS, 35 ± 3% versus 38 ± 15%; P = 0.59). Although the eight patients with dmins + HSRs fared worse than either of the individual subgroups (EFS, 18 ± 16% versus 35 ± 3% for dmins and 38 ± 15% for HSRs), these differences were not significant.

Conclusions: MYCN amplification in any form (HSRs or dmins) is associated with a poor outcome.

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