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Relationship Between MYCN Copy Number and Expression in Rhabdomyosarcomas and Correlation With Adverse Prognosis in the Alveolar Subtype

From the Molecular Cytogenetics, Section of Molecular Carcinogenesis and Section of Paediatric Oncology, The Institute of Cancer Research, Sutton, Surrey; Manchester Children's Hospital, Manchester; Department of Histopathology, the Royal Marsden National Health Service Trust; Unit of Molecular Haematology and Oncology, Institute of Child Health, London, United Kingdom; Department of Pathology, Catholic University of Leuven, Leuven, Belgium; and Institut fur Pathologie, Universitatsklinikum der Heinrich-Heine-Universitat, Dusseldorf, Germany

Address reprint requests to Janet Shipley, Molecular Cytogenetics, Male Urological Cancer Research Centre, Institute of Cancer Research, 15 Cotswold Rd, Sutton, Surrey SM2 5NG, United Kingdom; e-mail: janet.shipley{at}icr.ac.uk

PURPOSE: Amplification of the transcription factor MYCN is an important molecular diagnostic tool in stratifying treatment for neuroblastoma. Increased copy number and overexpression of MYCN in the pediatric cancer rhabdomyosarcoma has been described in a number of small studies with conflicting conclusions about its association with clinicopathologic characteristics. We aimed to study the phenomenon in the largest series to date.

PATIENTS AND METHODS: Using quantitative polymerase chain reaction, we measured MYCN copy number and expression levels in rhabdomyosarcoma samples from 113 and 92 individuals with a confirmed diagnosis of rhabdomyosarcoma, respectively.

RESULTS: Increased copy number of MYCN was found to be a feature of both the embryonal and alveolar subtypes. The copy number and expression levels were significantly greater in the alveolar subtype, although the range of expression in both subtypes spanned several orders of magnitude. MYCN copy number showed a significant correlation with expression in the alveolar subtype; this relationship between copy number and expression could be modeled as a logarithmic function. It is notable that relatively high expression frequently occurred in embryonal rhabdomyosarcoma without high copy number and that low expression was found in some cases with high copy number. In patients with alveolar rhabdomyosarcoma, overexpression (greater than median) or gain of genomic copies of MYCN were significantly associated with adverse outcome.

CONCLUSION: MYCN deregulation is a feature of rhabdomyosarcoma tumorigenesis, defines groups of patients with a poor prognosis, and is a potential target for novel therapies.

Supported by Cancer Research United Kingdom.

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

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