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Comprehensive Genetic and Histopathologic Study Reveals Three Types of Neuroblastoma Tumors

By Maria astowska, Catherine Cullinane, Sadick Variend, Simon Cotterill, Nick Bown, Seamus O’Neill, Katia Mazzocco, Paul Roberts, James Nicholson, Caroline Ellershaw, Andrew D.J. Pearson, Michael S. Jackson, for the United Kingdom Children Cancer Study Group and the United Kingdom Cancer Cytogenetics Group

From the Human Genetics Unit, School of Biochemistry and Genetics; and Institute of Child Health, University of Newcastle upon Tyne, Newcastle upon Tyne; Department of Histopathology; and Cytogenetics Unit, St James’s Hospital, Leeds; Department of Histopathology, Sheffield Children’s Hospital, Sheffield; Wessex Regional Laboratory, Salisbury; United Kingdom Children Cancer Study Group, Department of Epidemiology and Public Health, University of Leicester, Leicester; Department of Paediatrics, Addenbrooke’s Hospital, Cambridge, United Kingdom; and Unit of Solid Tumour Biology, Advanced Biotechnology Center, Genova, Italy.

Address reprint requests to Maria astowska, Human Genetics Unit, School of Biochemistry and Genetics, University of Newcastle upon Tyne, Ridley Building, Claremont Place, Newcastle upon Tyne NE1 7RU, United Kingdom; email: M.A.Lastowska{at}ncl.ac.uk

PURPOSE: To determine the relationship between multiple genetic features, tumor morphology, and prognosis in neuroblastoma.

PATIENTS AND METHODS: The genetic alterations and morphologic features that underpin three histopathologic risk classifications were analyzed in 108 neuroblastoma patients. Tumors were subdivided into four groups based on the three most frequent and prognostically significant genetic alterations (17q gain, 1p deletion, and MYCN amplification), and all other genetic, morphologic, and clinical data were analyzed with respect to these groups.

RESULTS: Our analyses identify three nonoverlapping tumor types with distinct genetic and morphologic features, defined here as types 1, 2, and 3. Type 1 tumors show none of the three significant genetic alterations and have good prognosis. Both type 2 (17q gain only or 17q gain and 1p del) and type 3 (17q gain, 1p del, and MYCN amplification) tumors progress. However, these tumor types are distinguished clinically by having significantly different median age at diagnosis and median progression-free survival (PFS). Multivariate analysis indicates that 17q gain is the only independent prognostic factor among all genetic, histopathologic, and clinical factors analyzed. Among histopathologic risk systems, the International Neuroblastoma Pathology Classification was the best predictor of PFS.

CONCLUSION: Our results indicate that specific combinations of genetic changes in neuroblastoma tumors contribute to distinct morphologic and clinical features. Furthermore, the identification of two genetically and morphologically distinct types of progressing tumors suggests that possibilities for different therapeutic regimens should be investigated.

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