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The Phox2B homeobox gene is mutated in sporadic neuroblastomas

Oncogene volume 23, pages 9280–9288 (2004)Cite this article

Abstract

Neuroblastomas are embryonal tumours of the sympatho-adrenal lineage with a clinical course ranging from spontaneous regression to fatal progression. The Phox2B homeobox transcription factor functions in the differentiation of the sympatho-adrenal lineage. Targets of Phox2B are, for example, genes of the (nor)adrenalin synthesis route, like Dopamine Beta Hydroxylase (DBH). Congenital Central Hypoventilation Syndrome was recently found to result from Phox2B mutations and two such patients in addition developed neuroblastoma. A germline mutation in Phox2B was identified in a family with hereditary neuroblastoma. Here, we report the first analysis of Phox2B in a series of 237 sporadic neuroblastomas and 22 cell lines. Six frameshift mutations were found in exons 2 and 3; including one in cell line SK-N-SH. Two patients showed de novo constitutional mutations. One of them was diagnosed with Haddad syndrome. All analysed cases expressed the mutated and wild-type Phox2B alleles. Ectopic expression of TrkA, the Nerve Growth Factor receptor, strongly downregulated Phox2B and DBH expression in cell line SH-SY5Y. However, TrkA and Phox2B showed a positive correlation in a panel of 66 neuroblastoma tumours. Although Phox2B mutations are infrequent (2.3%), they implicate a role for the Phox2B pathway in oncogenesis.

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Acknowledgements

We thank Dirk Geerts and Raoul Hennekam for stimulating discussions and Ingrid Revet for help with the Staden program. This research was supported by a grant from the Stichting Kindergeneeskundig Kankeronderzoek (SKK) and the Deutsche Krebshilfe (AE).

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Authors and Affiliations

  1. Department of Human Genetics, Academic Medical Center, University of Amsterdam, PO Box 22700, Amsterdam, 1100 DE, The Netherlands

    Vera van Limpt, Arjan Lakeman, Peter van Sluis, Alvin Chan, Max van Noesel & Rogier Versteeg

  2. Department of Oncology/Hematology and Endocrinology, University Children's Hospital of Essen, Hufelandstr. 55, Essen, 45122, Germany

    Alexander Schramm & Angelika Eggert

  3. Department of Neurogenetics, Academic Medical Center, University of Amsterdam, PO Box 22700, Amsterdam, 1100 DE, The Netherlands

    Frank Baas

  4. Department of Pediatric Oncology, Academic Medical Center, University of Amsterdam, PO Box 22700, Amsterdam, 1100 DE, The Netherlands

    Huib Caron

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  1. Vera van Limpt
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Correspondence to Rogier Versteeg.

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Limpt, V., Schramm, A., Lakeman, A. et al. The Phox2B homeobox gene is mutated in sporadic neuroblastomas. Oncogene 23, 9280–9288 (2004). https://doi.org/10.1038/sj.onc.1208157

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