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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References
Amiel J, Laudier B, Attie-Bitach T, Trang H, De Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C and Lyonnet S . (2003). Nat. Genet., 33, 459–461.
Bonfield JK, Rada C and Staden R . (1998). Nucleic Acids Res., 26, 3404–3409.
Boon K, Caron HN, van Asperen R, Valentijn L, Hermus MC, van Sluis P, Roobeek I, Weis I, Voute PA, Schwab M and Versteeg R . (2001). EMBO J, 20, 1383–1393.
Brodeur GM, Seeger RC, Schwab M, Varmus HE and Bishop JM . (1984). Science, 224, 1121–1124.
Caron H . (1995). Med. Pediatr. Oncol., 24, 215–221.
Caron H, van Sluis P, Buschman R, Pereira do TR, Maes P, Beks L, De Kraker J, Voute PA, Vergnaud G, Westerveld A, Slater R and Versteeg R . (1996). Hum. Genet., 97, 834–837.
Easton J, Wei T, Lahti JM and Kidd VJ . (1998). Cancer Res., 58, 2624–2632.
Eggert A, Grotzer MA, Ikegaki N, Liu XG, Evans AE and Brodeur GM . (2002). Cancer Res., 62, 1802–1808.
Eggert A, Ikegaki N, Liu X, Chou TT, Lee VM, Trojanowski JQ and Brodeur GM . (2000). Oncogene, 19, 2043–2051.
Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ and Joyner AL . (1993). Cell, 75, 463–476.
Han K and Manley JL . (1993). EMBO J., 12, 2723–2733.
Huber K, Combs S, Ernsberger U, Kalcheim C and Unsicker K . (2002). Ann. NY Acad. Sci., 971, 554–559.
Lanz RB, Wieland S, Hug M and Rusconi S . (1995). Nucleic Acids Res., 23, 138–145.
Lavoie H, Debeane F, Trinh QD, Turcotte JF, Corbeil-Girard LP, Dicaire MJ, Saint-Denis A, Page M, Rouleau GA and Brais B . (2003). Hum. Mol. Genet., 12, 2967–2979.
Limpt VAv, Chan AJ, Van Sluis PG, Caron HN, Van Noesel CJ and Versteeg R . (2003). Int. J. Cancer, 105, 61–69.
Molenaar JJ, van Sluis P, Boon K, Versteeg R and Caron HN . (2003). Genes Chromosomes Cancer, 36, 242–249.
Morin X, Cremer H, Hirsch MR, Kapur RP, Goridis C and Brunet JF . (1997). Neuron, 18, 411–423.
Mullenbach R, Lagoda PJ and Welter C . (1989). Trends Genet., 5, 391.
Nakagawara A, Arima-Nakagawara M, Scavarda NJ, Azar CG, Cantor AB and Brodeur GM . (1993). N. Engl. J. Med., 328, 847–854.
Nakagawara A, Azar CG, Scavarda NJ and Brodeur GM . (1994). Mol. Cell Biol., 14, 759–767.
Pattyn A, Morin X, Cremer H, Goridis C and Brunet JF . (1999). Nature, 399, 366–370.
Perri P, Longo L, Cusano R, McConville CM, Rees SA, Devoto M, Conte M, Ferrara GB, Seri M, Romeo G and Tonini GP . (2002). Oncogene, 21, 8356–8360.
Ross RA, Spengler BA and Biedler JL . (1983). J. Natl. Cancer Inst., 71, 741–747.
Sasaki A, Kanai M, Kijima K, Akaba K, Hashimoto M, Hasegawa H, Otaki S, Koizumi T, Kusuda S, Ogawa Y, Tuchiya K, Yamamoto W, Nakamura T and Hayasaka K . (2003). Hum. Genet., 114, 22–26.
Schulte JH, Schramm A, Klein-Hitpass L, Klenk M, Wessels H, Hauffa BP, Eils J, Eils R, Brodeur GM, Schweigerer L, Havers W and Eggert A . (2004). Oncogene in press.
Schwab M, Ellison J, Busch M, Rosenau W, Varmus HE and Bishop JM . (1984). Proc. Natl. Acad. Sci. USA, 81, 4940–4944.
Spieker N, Beitsma M, van Sluis P, Chan A, Caron H and Versteeg R . (2001a). Genes Chromosomes Cancer, 31, 172–181.
Spieker N, van Sluis P, Beitsma M, Boon K, van Schaik BD, van Kampen AH, Caron H and Versteeg R . (2001b). Genomics, 71, 214–221.
Stanke M, Stubbusch J and Rohrer H . (2004). Mol. Cell Neurosci., 25, 374–382.
Trochet D, Bourdeaut F, Janoueix-Lerosey I, Deville A, De Pontual L, Schleiermacher G, Coze C, Philip N, Frebourg T, Munnich A, Lyonnet S, Delattre O and Amiel J . (2004). Am. J. Hum. Genet., 74, 761–764.
van Roy N, Cheng NC, Laureys G, Opdenakker G, Versteeg R and Speleman F . (1995). Eur. J. Cancer, 31A, 530–535.
Vandesompele J, De Preter K, Pattyn F, Poppe B, van Roy N, De Paepe A and Speleman F . (2002). Genome Biol., 3, RESEARCH0034.
Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME and Marazita ML . (2003). Am. J. Med. Genet., 123A, 267–278.
Yang C, Kim HS, Seo H, Kim CH, Brunet JF and Kim KS . (1998). J. Neurochem., 71, 1813–1826.
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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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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DOI: https://doi.org/10.1038/sj.onc.1208157
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