Detection of sporadic PHOX2B gene mutations and association of tumor behavior in neuroblastomas

Neuroblastoma (NB) which typically occurs spontaneous is the most common childhood tumors. These tumors shows heterogeneous clinical signature and some genetic variations are identified in these tumors. Only MYCN gene with a causative role in neuroblastoma pathogenesis has been identified. The Phox2B homeobox transcription factor functions in the differentiation of the sympatho-adrenal lineage. Ondine?s Curse (CCHS) was recently found to result from PHOX2B mutations and two such patients in addition developed neuroblastoma. However we think that PHOX2B mutation or mutations lead to occur NB tumors. Our study aims to detect sporadic PHOX2B gene mutation at neuroblastoma tumor and other neuroblastic tumors. DNA sequence analyses of all PHOX2B exons were performed in 114 NB, 7 ganglioneuroblastoma, and 7 ganglioneuroma tumor samples. Mutation analyses revealed a novel mutation of c.96G>A (D32N) in exon 1 in a NB case. In addition, c.1101_1118het-del18 and c.1098_1136het-del39 deletions in exon 3, encodes polyalanine tract, were detected in NB and ganglioneuroma cases, respectively. Both of these deletions are previously undefined in terms of its size and reading frame. Two different SNP?s (c.552C>T, c.762A>C) were present in five NB samples. PHOX2B mutations are rare in NB?s and can be observed in fully differentiated histologic subtypes. Presence of PHOX2B mutation in tumor with maturation suggests that it is prognostically insignificant. Since deletion of polyalanine tract changes the three dimensional structure of PHOX2B and thus affects its function, its inactivating mutations may contribute to NB development.