Abstract
Neuroblastoma (NB), the most common solid cancer in early childhood, usually occurs sporadically but also its familial occurance is known in 1-2% of NB patients. Germline mutations in the ALK and PHOX2B genes have been found in a subset of familial NBs. However, because some individuals harbouring mutations in these genes do not develop this tumor, additional genetic alterations appear to be required for NB pathogenesis. Herein, we studied an Italian family with three NB patients, two siblings and a first cousin, carrying an ALK germline-activating mutation R1192P, that was inherited from their unaffected mothers and with no mutations in the PHOX2B gene. A comparison between somatic and germline DNA copy number changes in the two affected siblings by a high resolution array-based Comparative Genomic Hybridization (CGH) analysis revealed a germline gain at NKAIN2 (Na/K transporting ATPase interacting 2) locus in one of the sibling, that was inherited from the parent who does not carry the ALK mutation. Surprisingly, NKAIN2 was expressed at high levels also in the affected sibling that lacks the genomic gain at this locus, clearly suggesting the existance of other regulatory mechanisms. High levels of NKAIN2 were detected in the MYCN-amplified NB cell lines and in the most aggressive NB lesions as well as in the peripheral blood of a large cohort of NB patients. Consistent with a role of NKAIN2 in NB development, NKAIN2 was down-regulated during all-trans retinoic acid differentiation in two NB cell lines. Taken together, these data indicate a potential role of NKAIN2 gene in NB growth and differentiation.
Highlights
Neuroblastoma (NB), the most common extracranial solid tumor of childhood, originates from sympathetic neuronal progenitor cells and accounts for more than 15% of all pediatric cancer deaths [1,2]
DNA sequencing of their relatives indicated that the R1192P mutation was inherited from the unaffected mothers and the grandfather (II-1, II-2 and I1, respectively; Figure 1). Since this anaplastic lymphoma kinase (ALK) mutation was inherited from asymptomatic parents, additional genetic events are thought to be required for tumor development in these patients
To identify new candidate genes implicated in NB, we performed a comparison between somatic and germline DNA copy number changes in two NB-affected siblings carrying an ALK germline activating mutation (R1192P) This ALK mutation has been already reported in familial NB [14]
Summary
Neuroblastoma (NB), the most common extracranial solid tumor of childhood, originates from sympathetic neuronal progenitor cells and accounts for more than 15% of all pediatric cancer deaths [1,2]. Tumors showing hyper- or hypoploidy due to whole-chromosomal gains or losses, respectively, are more cured and frequently undergo spontaneous regression [1]. Germline missense mutations in PHOX2B were originally observed in a familial case of NB and in a patient with NB associated with congenital central hypoventilation syndrome (CCHS) and/or Hirschsprung disease [4]. ALK has been demostrated to be constitutively activated by gene mutations in the tyrosine kinase domain and/or amplification in sporadic [10,11,12,13], as well as in familial cases of NB [14,15]. The range of somatic and germline ALK mutations are different, being some mutations detected either in familial or in sporadic forms of NB
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