title: High-resolution array CGH profiling identifies Na/K transporting ATPase interacting 2 (NKAIN2) as a predisposing candidate gene in neuroblastoma.
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.
authors.affiliation: Paediatric Haematology/Oncology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Romania
authors.forename: Aurora
authors.initials: A
authors.lastname: Castellano
authors.forename: Cecilia
authors.initials: C
authors.lastname: Surace
authors.forename: Arianna
authors.initials: A
authors.lastname: Citti
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Ioris
authors.forename: Pietro
authors.initials: P
authors.lastname: Sirleto
authors.forename: Marilena
authors.initials: M
authors.lastname: De Mariano
authors.forename: Luca
authors.initials: L
authors.lastname: Longo
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.forename: Adriano
authors.initials: A
authors.lastname: Angioni
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Doriana
authors.initials: D
authors.lastname: Fruci
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization / Q000379:methods; D056915:DNA Copy Number Variations / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005809:Genes, Regulator / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D010375:Pedigree
chemical_list: D008565:Membrane Proteins; C460140:NKAIN2 protein, human