title: Analysis of neuroblastoma tumour progression; loss of PHOX2B on 4p13 and 17q gain are early events in neuroblastoma tumourigenesis.
abstract: Neuroblastomas are biologically and clinically heterogeneous tumours that most often occur sporadically in children at median age of 2 years. The PHOX2B gene is implicated in the development of the autonomic nervous system and has been found to be infrequently mutated in sporadic neuroblastoma tumours and in some patients with hereditary neuroblastoma. We have screened a selected series of 36 paediatric tumours with presumed genetic predisposition, 34 of them neuroblastomas, for mutations in PHOX2B. A constitutional heterozygous missense mutation was found in a boy who developed bilateral adrenal tumours and stage 4 disease during infancy. The second allele of the PHOX2B locus was lost in the tumour DNA. Histopathological evaluation of the tumours suggested growth of two primary tumours, one with diploid DNA content and the other with tetraploid DNA content, i.e. a case of neuroblastoma stage 4M (multifocal tumour). However, array CGH (comparative genomic hybridization) data performed on both tumour masses from the patient instead supported a model where a common malignant precursor gave rise to the diploid tumour and subsequently the tetraploid tumour have progressed from the common precursor or by metastasis from the diploid tumour with additional genetic changes. The whole genome dosage analysis showed that the remaining alleles of PHOX2B had been lost in both tumours together with a specific 17q gain pattern. The tetraploid tumour had these features together with additional whole chromosomal loss of chromosomes 3, 9, 14 and 15. Based on the data presented here we suggest that loss of PHOX2B and 17q gain are early events in neuroblastoma tumourigenesis. We also propose investigators to re-analyze the rare cases of multifocal neuroblastomas with the array CGH technique for better understanding of the origin of these tumours.
authors.affiliation: Department of Clinical Genetics, Institute of Biomedical Science, Sahlgrenska University Hospital East, Göteborg University, SE-41345 Göteborg, Sweden. cecilia.krona@clingen.gu.se
authors.forename: Cecilia
authors.initials: C
authors.lastname: Krona
authors.forename: Helena
authors.initials: H
authors.lastname: Carén
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Sjöberg
authors.forename: Bengt
authors.initials: B
authors.lastname: Sandstedt
authors.forename: Genevieve
authors.initials: G
authors.lastname: Laureys
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.forename: Tommy
authors.initials: T
authors.lastname: Martinsson
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D002894:Chromosomes, Human, Pair 4; D004252:DNA Mutational Analysis; D018450:Disease Progression; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D012333:RNA, Messenger; D014157:Transcription Factors