title: Identification of 2 putative critical segments of 17q gain in neuroblastoma through integrative genomics.
abstract: Partial gain of chromosome arm 17q is the most frequent genetic change in neuroblastoma (NB) and constitutes the strongest independent genetic factor for adverse prognosis. It is assumed that 1 or more genes on 17q contribute to NB pathogenesis by a gene dosage effect. In the present study, we applied chromosome 17 tiling path BAC arrays on a panel of 69 primary tumors and 28 NB cell lines in order to reduce the current smallest region of gain and facilitate identification of candidate dosage sensitive genes. In all tumors and cell lines with 17q gain, large distal segments were consistently present in extra copies and no interstitial gains were observed. In addition to these large regions of distal gain with breakpoints proximal to coordinate 44.3 Mb (17q21.32), smaller regions of gain (distal to coordinate 60 Mb at 17q24.1) were found superimposed on the larger region in a minority of cases. Positional gene enrichment analysis for 17q genes overexpressed in NB showed that dosage sensitive NB oncogenes are most likely located in the gained region immediately distal to the most distal breakpoint of the 2 breakpoint regions. Interestingly, comparison of gene expression profiles between primary tumors and normal fetal adrenal neuroblasts revealed 2 gene clusters on chromosome 17q that are overexpressed in NB, i.e. a region on 17q21.32 immediately distal to the most distal breakpoint (in cases with single regions of gain) and 17q24.1, a region coinciding with breakpoints leading to superimposed gain.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Evi
authors.initials: E
authors.lastname: Michels
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.forename: Björn
authors.initials: B
authors.lastname: Menten
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Peter F
authors.initials: PF
authors.lastname: Ambros
authors.forename: Valerie
authors.initials: V
authors.lastname: Combaret
authors.forename: Nadine
authors.initials: N
authors.lastname: Francotte
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonacci
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Geneviève
authors.initials: G
authors.lastname: Laureys
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
mesh_terms: D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D018628:Gene Dosage; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality; D011379:Prognosis