title: Integrated genomic profiling identifies two distinct molecular subtypes with divergent outcome in neuroblastoma with loss of chromosome 11q.
abstract: Imbalances in chromosome 11q occur in approximately 30% of primary neuroblastoma and are associated with poor outcome. It has been suggested that 11q loss constitutes a distinct clinico-genetic neuroblastoma subgroup by affecting expression levels of corresponding genes. This study analysed the relationship of 11q loss, clinical phenotype and global transcriptomic profiles in four clinico-genetic subgroups (11q alteration/favourable outcome, n=7; 11q alteration/unfavourable outcome, n=14; no 11q alteration/favourable outcome, n=81; no 11q alteration/unfavourable outcome, n=8; tumours with MYCN amplification and/or 1p loss were excluded). Unsupervised and supervised comparisons of gene expression profiles consistently showed significantly different mRNA patterns between favourable and unfavourable neuroblastomas, both in the subgroups with and without 11q loss. In contrast, favourable tumours with and without 11q loss showed highly similar transcriptomic profiles. Disproportionate downregulation of 11q genes was observed only in unfavourable tumours with 11q loss. The diverging molecular profiles were neither caused by considerable differences in the size of the deleted regions nor by differential methylation patterns of 11q genes. Together, this study shows that neuroblastoma with 11q loss comprises two biological subgroups that differ both in their clinical phenotype and gene expression patterns, indicating that 11q loss is not a primary determinant of neuroblastoma tumour behaviour.
authors.affiliation: Department of Paediatric Oncology, University Children's Hospital, and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany. matthias.fischer@uk-koeln.de
authors.forename: M
authors.initials: M
authors.lastname: Fischer
authors.forename: T
authors.initials: T
authors.lastname: Bauer
authors.forename: A
authors.initials: A
authors.lastname: Oberthür
authors.forename: B
authors.initials: B
authors.lastname: Hero
authors.forename: J
authors.initials: J
authors.lastname: Theissen
authors.forename: M
authors.initials: M
authors.lastname: Ehrich
authors.forename: R
authors.initials: R
authors.lastname: Spitz
authors.forename: R
authors.initials: R
authors.lastname: Eils
authors.forename: F
authors.initials: F
authors.lastname: Westermann
authors.forename: B
authors.initials: B
authors.lastname: Brors
authors.forename: R
authors.initials: R
authors.lastname: König
authors.forename: F
authors.initials: F
authors.lastname: Berthold
mesh_terms: D002675:Child, Preschool; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D008745:Methylation; D009447:Neuroblastoma / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics