title: The genetic tumor background is an important determinant for heterogeneous MYCN-amplified neuroblastoma.
abstract: Amplification of MYCN is the signature genetic aberration of 20-25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN-FISH. Tumors of patients ≤18m were mostly aneuploid with numeric chromosomal aberrations (NCAs), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCAs). In older patients, tumors were mostly di- or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di- or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment.
authors.affiliation: Department of Tumor Biology, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Dominik
authors.initials: D
authors.lastname: Bogen
authors.affiliation: Department of Tumor Biology, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Brunner
authors.affiliation: Department of Tumor Biology, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Diana
authors.initials: D
authors.lastname: Walder
authors.affiliation: Department of Tumor Biology, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: Department of Tumor Biology, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Reza
authors.initials: R
authors.lastname: Abbasi
authors.affiliation: S2IRP, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Ladenstein
authors.affiliation: Pathology Department, Medical School, University of Valencia, INCLIVA, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.affiliation: Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Tommy
authors.initials: T
authors.lastname: Martinsson
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Amann
authors.affiliation: Pediatric Oncology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: Freimut H
authors.initials: FH
authors.lastname: Schilling
authors.affiliation: Department of Pediatric Oncology, Hematology and BMT, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Ussowicz
authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Benesch
authors.affiliation: Department of Tumor Biology, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Ambros
authors.affiliation: Department of Tumor Biology, CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Inge M
authors.initials: IM
authors.lastname: Ambros
mesh_terms: D000293:Adolescent; D000782:Aneuploidy; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D005260:Female; D005784:Gene Amplification; D018740:Genetic Heterogeneity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins
keywords: MYCN amplification; intratumoral heterogeneity; neuroblastoma; uniparental disomy