title: Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism.
abstract: Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma.
authors.affiliation: Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Stefano J
authors.initials: SJ
authors.lastname: Mandriota
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Valentijn
authors.affiliation: Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lesne
authors.affiliation: Department of Clinical Genetics, Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: David R
authors.initials: DR
authors.lastname: Betts
authors.affiliation: Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Marino
authors.affiliation: Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Mary
authors.initials: M
authors.lastname: Boudal-Khoshbeen
authors.affiliation: Division of Pediatric Hematology/Oncology, Harvard Medical School, Dana-Farber/Children's Hospital Cancer and Blood Disorders Center, Boston, MA, USA.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.affiliation: Department of Pathology, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Rougemont
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.|Department of Pediatrics, Onco-Hematology Unit, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Ansari
authors.affiliation: Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland.|Department of Pediatrics, Onco-Hematology Unit, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Gumy-Pause
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002648:Child; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: 11q; MYCN; ataxia-telangiectasia mutated; neuroblastoma