Oncotarget

Research Papers:

Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism

Stefano J. Mandriota _, Linda J. Valentijn, Laurence Lesne, David R. Betts, Denis Marino, Mary Boudal-Khoshbeen, Wendy B. London, Anne-Laure Rougemont, Edward F. Attiyeh, John M. Maris, Michael D. Hogarty, Jan Koster, Jan J. Molenaar, Rogier Versteeg, Marc Ansari and Fabienne Gumy-Pause

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Oncotarget. 2015; 6:18558-18576. https://doi.org/10.18632/oncotarget.4061

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Abstract

Stefano J. Mandriota1, Linda J. Valentijn2, Laurence Lesne1, David R. Betts3, Denis Marino1, Mary Boudal-Khoshbeen1, Wendy B. London4, Anne-Laure Rougemont5, Edward F. Attiyeh6, John M. Maris6, Michael D. Hogarty6, Jan Koster2, Jan J. Molenaar2, Rogier Versteeg2, Marc Ansari1,7,*, Fabienne Gumy-Pause1,7,*

1Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, University of Geneva, Geneva, Switzerland

2Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

3Department of Clinical Genetics, Our Lady’s Children’s Hospital, Dublin, Ireland

4Division of Pediatric Hematology/Oncology, Harvard Medical School, Dana-Farber/Children’s Hospital Cancer and Blood Disorders Center, Boston, MA, USA

5Department of Pathology, University Hospital of Geneva, Geneva, Switzerland

6Department of Pediatrics, Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA, USA

7Department of Pediatrics, Onco-hematology Unit, University Hospital of Geneva, Geneva, Switzerland

*These authors have contributed equally to this work

Correspondence to:

Stefano J. Mandriota, e-mail: [email protected]

Fabienne Gumy-Pause, e-mail: [email protected]

Keywords: ataxia-telangiectasia mutated, neuroblastoma, MYCN, 11q

Received: December 19, 2014     Accepted: May 14, 2015     Published: May 26, 2015

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.


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