Cancers (Apr 2021)
A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma
- Laura D. Gamble,
- Stefania Purgato,
- Michelle J. Henderson,
- Simone Di Giacomo,
- Amanda J. Russell,
- Paolo Pigini,
- Jayne Murray,
- Emanuele Valli,
- Giorgio Milazzo,
- Federico M. Giorgi,
- Mark Cowley,
- Lesley J. Ashton,
- Jaydutt Bhalshankar,
- Gudrun Schleiermacher,
- Ali Rihani,
- Tom Van Maerken,
- Jo Vandesompele,
- Frank Speleman,
- Rogier Versteeg,
- Jan Koster,
- Angelika Eggert,
- Rosa Noguera,
- Raymond L. Stallings,
- Gian Paolo Tonini,
- Kwun Fong,
- Zalman Vaksman,
- Sharon J. Diskin,
- John M. Maris,
- Wendy B. London,
- Glenn M. Marshall,
- David S. Ziegler,
- Michael D. Hogarty,
- Giovanni Perini,
- Murray D. Norris,
- Michelle Haber
Affiliations
- Laura D. Gamble
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- Stefania Purgato
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
- Michelle J. Henderson
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- Simone Di Giacomo
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
- Amanda J. Russell
- Cancer Research Program, The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
- Paolo Pigini
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
- Jayne Murray
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- Emanuele Valli
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- Giorgio Milazzo
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
- Federico M. Giorgi
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
- Mark Cowley
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- Lesley J. Ashton
- Research Portfolio, University of Sydney, Sydney, NSW 2008, Australia
- Jaydutt Bhalshankar
- SIREDO, Department of Paediatric, Adolescents and Young Adults Oncology and INSERM U830, Institut Curie, 26 rue d’Ulm, 75005 Paris, France
- Gudrun Schleiermacher
- SIREDO, Department of Paediatric, Adolescents and Young Adults Oncology and INSERM U830, Institut Curie, 26 rue d’Ulm, 75005 Paris, France
- Ali Rihani
- Center for Medical Genetics, Ghent University, C. Heymanslaan 10, 9000 Ghent, Belgium
- Tom Van Maerken
- Center for Medical Genetics, Ghent University, C. Heymanslaan 10, 9000 Ghent, Belgium
- Jo Vandesompele
- Center for Medical Genetics, Ghent University, C. Heymanslaan 10, 9000 Ghent, Belgium
- Frank Speleman
- Center for Medical Genetics, Ghent University, C. Heymanslaan 10, 9000 Ghent, Belgium
- Rogier Versteeg
- Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1100 Amsterdam, The Netherlands
- Jan Koster
- Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1100 Amsterdam, The Netherlands
- Angelika Eggert
- Department of Pediatric Hematology, Oncology and SCT, Charité-University Hospital Berlin, Campus Virchow-Klinikum, 10117 Berlin, Germany
- Rosa Noguera
- Department of Pathology, Medical School, University of Valencia, 46010 Valencia, Spain
- Raymond L. Stallings
- Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, D02 YN77 Dublin 2, Ireland
- Gian Paolo Tonini
- Neuroblastoma Laboratory, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35127 Padova, Italy
- Kwun Fong
- Thoracic Research Centre, University of Queensland, The Prince Charles Hospital, Brisbane, QLD 4032, Australia
- Zalman Vaksman
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Sharon J. Diskin
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- John M. Maris
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Wendy B. London
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02215, USA
- Glenn M. Marshall
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- David S. Ziegler
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- Michael D. Hogarty
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Giovanni Perini
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
- Murray D. Norris
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- Michelle Haber
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, Randwick, NSW 2031, Australia
- DOI
- https://doi.org/10.3390/cancers13081807
- Journal volume & issue
-
Vol. 13,
no. 8
p. 1807
Abstract
Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of ODC1, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype MYCN-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased ODC1 expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the ODC1 promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in MYCN-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the ODC1 G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.
Keywords