@article{9ce73b4aa83b43fcbcb3395a36dfdabb,
title = "A g316a polymorphism in the ornithine decarboxylase gene promoter modulates mycn‐driven childhood neuroblastoma",
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 neu-roblastoma 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, re-spectively. 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 = "MYCN, Neuroblastoma, ODC1, SNP",
author = "Gamble, {Laura D.} and Stefania Purgato and Henderson, {Michelle J.} and {di Giacomo}, Simone and Russell, {Amanda J.} and Paolo Pigini and Jayne Murray and Emanuele Valli and Giorgio Milazzo and Giorgi, {Federico M.} and Mark Cowley and Ashton, {Lesley J.} and Jaydutt Bhalshankar and Gudrun Schleiermacher and Ali Rihani and {van Maerken}, Tom and Jo Vandesompele and Frank Speleman and Rogier Versteeg and Jan Koster and Angelika Eggert and Rosa Noguera and Stallings, {Raymond L.} and Tonini, {Gian Paolo} and Kwun Fong and Zalman Vaksman and Diskin, {Sharon J.} and Maris, {John M.} and London, {Wendy B.} and Marshall, {Glenn M.} and Ziegler, {David S.} and Hogarty, {Michael D.} and Giovanni Perini and Norris, {Murray D.} and Michelle Haber",
note = "Funding Information: Funding: This study was supported by grants to G.M.M., M.D.N. and M.H. from the National Health and Medical Research Council (APP1132608), Cancer Council NSW (PG16‐01), Cancer Insti‐ tute NSW (12/TPG/1‐13), grants from the Italian Association for Research on Cancer (AIRC) to G.P. (IG11400 and IG15182), grants from the Ghent University research fund to A.R. (BOF/01D02210) and the Research Foundation—Flanders to T.V.M. (FWO/1803115N), and grants from NIH to J.M.M. (R35 CA220500 and R01 CA124709). In addition this study was supported by the Annenberg Foun‐ dation, the Association Hubert Gouin Enfance et Cancer, the Association Enfants et Sant{\'e}, Les Ba‐ gouz {\`a} Manon, Les amis de Claire. Funding was obtained from SiRIC/INCa (Grant INCa‐DGOS‐ 4654), as well as from the Fondation ARC pour la recherche sur le cancer. Funding Information: This study was supported by grants to G.M.M., M.D.N. and M.H. from the National Health and Medical Research Council (APP1132608), Cancer Council NSW (PG16?01), Cancer Institute NSW (12/TPG/1?13), grants from the Italian Association for Research on Cancer (AIRC) to G.P. (IG11400 and IG15182), grants from the Ghent University research fund to A.R. (BOF/01D02210) and the Research Foundation?Flanders to T.V.M. (FWO/1803115N), and grants from NIH to J.M.M. (R35 CA220500 and R01 CA124709). In addition this study was supported by the Annenberg Foun-dation, the Association Hubert Gouin Enfance et Cancer, the Association Enfants et Sant?, Les Ba-gouz ? Manon, Les amis de Claire. Funding was obtained from SiRIC/INCa (Grant INCa?DGOS? 4654), as well as from the Fondation ARC pour la recherche sur le cancer. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = apr,
day = "2",
doi = "https://doi.org/10.3390/cancers13081807",
language = "English",
volume = "13",
journal = "Cancers",
issn = "2072-6694",
publisher = "MDPI Multidisciplinary Digital Publishing Institute",
number = "8",
}