A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma.
Authors
Gamble, Laura DPurgato, Stefania
Henderson, Michelle J
Di Giacomo, Simone
Russell, Amanda J
Pigini, Paolo
Murray, Jayne
Valli, Emanuele
Milazzo, Giorgio
Giorgi, Federico M
Cowley, Mark
Ashton, Lesley J
Bhalshankar, Jaydutt
Schleiermacher, Gudrun
Rihani, Ali
Van Maerken, Tom
Vandesompele, Jo
Speleman, Frank
Versteeg, Rogier
Koster, Jan
Eggert, Angelika
Noguera, Rosa
Stallings, Raymond L
Tonini, Gian Paolo
Fong, Kwun
Vaksman, Zalman
Diskin, Sharon J
Maris, John M
London, Wendy B
Marshall, Glenn M
Ziegler, David S
Hogarty, Michael D
Perini, Giovanni
Norris, Murray D
Haber, Michelle
Issue Date
2021-04-09Keywords
MYCNODC1
SNP
Neuroblastoma
BRAIN
Metadata
Show full item recordJournal
CancersDOI
10.3390/cancers13081807PubMed ID
33918978Abstract
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.Item Type
ArticleLanguage
enISSN
2072-6694ae974a485f413a2113503eed53cd6c53
10.3390/cancers13081807