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RESEARCH PRODUCT
A g316a polymorphism in the ornithine decarboxylase gene promoter modulates mycn‐driven childhood neuroblastoma
Rogier VersteegGian Paolo ToniniGudrun SchleiermacherAmanda J. RussellAngelika EggertMurray D. NorrisJaydutt BhalshankarMichael D. HogartyMichael D. HogartyTom Van MaerkenGlenn M. MarshallGlenn M. MarshallMark J. CowleyKwun M. FongLesley J. AshtonJohn M. MarisJohn M. MarisSharon J. DiskinSharon J. DiskinMichelle HaberJayne MurrayMichelle J. HendersonStefania PurgatoRaymond L. StallingsJan KosterPaolo PiginiAli RihaniZalman VaksmanZalman VaksmanJo VandesompeleWendy B. LondonRosa NogueraEmanuele ValliLaura D. GambleFranki SpelemanFederico M. GiorgiGiovanni PeriniGiorgio MilazzoSimone Di GiacomoDavid S. ZieglerDavid S. Zieglersubject
0301 basic medicineCancer ResearchSNPSingle-nucleotide polymorphismBiologylcsh:RC254-282ArticleOrnithine decarboxylase03 medical and health sciencesneuroblastomaNeuroblastoma0302 clinical medicineNeuroblastomaGenotypeMYCNMedicine and Health SciencesTranscriptional regulationmedicineODC1neoplasmsWild typePromotermedicine.diseaselcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogensMolecular biology030104 developmental biologyOncology030220 oncology & carcinogenesisChildhood Neuroblastomadescription
Simple Summary Neuroblastoma is a devasting childhood cancer in which multiple copies (amplification) of the cancer-causing gene MYCN strongly predict poor outcome. Neuroblastomas are reliant on high levels of cellular components called polyamines for their growth and malignant behavior, and the gene regulating polyamine synthesis is called ODC1. ODC1 is often coamplified with MYCN, and in fact is regulated by MYCN, and like MYCN is prognostic of poor outcome. Here we studied a naturally occurring genetic variant or polymorphism that occurs in the ODC1 gene, and used gene editing to demonstrate the functional importance of this variant in terms of ODC1 levels and growth of neuroblastoma cells. We showed that this variant impacts the ability of MYCN to regulate ODC1, and that it also influences outcome in neuroblastoma, with the rarer variant associated with a better survival. This study addresses the important topic of genetic polymorphisms in cancer. 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-04-01 |