CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity
Summary: Pleiotropic genetic factors (e.g., DNA polymorphisms) may be involved in the initiation of neuroblastoma (NB) and coronary artery disease (CAD) given their common origin from defects in neural crest development. To discover novel NB susceptibility genes, we conducted a three-stage survey in...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247722000756 |
| _version_ | 1797984147870842880 |
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| author | Daniela Formicola Vito Alessandro Lasorsa Sueva Cantalupo Alessandro Testori Antonella Cardinale Marianna Avitabile Sharon Diskin Achille Iolascon Mario Capasso |
| author_facet | Daniela Formicola Vito Alessandro Lasorsa Sueva Cantalupo Alessandro Testori Antonella Cardinale Marianna Avitabile Sharon Diskin Achille Iolascon Mario Capasso |
| author_sort | Daniela Formicola |
| collection | DOAJ |
| description | Summary: Pleiotropic genetic factors (e.g., DNA polymorphisms) may be involved in the initiation of neuroblastoma (NB) and coronary artery disease (CAD) given their common origin from defects in neural crest development. To discover novel NB susceptibility genes, we conducted a three-stage survey including a meta-analysis of NB and CAD genome-wide association data, prioritization of NB causal variants, and validation in an independent cohort of affected individuals–control subjects. The lead SNP, rs13337397 at the 16q23.1 locus, associated with both diseases in the meta-analysis and with NB in the validation study. All the SNPs in linkage disequilibrium with rs13337397 were annotated using the H3K27ac epigenetic marker of neural crest cells (NCC) and NB cell lines. Indeed, we identified the functional SNP rs13337017, mapping within an enhancer of NCCs and NB cell lines and showing long-range interactions with CFDP1 by Hi-C analysis. Luciferase assays indicated that the risk allele of rs13337017 increased CFDP1 expression in NB cell lines. Of note, CFDP1 high expression associated with unfavorable prognostic markers in an analysis including 498 NB transcriptomes. Moreover, depletion of CFDP1 markedly decreased viability and migration and increased apoptotic rates in NB cell lines. Finally, transcriptome and qPCR analyses revealed that the depletion of CFDP1 may affect noradrenergic neuron differentiation by downregulating master regulators of sympathetic noradrenergic identity, including PHOX2B, HAND2, and GATA3. Our data strongly suggest that CFDP1 acts as oncogene in NB. In addition, we provide evidence that genetic predisposition to NB can be mediated by the alteration of noradrenergic lineage-specific gene expression. |
| first_indexed | 2024-04-11T06:58:01Z |
| format | Article |
| id | doaj.art-9a7c30faddfd4f2185e66863ef345267 |
| institution | Directory Open Access Journal |
| issn | 2666-2477 |
| language | English |
| last_indexed | 2024-04-11T06:58:01Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj.art-9a7c30faddfd4f2185e66863ef3452672022-12-22T04:38:57ZengElsevierHGG Advances2666-24772023-01-0141100158CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identityDaniela Formicola0Vito Alessandro Lasorsa1Sueva Cantalupo2Alessandro Testori3Antonella Cardinale4Marianna Avitabile5Sharon Diskin6Achille Iolascon7Mario Capasso8Dipartimento di Neurobiologia e Medicina Molecolare, IRCSS Fondazione Stella Maris, 56128 Pisa, Italy; CEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini, 5, 80131 Napoli, ItalyCEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini, 5, 80131 Napoli, ItalyCEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini, 5, 80131 Napoli, ItalyCEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini, 5, 80131 Napoli, Italy; Division of Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USACEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Napoli, Italy; Department of Pediatric Hematology and Oncology, Bambino Gesù Children’s Hospital, IRCCS, Roma, ItalyCEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini, 5, 80131 Napoli, ItalyDivision of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USACEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini, 5, 80131 Napoli, ItalyCEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini, 5, 80131 Napoli, Italy; Corresponding authorSummary: Pleiotropic genetic factors (e.g., DNA polymorphisms) may be involved in the initiation of neuroblastoma (NB) and coronary artery disease (CAD) given their common origin from defects in neural crest development. To discover novel NB susceptibility genes, we conducted a three-stage survey including a meta-analysis of NB and CAD genome-wide association data, prioritization of NB causal variants, and validation in an independent cohort of affected individuals–control subjects. The lead SNP, rs13337397 at the 16q23.1 locus, associated with both diseases in the meta-analysis and with NB in the validation study. All the SNPs in linkage disequilibrium with rs13337397 were annotated using the H3K27ac epigenetic marker of neural crest cells (NCC) and NB cell lines. Indeed, we identified the functional SNP rs13337017, mapping within an enhancer of NCCs and NB cell lines and showing long-range interactions with CFDP1 by Hi-C analysis. Luciferase assays indicated that the risk allele of rs13337017 increased CFDP1 expression in NB cell lines. Of note, CFDP1 high expression associated with unfavorable prognostic markers in an analysis including 498 NB transcriptomes. Moreover, depletion of CFDP1 markedly decreased viability and migration and increased apoptotic rates in NB cell lines. Finally, transcriptome and qPCR analyses revealed that the depletion of CFDP1 may affect noradrenergic neuron differentiation by downregulating master regulators of sympathetic noradrenergic identity, including PHOX2B, HAND2, and GATA3. Our data strongly suggest that CFDP1 acts as oncogene in NB. In addition, we provide evidence that genetic predisposition to NB can be mediated by the alteration of noradrenergic lineage-specific gene expression.http://www.sciencedirect.com/science/article/pii/S2666247722000756GWASSNPneuroblastomaneural crest cellscoronary artery diseasepleiotropic variants |
| spellingShingle | Daniela Formicola Vito Alessandro Lasorsa Sueva Cantalupo Alessandro Testori Antonella Cardinale Marianna Avitabile Sharon Diskin Achille Iolascon Mario Capasso CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity HGG Advances GWAS SNP neuroblastoma neural crest cells coronary artery disease pleiotropic variants |
| title | CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity |
| title_full | CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity |
| title_fullStr | CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity |
| title_full_unstemmed | CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity |
| title_short | CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity |
| title_sort | cfdp1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity |
| topic | GWAS SNP neuroblastoma neural crest cells coronary artery disease pleiotropic variants |
| url | http://www.sciencedirect.com/science/article/pii/S2666247722000756 |
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