The Non‐Coding Regulatory Variant rs2863002 at chr11p11.2 Increases Neuroblastoma Risk by Affecting <i>HSD17B12</i> Expression and Lipid Metabolism
A Genome-wide association study (GWAS) on a European-American cohort identified chr11p11.2 as a neuroblastoma predisposition locus. Combining in-house and public genomic data from neuroblastoma cell lines, this work implicates rs2863002 as the candidate causal variant at the 11p11.2 locus, confirming its cis-regulatory activity through a luciferase reporter assay. The genetic association of rs2863002 with neuroblastoma risk is validated in an Italian case-control cohort. Using ChIP-qPCR, Hi-C, and CRISPR genome editing, this work deciphers the regulatory mechanisms at the risk locus, demonstrating that the rs2863002-C risk allele regulates HSD17B12 expression and reduces GATA3 binding affinity. In vitro functional assays and targeted lipidomic analyses reveal the involvement of the rs2863002-C risk allele in tumorigenicity and modulation of lipid metabolism in neuroblastoma cells through HSD17B12 regulation. This study provides new insights into the genetic basis of neuroblastoma and underscores the importance of post-GWAS functional characterization of risk loci in uncovering relevant biological findings for understanding complex diseases.
Authors
- John M. Maris (ORCID: https://orcid.org/0000-0002-8088-7929)
- Vito Alessandro Lasorsa (ORCID: https://orcid.org/0000-0002-9552-7192)
- Ferdinando Bonfiglio (ORCID: https://orcid.org/0000-0003-2488-3867)
- Lucia Mauriello
- Achille Iolascon (ORCID: https://orcid.org/0000-0002-9558-0356)
- Martina Morini (ORCID: https://orcid.org/0000-0003-2569-4515)
- Martina Ardito (ORCID: https://orcid.org/0000-0002-6008-9356)
- Teresa Maiorino (ORCID: https://orcid.org/0000-0003-3005-7836)
- Alessandra Eva (ORCID: https://orcid.org/0000-0003-2949-078X)
- Marianna Caterino (ORCID: https://orcid.org/0000-0001-8228-0963)
- Margherita Ruoppolo (ORCID: https://orcid.org/0000-0002-7364-0602)
- Vincenzo Aievola (ORCID: https://orcid.org/0000-0001-7671-1034)
- Sharon J. Diskin (ORCID: https://orcid.org/0000-0002-7200-8939)
- Matilde Tirelli (ORCID: https://orcid.org/0009-0001-6778-5151)
- Mario Capasso (ORCID: https://orcid.org/0000-0003-3306-1259)
- Marianna Avitabile (ORCID: https://orcid.org/0000-0002-5352-6503)
- Annalaura Montella (ORCID: https://orcid.org/0000-0003-0858-228X)
- Vincenza Cerbone
- Sueva Cantalupo (ORCID: https://orcid.org/0000-0001-6173-281X)
- Mariagrazia Cantalupo
- Gilda Estinto
Institutions
- Children's Hospital of Philadelphia (US)
- Istituto Giannina Gaslini (IT)
- Federico II University Hospital (IT)
- CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Naples Federico II (IT)
- University of Pennsylvania (US)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1002/advs.202415181
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fondazione Italiana per la Lotta al Neuroblastoma
- Associazione Oncologia Pediatrica e Neuroblastoma ONLUS
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health