Inherited rare variants in homologous recombination and neurodevelopmental genes are associated with increased risk of neuroblastoma

Ferdinando Bonfiglio; Vito Alessandro Lasorsa; Sueva Cantalupo; Giuseppe D'Alterio; Vincenzo Aievola; Angelo Boccia; Martina Ardito; Simone Furini; Alessandra Renieri; Martina Morini; Sabine Stainczyk; Frank Westermann; Giovanni Paolella; Alessandra Eva; Achille Iolascon; Mario Capasso

doi:10.1016/j.ebiom.2022.104395

Inherited rare variants in homologous recombination and neurodevelopmental genes are associated with increased risk of neuroblastoma

EBioMedicine. 2023 Jan:87:104395. doi: 10.1016/j.ebiom.2022.104395. Epub 2022 Dec 6.

Authors

Ferdinando Bonfiglio¹, Vito Alessandro Lasorsa², Sueva Cantalupo², Giuseppe D'Alterio³, Vincenzo Aievola², Angelo Boccia⁴, Martina Ardito⁵, Simone Furini⁶, Alessandra Renieri⁶, Martina Morini⁵, Sabine Stainczyk⁷, Frank Westermann⁷, Giovanni Paolella², Alessandra Eva⁵, Achille Iolascon², Mario Capasso⁸

Affiliations

¹ CEINGE Biotecnologie Avanzate s.c.ar.l., Naples, Italy; Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Naples, Italy.
² CEINGE Biotecnologie Avanzate s.c.ar.l., Naples, Italy; Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.
³ CEINGE Biotecnologie Avanzate s.c.ar.l., Naples, Italy; European School of Medical Medicine, University of Milan, Milan, Italy.
⁴ CEINGE Biotecnologie Avanzate s.c.ar.l., Naples, Italy.
⁵ Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Genova, Italy.
⁶ Department of Medical Biotechnologies, University of Siena, Siena, Italy.
⁷ Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
⁸ CEINGE Biotecnologie Avanzate s.c.ar.l., Naples, Italy; Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy. Electronic address: mario.capasso@unina.it.

Abstract

Background: Neuroblastoma (NB) is the most common solid extracranial paediatric tumour. Genome-wide association studies have driven the discovery of common risk variants, but no large study has investigated the contribution of rare variants to NB susceptibility. Here, we conducted a whole-exome sequencing (WES) of 664 NB cases and 822 controls and used independent validation datasets to identify genes with rare risk variants and involved pathways.

Methods: WES was performed at 50× depth and variants were jointly called in cases and controls. We developed two models to identify mutations with high clinical impact (P/LP model) and to discover less penetrant risk mutations affecting non-canonical cancer pathways (RPV model). We performed a gene-level collapsing test using Firth's logistic regression in 242 selected cancer predisposition genes (CPGs) and a gene-sets burden analysis of biologically-informed pathways.

Findings: Twelve percent of patients carried P/LP variants in CPGs and showed a significant enrichment (P = 2.3 × 10^-4) compared to controls (6%). We identified P/LP variants in 45 CPGs enriched in homologous recombination (HR) pathway. The most P/LP enriched genes in NB were BRCA1, ALK and RAD51C. Additionally, we found higher RPV burden in gene-sets of neuron differentiation, neural tube development and synapse assembly, and in gene-sets associated with neurodevelopmental disorders (NDD).

Interpretation: The high fraction of NB patients with P/LP variants indicates the need of genetic counselling. Furthermore, inherited rare variants predispose to NB development by affecting mechanisms related to HR and neurodevelopmental processes, and demonstrate that NDD genes are altered in NB at the germline level.

Funding: Associazione Italiana per la Ricerca sul Cancro, Fondazione Italiana per la Lotta al Neuroblastoma, Associazione Oncologia Pediatrica e Neuroblastoma, Regione Campania, Associazione Giulio Adelfio onlus, and Italian Health Ministry.

Keywords: Genetic susceptibility; Neuroblastoma; Rare variants; Whole-exome sequencing.

MeSH terms

Child
Genetic Predisposition to Disease*
Genome-Wide Association Study
Homologous Recombination
Humans
Mutation
Neuroblastoma* / genetics