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

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

doi:10.1016/j.ebiom.2022.104395

Cited by 11 publications

(10 citation statements)

References 57 publications

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“…WES data in the format of FASTQ files were produced internally on Illumina HiSeq instrument (Â50 target depth in average) as previously described, 20 or downloaded from dbGaP and stored on a secure high performance computing system. Each sample set was processed with the same bioinformatic pipeline based on Genome Analysis Toolkit (GATK) best practice.…”

Section: Ngs Data Processingmentioning

confidence: 99%

“…18,19 More recently, in a large whole exome sequencing (WES) case-control study, we found a significantly higher percentage of rare germline pathogenetic variants among NB patients (12%) rather than in controls (6%). 20 However, the currently known genetic risk factors explain just a small fraction of the NB heritability, 21 suggesting that other genetic factors remain to be discovered.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the role of HLA variants in neuroblastoma susceptibility through whole exome sequencing

Bonfiglio,

Lasorsa,

Aievola

et al. 2024

HLA

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Although a number of susceptibility loci for neuroblastoma (NB) have been identified by genome‐wide association studies, it is still unclear whether variants in the HLA region contribute to NB susceptibility. In this study, we conducted a comprehensive genetic analysis of variants in the HLA region among 724 NB patients and 2863 matched controls from different cohorts. We exploited whole‐exome sequencing data to accurately type HLA alleles with an ensemble approach on the results from three different typing tools, and carried out rigorous sample quality control to ensure a fine‐scale ancestry matching. The frequencies of common HLA alleles were compared between cases and controls by logistic regression under additive and non‐additive models. Population stratification was taken into account adjusting for ancestry‐informative principal components. We detected significant HLA associations with NB. In particular, HLA‐DQB1*05:02 (OR = 1.61; padj = 5.4 × 10−3) and HLA‐DRB1*16:01 (OR = 1.60; padj = 2.3 × 10−2) alleles were associated to higher risk of developing NB. Conditional analysis highlighted the HLA‐DQB1*05:02 allele and its residue Ser57 as key to this association. DQB1*05:02 allele was not associated to clinical features worse outcomes in the NB cohort. Nevertheless, a risk score derived from the allelic combinations of five HLA variants showed a substantial predictive value for patient survival (HR = 1.53; p = 0.032) that was independent from established NB prognostic factors. Our study leveraged powerful computational methods to explore WES data and HLA variants and to reveal complex genetic associations. Further studies are needed to validate the mechanisms of these interactions that contribute to the multifaceted pattern of factors underlying the disease initiation and progression.

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Section: Ngs Data Processingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the role of HLA variants in neuroblastoma susceptibility through whole exome sequencing

Bonfiglio,

Lasorsa,

Aievola

et al. 2024

HLA

Self Cite

View full text Add to dashboard Cite

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“…Studies of genome-wide association (GWAS) and mutational screening of cancer predisposition genes in large cohorts have identified GWAS polymorphic variants and pathogenic/likely pathogenic (P/LP) germline mutations, respectively, in BARD1 [4][5][6][7][8][9][10][11][12][13][14][15][16][17] . BARD1 encodes the BRCA1associated RING domain 1 protein which forms the BRCA1-BARD1 heterodimer to repair DNA double-strand breaks by homologous recombination.…”

Section: Mainmentioning

confidence: 99%

Clinical Response to a PARP Inhibitor and Chemotherapy in a Child with BARD1-Mutated Refractory Neuroblastoma: A Case Report

Federico,

Cupit-Link,

Hagiwara

et al. 2023

Preprint

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Despite advances in the treatment of high-risk neuroblastoma, approximately half of these patients die from the disease. Targeted therapy based on synthetic lethality associated with homologous recombination deficiency (HRD) caused by germline mutations in homologous recombination repair genes has shown great efficacy in several adult solid tumors. Here we report the first successful treatment of a pediatric patient with refractory neuroblastoma and a germline pathogenic mutation in BARD1 using a PARP inhibitor, talazoparib, in combination with cytotoxic chemotherapy and radiation therapy. Allele-specific expression in RNA-seq indicates bi-allelic loss of BARD1 in tumor; however, the HRD score was below the threshold currently used for HRD classification in adult cancers. Our study demonstrates that the use of PARP inhibition in combination with DNA-damaging agents should be considered in children with BARD1-mutated neuroblastoma and cautions against the use of HRD score alone as a biomarker for this pediatric population.

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“…Given the neural origin of neuroblastoma and the active neurodevelopmental processes involved in tumor formation, elucidating the intricate interplay among age, neuroblastoma, outcome, and neurodevelopment is paramount for optimizing treatment strategies and improving long-term outcomes for affected children [ 2 , 3 ]. However, the relationship between neurodevelopmental mechanisms and the outcome of neuroblastoma has not been fully explored [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Cell communication pathway prognostic model identified detrimental neurodevelopmental pathways in neuroblastoma

Wang,

Li,

Xue

et al. 2024

Neoplasia

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

Cited by 11 publications

References 57 publications

Exploring the role of HLA variants in neuroblastoma susceptibility through whole exome sequencing

Exploring the role of HLA variants in neuroblastoma susceptibility through whole exome sequencing

Clinical Response to a PARP Inhibitor and Chemotherapy in a Child with BARD1-Mutated Refractory Neuroblastoma: A Case Report

Cell communication pathway prognostic model identified detrimental neurodevelopmental pathways in neuroblastoma

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