Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival
A partir du séquençage génomique de l'ADN de 786 patients atteints d'un neuroblastome, cette étude met en évidence une association entre la présence de variants constitutionnels pathogènes ou probablement pathogènes au niveau du gène BARD1 et un pronostic défavorable
Background : Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic (P-LP) germline variants in patients without a family history remains unclear.
Methods : Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene (CPG) P-LP variants in cases was compared to two cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for “second hits” and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs). Patients with germline P-LP variants were compared to those without to test for association with clinical characteristics, tumor features, and survival.
Results : We observed 116 P-LP variants involving 13.9% (109/786) of patients, representing a significant excess burden compared to controls (odds ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant enrichment of P-LP variants (odds ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were identified in patients but absent in controls (odds ratio: 29.47, 95% confidence interval: 1.52–570.70). Patients harboring a germline P-LP variant had a worse overall survival compared to those without (P = 8.6x10−3).
Conclusions : BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline P-LP variation. The presence of any germline P-LP variant in a CPG was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation.
Journal of the National Cancer Institute , résumé, 2022