Differences in Genomic Profiles and Outcomes between Thoracic and Adrenal Neuroblastoma

A partir de données portant sur 764 puis 1 027 patients atteints d'un neuroblastome, cette étude compare les profils génomiques des neuroblastomes de la glande surrénale et des neuroblastomes des ganglions sympathiques du thorax, puis évalue l'association entre des variants génétiques constitutionnels et la localisation de la tumeur

Résumé en anglais

Background : Neuroblastoma is a biologically and clinically heterogeneous disease. Based on recent studies demonstrating an association between the primary tumor site, prognosis, and commonly measured tumor biological features, we hypothesized that neuroblastomas arising in different sites would show distinct genomic features reflective of the developmental biology of the sympathicoadrenal nervous system.

Methods : We first compared genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (N = 646) compared to thoracic sympathetic ganglia (N = 118). We also evaluated association of common germline variation with these primary sites in 1,027 European-American neuroblastoma patients.

Results : We observed higher rates of MYCN amplification, chromosome 1q gain, and chromosome 11q deletion among adrenal tumors, which were highly predictive of functional RNA signatures. Surprisingly, thoracic neuroblastomas were more likely to harbor ALK driver mutations than adrenal cases among all cases (OR = 1.89, 95% CI = 1.04-3.43), and among cases without MYCN amplification (OR = 2.86, 95% CI = 1.48-5.49). Common germline SNPs in BARD1 (previously associated with high-risk neuroblastoma) were found to be strongly associated with predisposition for origin at adrenal, rather than thoracic, sites.

Conclusions : Neuroblastomas arising in the adrenal gland are more likely to harbor structural DNA aberrations including MYCN amplification, whereas thoracic tumors show defects in mitotic checkpoints resulting in hyperdiploidy. Despite the general association of ALK mutations with high-risk disease, thoracic tumors are more likely to harbor gain-of-function ALK aberrations. Site of origin is likely reflective of stage of sympathetic nervous system development when malignant transformation occurs and is a surrogate for underlying tumor biology.