Abstract Background FOXR2 is a forkhead box transcription factor implicated in central nervous system neuroblastoma (CNS-NB FOXR2). The underlying genetic mechanisms and clinical features of CNS-NB FOXR2 have yet to be elucidated. Methods Six CNS-NB FOXR2 cases were identified through DNA methylation profiling. Optical genome mapping, chromosomal microarray, whole genome sequencing, OncoKids panel, RNA-sequencing, and clinical data were analyzed. Results Case 1 demonstrated a 13-kb insertion approximately 25 kb upstream of FOXR2. Case 2 showed two non-contiguous focal gains in Xp11.21 (encompassing FOXR2) and Xp22.2p22.13, approximately 37 Mb apart, resulting from a complex rearrangement disrupting the FOXR2 regulatory region. Case 3 harbored a pericentric inversion between RLIM and a site 17.98 kb upstream of FOXR2. Recurrent copy number alterations included 1q gain (100%), 16q loss (80%), distal 11q loss (60%), and gain of chromosomes 8 and 17q (40% each). All three female patients showed X chromosome loss. FOXR2 expression was elevated in both cases with available RNA-seq data. Overall survival ranged from 1.81-15.62 years. Clinical treatment was highly variable, and molecular testing was unavailable at diagnosis for 4 of 5 patients. Conclusions Structural disruption of the FOXR2 regulatory region, recurrent copy number alterations, and elevated FOXR2 expression are features of CNS-NB FOXR2. These rearrangements do not alter the coding region and may not be detected by routine testing. Initial pathology may suggest other entities, highlighting the importance of molecular testing at diagnosis. Favorable clinical outcomes require accurate initial diagnosis as evidenced by our clinical cohort.
Ji et al. (2026) studied this question.