BCOR mutations deregulate cell cycle and hypoxic adaptation pathways in retinoblastoma.

Retinoblastoma (RB) is the most common pediatric eye cancer. Most cases of RB are initiated by bi-allelic mutational inactivation of the RB1 gene, yet most RB tumors harbor additional genomic aberrations that may promote tumor progression. After RB1, the gene that is most commonly mutated gene in RB is BCOR, which is mutated in approximately 20% of RB tumors and is associated with a more aggressive tumor phenotype and worse patient outcomes. Despite its importance, little is known about the role of BCOR in RB. Here, we interrogated BCOR in low passage RB cell lines using mass spectrometry, chromatin immunoprecipitation sequencing, and RNA sequencing. We show that the BCOR protein interacts with members of the ncPRC1.1 Polycomb Repressive Complex and localizes at gene loci with traditionally activating and repressing chromatin markers. Loss of BCOR downregulates the expression of genes associated with cell cycle regulation and upregulates genes associated with hypoxic adaptation. We conclude that BCOR mutations slow cell proliferation and drive hypoxic adaptation in RB via epigenetic mechanisms that may be amenable to targeted therapy. Implications: This study reveals that BCOR may play a noncanonical, multi-faceted role in retinoblastoma with implications in cell cycle, differentiation, and hypoxic adaptation, ultimately shedding insight into its molecular framework for future therapeutic strategies.