RB1 loss triggers dependence on ESRRG in retinoblastoma

Abstract

Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 16 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify novel Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death which is exacerbated in hypoxia. These findings reveal a novel dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb.

Non-Synonymous, Synonymous, and Non-Coding Nucleotide Variants Contribute to Recurrently Altered Biological Processes During Retinoblastoma Progression

“…Using pathway analysis, Field et al . observed that some secondary mutations could be connected in a protein interaction network that included the estrogen-related receptor ESRRG, which in turn was implicated in the retinoblastoma cell hypoxic response 14 . ESRRG- and hypoxic response-related ontologies were not enriched in our over-representation analyses or in an Ingenuity pathway analysis of the 542 somatic variants, though this could relate to deficiencies in ontology enrichment databases.…”

“…In line with this finding, Field et al . have proposed that BCOR represses ESRRG1 to enable a hypoxic survival response, a function that would have no advantage in the hyperoxic tissue culture setting 14 . CHLA-VC-RB cell lines also had over-representation of ATM, SPRED1 , and PYHIN1 variants related to the p53-mediated DNA damage response.…”

“…Other overrepresented biological process ontologies also included mitotic cytokinesis and sister chromatid segregation, cell adhesion mediated by integrin, semaphorin-plexin signaling, and phosphatidylinositol phosphorylation, suggesting additional tumor progression-related mechanisms. Using pathway analysis, Field et al observed that some secondary mutations could be connected in a protein interaction network that included the estrogenrelated receptor ESRRG, which in turn was implicated in the retinoblastoma cell hypoxic response 14 . ESRRG-and hypoxic response-related ontologies were not enriched in our over-representation analyses or in an Ingenuity pathway analysis of the 542 somatic variants, though this could relate to deficiencies in ontology enrichment databases.…”

“…In contrast to highly recurrent SCNAs, prior whole genome or exome sequencing (WGS/WES) of 156 treatment-naïve retinoblastomas revealed no significantly recurrently altered genes with exome tier-1 mutations, according to standard metrics 10 , despite identification of BCOR variants in 20, CREBBP variants in three, and 10 genes in two samples (Supplementary Tables S1, S2) 6,[11][12][13] . A similar number of genes had multiple mutations in a more recent analysis of 103 retinoblastomas 14 and ultra-sensitive targeted sequencing revealed additional mutated genes 15,16 , yet significantly recurrently altered cellular functions have not been identified.…”