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, 20 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify previously unknown 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 previously unidentified 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

“…Other over‐represented biological process ontologies included mitotic cytokinesis and sister chromatid segregation , cell adhesion mediated by integrin , semaphorin‐plexin signaling , and phosphatidylinositol phosphorylation , suggesting other tumor progression mechanisms. Additionally, using pathway analysis, Field et al connected several secondary mutations 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 identified herein, although this could relate to deficiencies in ontology annotation databases.…”

“…Concordantly, only ~50% of SNVs were enriched during cell line establishment and variants in recurrently altered genes implicated in retinoblastoma oncogenesis were not always retained, including two inactivating BCOR variant alleles. In line with this finding, Field et al proposed that BCOR loss enables retinoblastoma cell survival under hypoxic conditions, 14 a function that would have no advantage in the hyperoxic tissue culture setting. CHLA‐VC‐RB cell lines also had over‐representation of variants related to the p53‐mediated DNA damage response.…”

“…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 identified herein, although this could relate to deficiencies in ontology annotation databases. For example, if BCOR had been annotated as a repressor of hypoxic adaptation, as suggested, 14 then hypoxic response ontologies would likely have been identified.…”

“…The most commonly altered genes were BCOR with somatic variants in 20 tumors, CREBBP with variants in three, and nine other genes with variants in two of the 156 samples (Tables S1, S2). 6,11–13 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.…”

“…Gene ontology and protein interaction network analyses may be used to identify recurrently altered cellular functions or provide clues to affected pathways in the absence of significantly recurrently altered genes 14,17 . While these approaches are often applied to non‐synonymous variants, they rarely include synonymous and non‐coding variants owing to their presumed passenger status.…”