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The nature of the retinal cell-type-specific circuitry that predisposes to retinoblastoma is demonstrated, in which a program that is unique to post-mitotic human cone precursors sensitizes to the oncogenic effects of retinoblastoma (Rb) protein depletion; hence, the loss of Rb collaborates with the molecular framework of cone precursors to initiate tumorigenesis. Origins of retinoblastoma Inactivation of both alleles of the retinoblastoma ( RB ) gene generally leads to the formation of retinoblastomas, but rarely to other tumour types. David Cobrinik and colleagues now provide an explanation for this in a study that identifies the human retinal cell-of-origin from which retinoblastomas arise. They find that of the various human retinal cell types, cone precursor cells are uniquely sensitive to transformation upon loss of RB . This is due to the cone precursor cell-specific molecular framework, for example, the high expression levels of MDM2 and MYCN which can collaborate with RB loss. These principles may more generally explain why certain initiating oncogenic mutations tend to be associated with specific cancer types. Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers 1 , 2 , 3 , 4 , 5 , germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies 6 . This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear 7 , 8 . Here we show that post-mitotic human cone precursors are uniquely sensitive to Rb depletion. Rb knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN and MDM2. Proliferation of Rb-depleted cones and retinoblastoma cells also depended on the Rb-related protein p107, SKP2, and a p27 downregulation associated with cone precursor maturation. Moreover, Rb-depleted cone precursors formed tumours in orthotopic xenografts with histological features and protein expression typical of human retinoblastoma. These findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. More generally, they demonstrate that cell-type-specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis.

BackgroundRetinoblastoma, the most common childhood eye cancer, can be fatal if untreated. We report the presentations and outcomes of children presenting with retinoblastoma since the paediatric oncology unit in Sierra Leone was established in 2017.MethodsA retrospective case series of retinoblastoma cases from 2017 to date presenting to Ola During Children’s Hospital is presented. Data were collected from records and reviewed for presentation, treatment, and outcomes.Results50 cases were identified from 2017 to January 2023. The average age of presentation was 33 months, with a range of 5-83 months. 21 cases (42%) were female. There was a family history of retinoblastoma in 2 cases (4%). 39 cases (78%) were unilateral and 8 (16%) were bilateral. 40 cases had a known presenting complaint; 33 (82.5%) presented with proptosis, 4 (10%) with leukocoria and the remainder with strabismus, cloudy cornea or incidentally upon screening. The median number of months between caregiver-reported symptom onset to diagnosis was 3 months (IQR 4 months). 13 patients completed the treatment of chemotherapy and enucleation, however 5 later died from presumed metastasis (n=3, 23.1%) and febrile illness (n=2, 15.4%). Outcomes were that 28 cases (56%) of cases died, 8 (16%) were discharged successfully after treatment, 1 remains on treatment, 11 did not engage so outcomes are unknown and 2 had missing records.ConclusionAdvanced stage of presentation accounts for high mortality even in treated cases. Interventions including family support team involvement, improved diagnostics and follow-up of cases, advocacy and education of health workers and stakeholders may improve outcome.

About half of the human genome is composed of repeated sequences derived from mobile elements, mainly retrotransposons, generally without pathogenic effect. Familial forms of retinoblastoma are caused by germline pathogenic variants in RB1 gene. Here, we describe a family with retinoblastoma affecting a father and his son. No pathogenic variant was identified after DNA analysis of RB1 gene coding sequence and exon-intron junctions. However, RB1 mRNA analysis showed a chimeric transcript with insertion of 114 nucleotides from HPF1 gene inside RB1 gene. This chimeric transcript led to an insertion of 38 amino acids in functional domain of retinoblastoma protein. Subsequent DNA analysis in RB1 intron 17 revealed the presence of a full-length HPF1 retrogene insertion in opposite orientation. Functional assay shows that this insertion has a deleterious impact on retinoblastoma protein function. This is the first report of a full-length retrogene insertion involved in human Mendelian disease leading to a chimeric transcript and a non-functional chimeric protein. Some retrogene insertions may be missed by standard diagnostic genetic testing, so contribution of retrogene insertions to human disease may be underestimated. The increasing use of whole genome sequencing in diagnostic settings will help to get a more comprehensive view of retrogenes.

The Retinoblastoma (Rb) family of pocket proteins (p107, Rb, and p130) controls all aspects of neurogenesis from stem cell activation to long-term neuronal survival in the brain. Previous studies have reported non-overlapping, often complementary, roles for these cell cycle regulators with possibility for functional compensation. Yet the extent to which each protein might compensate for other family members and whether synergistic effects exist during neural stem cell (NSC) lineage development remain unclear. Fong et al. recently revealed that a triple knock-out (TKO) of all pocket proteins results in a transcriptomic switch from NSC quiescence to activation, followed by niche depletion in the adult hippocampus. Here, we investigated whether pocket proteins are equally critical in NSC fate regulation in the adult subventricular zone (aSVZ) and during embryogenesis. We report that TKO of these proteins results in NSC activation coupled to ectopic progenitor proliferation and massive apoptosis, leading to niche depletion and premature loss of neurogenesis inside the olfactory bulb (OB). Notably, a p107–p130 double knockout carrying a single wild-type Rb allele (DKO) substantially rescues the above defects and maintains adult neurogenesis. In comparison, TKO embryos display severe disruptions in all stages of neurogenesis at E14.5, leading to embryonic lethality. Similar defects are detected when any five out of the six alleles of pocket proteins are lost, with only partial rescue of the proliferation defects observed in DKO embryos. The above TKO phenotypes are partially mediated by opposed deregulations in the Notch-Hes signaling pathway in the embryonic versus the adult brain. Such deregulation is linked to opposite changes in E2F3a and E2F3b embryonic gene expressions. Our data identifies Rb as a critical pocket protein in the control and maintenance of adult OB neurogenesis, and uncovers interchangeable, dose-dependent roles for pocket proteins in the control of neuronal differentiation and survival during development.

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1 . Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo . Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss. The retinoblastoma genome is shown to be stable, but multiple cancer pathways are identified that are epigenetically deregulated, providing potential new therapeutic targets. SYK is a target in retinoblastoma Retinoblastoma is a rare and aggressive childhood cancer of the retina caused by loss of the RB1 gene. Whole-genome sequencing of four retinoblastomas now shows that the retinoblastoma genome is relatively stable, with a mutational rate among the lowest reported in human cancers and a remarkable lack of mutations in other tumour suppressor/oncogenic pathways. However, RB1 loss is associated with epigenetic deregulation of several cancer pathways. Significantly, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. A small-molecule inhibitor of SYK induced retinoblastoma tumour cell death in vitro and in vivo .

Retinoblastoma (Rb) is the most prevalent intraocular malignancy in children, with a worldwide survival rate <30%. We have developed a cancerous model of Rb in retinal organoids derived from genetically engineered human embryonic stem cells (hESCs) with a biallelic mutagenesis of the RB1 gene. These organoid Rbs exhibit properties highly consistent with Rb tumorigenesis, transcriptome, and genome-wide methylation. Single-cell sequencing analysis suggests that Rb originated from ARR3-positive maturing cone precursors during development, which was further validated by immunostaining. Notably, we found that the PI3K-Akt pathway was aberrantly deregulated and its activator spleen tyrosine kinase (SYK) was significantly up-regulated. In addition, SYK inhibitors led to remarkable cell apoptosis in cancerous organoids. In conclusion, we have established an organoid Rbmodel derived from genetically engineered hESCs in a dish that has enabled us to trace the cell of origin and to test novel candidate therapeutic agents for human Rb, shedding light on the development and therapeutics of other malignancies.

Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in 13 C-glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate α-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly regulates a major energetic and anabolic pathway that is required for neoplastic growth.

Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations. Of 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations (RB1+/+) with tumours carrying a mutation in both alleles (RB1−/−). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data. No RB1 mutations (RB1+/+) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1+/+ tumours had high-level MYCN oncogene amplification (28–121 copies; RB1+/+MYCNA), whereas none of 93 RB1−/− primary tumours tested showed MYCN amplification (p<0·0001). RB1+/+MYCNA tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1−/− tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1+/+MYCNA retinoblastoma. One additional MYCNA tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1+/+MYCNA tumours was 4·5 months (IQR 3·5–10), compared with 24 months (15–37) for 79 children with non-familial unilateral RB1−/− retinoblastoma. Amplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1+/+MYCNA retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis. National Cancer Institute–National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa.

For outstanding visual clarity in ocular diagnosis … nothing else comes close. In this updated and revised third edition, world-renowned authorities at the Wills Eye Hospital provide outstanding guidance on recognition, evaluation, and treatment of ocular tumors, highlighted by more than 2,500 stunning photographs and surgical drawings. This unsurpassed ocular oncology resource is a comprehensive guide to the clinical features, diagnosis, management, and pathology of intraocular tumors and pseudotumors, depicting clinical variations, treatment, and histopathologic characteristics of the many varied benign and malignant lesions that affect the uveal tract, retina, and other intraocular structures. Now brought thoroughly up to date with recent clinical and scientific innovations, this unique volume has been greatly expanded with over 25% new material, and offers more high-quality images than any other text/atlas in the field. Presents each entity in an easy-to-follow format: a concise description with references on the left-hand page and six illustrations on the right-hand page. Depicts in precise photographic detail the gross and microscopic features that distinguish each condition, while professional drawings and intraoperative photographs demonstrate key surgical principles and procedures. Features numerous new references regarding diagnosis and treatment, as well as new scientific tables containing key information for your clinical practice. Features 25% new images, including panoramic images, surgical images, diagnostic testing images from multiple modalities, and updated OCT images with numerous enhanced depth imaging OCT (EDI-OCT). Covers new information on evolving conditions such as the management of choroidal nevus and melanoma with guidance for early detection using risk factors; information on the newest treatment for retinoblastoma with intra-arterial and intravenous chemotherapy; management of intraocular tumors with photodynamic therapy. Important new information on genetics of uveal melanoma, the implications of genetics, and treatment outcomes is described

The retinoblastoma (RB) tumor suppressor is known as a master regulator of the cell cycle. RB is mutated or functionally inactivated in the majority of human cancers. This transcriptional regulator exerts its function in cell cycle control through its interaction with the E2F family of transcription factors and with chromatin remodelers and modifiers that contribute to the repression of genes important for cell cycle progression. Over the years, studies have shown that RB participates in multiple processes in addition to cell cycle control. Indeed, RB is known to interact with over 200 different proteins and likely exists in multiple complexes. RB, in some cases, acts through its interaction with E2F1, other members of the pocket protein family (p107 and p130), and/or chromatin remodelers and modifiers. RB is a tumor suppressor with important chromatin regulatory functions that affect genomic stability. These functions include the role of RB in DNA repair, telomere maintenance, chromosome condensation and cohesion, and silencing of repetitive regions. In this review we will discuss recent advances in RB biology related to RB, partner proteins, and their non-transcriptional functions fighting back against genomic instability.