Retinoblastoma is a malignancy arising in the retina, mostly diagnosed in youn children; two-thirds of all cases of retinoblastoma are diagnosed before age 2 years, and 95% before age 5 years. Between 25–30% of Retinoblastoma cases are heritable, having a germline mutation of the RB1 gene. The heritable cases are more likely to be bilateral (both eyes) and younger age, compared to the 70-75% of nonheritable cases. For children with germline mutation of RB1, approximately 25% are inherited from an affected parent, while 75% are thought to have occurred in utero at the time of conception. (Source: National Cancer Institute).

The penetrance of the RB1 mutation in retinoblastoma is thought to be dependent on concurrent genetic modifiers, in particular MDM2 and MDM4. In a family-based association analyses of 212 mutation carriers in 70 retinoblastoma families, Castéra L et al, 2010 reported a strong association between the MDM2 309G allele and incidence of bilateral or unilateral retinoblastoma among members of retinoblastoma families (p<0.001). de Oliveira Reis AH et al, 2012 reported findings that suggest that MDM2 and MDM4 polymorphisms may influence development and/or survival in RB.

See also: Retinoblastoma - clinical resources (12)

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (27)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 Germline
-RB1 mutation in Retinoblastoma
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 Amplification
-MYCN Amplification in Retinoblastoma
RBL2 16q12.2 Rb2, P130 -RBL2 and Retinoblastoma
MDM2 12q15 HDMX, hdm2, ACTFS -MDM2 and Retinoblastoma
MDM4 1q32.1 HDMX, MDMX, MRP1 -MDM4 and Retinoblastoma
E2F3 6p22.3 E2F-3 -E2F3 and Retinoblastoma
RBL1 20q11.23 PRB1, p107, CP107 -RBL1 and Retinoblastoma
PRB1 12p13.2 PM, PMF, PMS, PRB1L, PRB1M -PRB1 and Retinoblastoma
KIF14 1q32.1 MKS12, MCPH20 -KIF14 and Retinoblastoma
DEK 6p22.3 D6S231E -DEK and Retinoblastoma
CDH11 16q21 OB, CAD11, CDHOB, OSF-4 -CDH11 and Retinoblastoma
PRB2 12p13.2 Ps, cP7, IB-9, PRPPRB1 -PRB2 and Retinoblastoma
CDK6 7q21.2 MCPH12, PLSTIRE -CDK6 and Retinoblastoma
OTX2 14q22.3 CPHD6, MCOPS5 -OTX2 and Retinoblastoma
CDH13 16q23.3 CDHH, P105 -CDH13 and Retinoblastoma
CD82 11p11.2 R2, 4F9, C33, IA4, ST6, GR15, KAI1, SAR2, TSPAN27 -CD82 and Retinoblastoma
RXRA 9q34.2 NR2B1 -RXRA and Retinoblastoma
DDX1 2p24 DBP-RB, UKVH5d Amplification
-DDX1 Amplification in Retinoblastoma cell lines
EZH2 7q36.1 WVS, ENX1, EZH1, KMT6, WVS2, ENX-1, EZH2b, KMT6A -EZH2 and Retinoblastoma
CHAT 10q11.23 CMS6, CMS1A, CMS1A2, CHOACTASE -CHAT and Retinoblastoma
NEUROG1 5q31.1 AKA, ngn1, Math4C, bHLHa6, NEUROD3 -NEUROG1 and Retinoblastoma
PDCD10 3q26.1 CCM3, TFAR15 -PDCD10 and Retinoblastoma
HLA-B 6p21.33 AS, HLAB, B-4901 -HLA-B and Retinoblastoma
HLA-C 6p21.33 MHC, HLAC, HLC-C, D6S204, PSORS1, HLA-JY3 -HLA-C and Retinoblastoma
MIRLET7E 19q13.41 LET7E, let-7e, MIRNLET7E, hsa-let-7e -MicroRNA let-7e and Retinoblastoma
RCVRN 17p13.1 RCV1 -RCVRN and Retinoblastoma
CACNA1G 17q21.33 NBR13, SCA42, Cav3.1, Ca(V)T.1 -CACNA1G and Retinoblastoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Recurrent Chromosome Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
i(6p10) in RetinoblastomaIsochromosome

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

i(6p10) in Retinoblastoma

Gain of the short arm of chromosome 6, usually through isochromosome 6p formation, is present in approximately 50% of retinoblastoma tumors. The minimal region of gain maps to chromosome band 6p22. Paderova et al (2007) suggested these may be due to translocations.

Horsthemke B, Greger V, Becher R, Passarge E
Mechanism of i(6p) formation in retinoblastoma tumor cells.
Cancer Genet Cytogenet. 1989; 37(1):95-102 [PubMed] Related Publications
Isochromosome (6p) represents a highly characteristic cytogenetic abnormality of human retinoblastoma (RB) cells and may be important for tumor progression. To elucidate the mechanism by which this abnormal chromosome is formed, 24 RB tumors and three cell lines were studied by means of DNA polymorphisms specific for the short arm and the long arm of chromosome 6. Our results indicate that mitotic nondisjunction leading to trisomy 6 precedes the isochromosome formation. The isochromosome may then be formed by transverse division of the centromere or intrachromosomal chromatid exchange.

Paderova J, Orlic-Milacic M, Yoshimoto M, et al.
Novel 6p rearrangements and recurrent translocation breakpoints in retinoblastoma cell lines identified by spectral karyotyping and mBAND analyses.
Cancer Genet Cytogenet. 2007; 179(2):102-11 [PubMed] Related Publications
Gain of the short arm of chromosome 6, usually through isochromosome 6p formation, is present in approximately 50% of retinoblastoma tumors. The minimal region of gain maps to chromosome band 6p22. Two genes, DEK and E2F3, are implicated as candidate oncogenes. However, chromosomal translocations have been overlooked as a potential mechanism of activation of oncogenes at 6p22 in retinoblastoma. Here, we report combined spectral karyotyping), 4',6-diamidino-2-phenylindole banding, mBAND, and locus-specific fluorescence in situ hybridization analyses of four retinoblastoma cell lines, RB1021, RB247c, RB383, and Y79. In RB1021 and RB247c, 6p undergoes structural rearrangements involving a common translocation breakpoint at 6p22. These data imply that 6p translocations may represent another mechanism of activation of 6p oncogene(s) in a subset of retinoblastomas, besides the copy number increase. In addition to 6p22, other recurrent translocation breakpoints identified in this study are 4p16, 11p15, 17q21.3, and 20q13. Common regions of gain map to chromosomal arms 1q, 2p, 6p, 17q, and 21q.

Latest Publications

Choudhury AD, Beltran H
Retinoblastoma Loss in Cancer: Casting a Wider Net.
Clin Cancer Res. 2019; 25(14):4199-4201 [PubMed] Article available free on PMC after 15/01/2020 Related Publications
Capturing both genomic and nongenomic mechanisms of retinoblastoma gene dysfunction has potential to improve risk stratification and patient selection for biomarker-driven therapy. A 186-gene expression signature is capable of identifying Rb loss across cancer types, providing a new framework for assessing Rb dysfunction based on transcriptome data.

Yan G, Su Y, Ma Z, et al.
Long Noncoding RNA LINC00202 Promotes Tumor Progression by Sponging miR-3619-5p in Retinoblastoma.
Cell Struct Funct. 2019; 44(1):51-60 [PubMed] Related Publications
Retinoblastoma (RB) is the most common intraocular malignancy in childhood, and the prognosis in the advanced RB is poor. It is urgent to find novel therapeutic targets. Long noncoding RNAs (lncRNAs) have critical functions in cancer progression, and lncRNA LINC00202 is found associated with poor prognosis in RB. However, the functions of LINC00202 in RB remain unclear. We employed qRT-PCR and immunoblot to detect the expression levels of mRNAs and proteins, respectively. Cell proliferation was determined by CCK-8 assay and colony formation assay. Transwell assays were applied to evaluate the cell abilities of migration and invasion. Luciferase reporter assay was applied to examine RNA stability, and RNA pulldown assays were used to detect interaction between lncRNA and microRNA (miRNA). LINC00202 expression in RB tissues is higher than that in the paired adjacent normal tissues, which has correlation with poor prognosis in RB. RB cell proliferation, migration and invasion were weakened by LINC00202 depletion, but enhanced by LINC00202 overexpression. MiR-3619-5p was identified to directly bind and mediate LINC00202-promoted RB progression, meanwhile, miR-3619-5p directly regulated expression of an oncongene, RIN1. Moreover, RIN1 knockdown completely blocked miR-3619-5p-enhanced RB progression. In summary, high LINC00202 levels are correlated with poor prognosis in RB, and it promotes RB progression by sponging miR-3619-5p and therefore up-regulating RIN1 expression.Key words: LINC00202, miR-3619-5p, retinoblastoma, progression, RIN1.

Lyu X, Wang L, Lu J, et al.
microRNA‑485 inhibits the malignant behaviors of retinoblastoma by directly targeting Wnt3a.
Oncol Rep. 2019; 41(5):3137-3147 [PubMed] Related Publications
Deregulation of microRNAs (miRNAs) has been widely reported in retinoblastoma (RB), and the aberrantly expressed miRNAs may serve as crucial epigenetic regulators in the occurrence and development of RB. Therefore, the identification of dysregulated miRNAs in RB may be useful for the development of effective targets for the therapy patients with this disease. miRNA (miR)‑485‑5p (miR‑485) is deregulated in multiple human cancer types and serves crucial roles in their progression and development. However, the expression pattern of miR‑485 and its role in RB have not been well investigated. In the present study, expression levels of miR‑485 in RB tissues and cell lines were measured using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The effects of miR‑485 overexpression on RB cell proliferation, apoptosis, migration and invasion were examined using Cell Counting Kit‑8 assay, flow cytometric analysis and in vitro migration and invasion assays, respectively. Xenograft tumor formation assay was utilized to determine the influence of miR‑485 on RB tumor growth in vivo. The mechanism responsible for the tumor‑suppressing roles of miR‑485 in RB progression was determined through a series of experiments, including bioinformatics prediction, luciferase reporter assay, RT‑qPCR, western blot analysis and rescue experiments. Herein, a marked downregulation of miR‑485 expression in human RB tissues and cell lines was observed. miR‑485 overexpression suppressed RB cell proliferation, induced cell apoptosis, attenuated cell migration and cell invasion in vitro, and restrained the growth of RB cells in vivo. Additionally, Wnt3a was revealed to be a direct target gene of miR‑485 in RB cells. Wnt3a was upregulated in human RB tissues, and its upregulation was inversely associated with miR‑485. Furthermore, the tumor suppressive roles of Wnt3a silencing were similar to those of miR‑485 overexpression in RB cells. In addition, restoration of Wnt3a expression partially reversed the tumor suppressor action of miR‑485 in RB cells. However, miR‑485 upregulation directly targeted Wnt3a to inhibit activation of the Wnt/β‑catenin signaling pathway in RB cells both in vitro and in vivo. Notably, these results demonstrated that the tumor‑suppressive roles of miR‑485 were at least partially mediated by Wnt3a in RB cells. Therefore, miR‑485 is a potential therapeutic target for treating patients with RB.

Ke N, Liu Q, Pi L, et al.
The antitumor function of arctigenin in human retinoblastoma cells is mediated by jagged‑1.
Mol Med Rep. 2019; 19(5):3642-3648 [PubMed] Article available free on PMC after 15/01/2020 Related Publications
Retinoblastoma is an intraocular malignant tumor that may severely affect vision and represents a life‑threatening disease in children. Arctigenin (ATG) is an active compound that exhibits numerous pharmacological activities, which is isolated from the seeds of greater burdock (Arctium lappa Linnaeus), a plant used in traditional Chinese herbal medicine. The present study aimed to investigate the effects of ATG on cancer progression by analyzing the retinoblastoma cell line Y79. ATG exhibited a significant inhibitory effect on the viability of Y79 cells in a dose‑dependent manner. Furthermore, treatment with ATG promoted apoptosis, and increased the protein expression levels of B‑cell lymphoma 2 (BCL‑2)‑associated X protein and decreased the protein expression levels of BCL‑2. Cell migration was suppressed following treatment with ATG, as assessed by Transwell migration assay. Furthermore, the protein expression levels of jagged‑1 (JAG1) were decreased, and various factors involved in the Notch signaling pathway, including the Notch intracellular domain (NICD), transcription factor HES (HES)5 and HES1 were downregulated following treatment with ATG. The decreased expression levels of JAG1 were restored in response to JAG1 overexpression, alongside increases in the protein expression levels of NICD, HES5 and HES1. Furthermore, overexpression of JAG1 partly restored the cell viability and migration suppressed following treatment with ATG. In addition, ATG‑induced apoptosis was reduced by JAG1 overexpression. Collectively, the present results suggested that ATG may serve as an antitumor compound by suppressing the proliferation and migration of retinoblastoma cells, inducing apoptosis, downregulating the protein expression levels of JAG1, and decreasing the activity of the Notch signaling pathway.

Wu XZ, Cui HP, Lv HJ, Feng L
Knockdown of lncRNA PVT1 inhibits retinoblastoma progression by sponging miR-488-3p.
Biomed Pharmacother. 2019; 112:108627 [PubMed] Related Publications
Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a regulatory role in the pathogenesis and progression of retinoblastoma (RB). lncRNA plasmacytoma variant translocation 1 (PVT1) is highly expressed in a plenty of tumors, and is believed to serve as an oncogene. However, the expression, roles, and action mechanisms of PVT1 in the carcinogenesis and progression of RB are still largely unknown. In this study, we found that PVT1 was upregulated in RB tissues and cell lines. PVT1 levels correlated with optic nerve invasion, and intraocular international retinoblastoma classify (IIRC) stage. In addition, the results demonstrated that patients with RB who showed higher expression of PVT1 had worse overall survivals. In WERI-Rb1 and Y79 cells, PVT1 silencing significantly inhibited cell proliferation, migration, invasion, and cell cycle progression and induced cell apoptosis in vitro. Moreover, in vivo xenograft assay indicated that PVT1 knockdown suppressed the tumor volume and tumor weight. The analysis of the mechanisms of action revealed that the reduction of PVT1 inhibited the expression of notch2 by upregulating miR-488-3p. In general, our results demonstrated that PVT1 may be a novel biomarker for prognosis and a new target for the treatment of RB.

Abraham A, Thirumalairaj K, Gaikwad N, et al.
Retinoblastoma discordance in families with twins.
Indian J Ophthalmol. 2019; 67(3):436-439 [PubMed] Article available free on PMC after 15/01/2020 Related Publications
Retinoblastoma has an increased inheritance risk of germline RB1 mutations in offspring and siblings, especially twins. Three families, each having one retinoblastoma-affected twin, were selected for genetic analysis and DNA profiling. Germline RB1 mutations were found in all probands. DNA profiling carried on similar-looking twins of families I and II, proved them to be fraternal. This study demonstrates the importance of genetic analysis of RB1 gene for risk prediction in retinoblastoma families. It also emphasizes that DNA profiling is a mandate for genetic screening of families with twins, thus adding a new dimension in counseling of retinoblastoma.

Wang L, Lyu X, Ma Y, et al.
MicroRNA‑504 targets AEG‑1 and inhibits cell proliferation and invasion in retinoblastoma.
Mol Med Rep. 2019; 19(4):2935-2942 [PubMed] Related Publications
The dysregulation of microRNAs (miRNAs/miRs) has become increasingly recognized as a primary feature of retinoblastoma (RB). Furthermore, miRNAs have been demonstrated to be involved in the occurrence and development of RB. Therefore, it is crucial to investigate the expression profile and roles of miRNAs in RB in order to identify potential therapeutic targets to treat patients with RB. The expression profile and biological roles of miRNA‑504 (miR‑504) have been reported in numerous types of human cancer; however, the roles of miR‑504 in RB remain unknown. In the present study, it was demonstrated that miR‑504 expression was significantly decreased in RB tissues and cell lines. Functional analysis identified that resumption of miR‑504 expression suppressed cell proliferation and invasion in RB. Furthermore, astrocyte elevated gene‑1 (AEG‑1) was determined to be a direct target of miR‑504 in RB, and a negative correlation between miR‑504 and AEG‑1 mRNA expression levels was observed in RB tissues. Additionally, the tumor‑suppressing effects of miR‑504 overexpression in RB cells could be rescued by AEG‑1 upregulation. In conclusion, these results indicated a significant role of the miR‑504/AEG‑1 pathway in inhibiting the aggressiveness of RB, suggesting that this miRNA may be employed as a therapeutic target for the treatment of patients with this disease.

Yu F, Pang G, Zhao G
ANRIL acts as onco-lncRNA by regulation of microRNA-24/c-Myc, MEK/ERK and Wnt/β-catenin pathway in retinoblastoma.
Int J Biol Macromol. 2019; 128:583-592 [PubMed] Related Publications
Retinoblastoma is the most common intraocular malignant tumor in infants and children with metastatic potential. This study aimed to investigate the effects of antisense non-coding RNA in the INK4 locus (ANRIL) on retinoblastoma cell viability, migration and invasion, as well as the potential downstream molecules and possible signaling pathways. We found that ANRIL was highly expressed in retinoblastoma tissues and cells. Overexpression of ANRIL promoted the viability, migration and invasion of retinoblastoma Y79 cells and retinal pigment epithelial ARPE-19 cells, as well as activated MEK/ERK and Wnt/β-catenin pathways. Suppression of ANRIL had opposite effects. Moreover, ANRIL negatively regulated the expression of miR-24, which played tumor suppressive roles in retinoblastoma cells. Furthermore, ANRIL positively regulated the expression of c-Myc, which was a target gene of miR-24 in retinoblastoma cells. In Conclusion, Our research verified the oncogenic roles of ANRIL in retinoblastoma. Overexpression of ANRIL promoted viability, migration and invasion of retinoblastoma cells by activating MEK/ERK and Wnt/β-catenin pathways, as well as down-regulating miR-24 and then up-regulating c-Myc.

Bai H, Chang Y, Li B, et al.
Effects of lentivirus-mediated astrocyte elevated gene-1 overexpression on proliferation and apoptosis of human retinoblastoma cells.
Acta Ophthalmol. 2019; 97(3):e397-e402 [PubMed] Related Publications
PURPOSE: To investigate the effect of astrocyte elevated gene-1 (AEG-1) overexpression on the biological behaviour of human retinoblastoma (RB) cells and its possible mechanism.
METHODS: Three human RB cell lines (SO-RB50, Y79 and WERI-RB1) were infected with AEG-1-GFP recombinant lentiviral vectors to induce AEG-1 overexpression, while the cells infected with negative lentiviral vectors and cells without any intervention formed control groups.
RESULTS: All three RB cell lines showed an overexpression of AEG-1 after lentivirus infection (p < 0.001 for all three cell lines). The survival rate of RB cells increased (all p < 0.001) in the AEG-1 overexpressed groups when compared with the control groups. There was a decrease in G0/G1 cell cycle phase arrest and an accumulation in G2/M cell cycle phase in all three RB cell lines (p < 0.001), with an induction in the S phase in WERI-RB1 cells. It was paralleled by a downregulation of p21 and p27 proteins and an upregulation of the Cdc2 protein. The apoptosis rate of RB cells declined (p < 0.001) when AEG-1 was overexpressed, in association with an upregulation of Bcl-2 protein and a downregulation of Bax protein and cleaved caspase-3 proteins.
CONCLUSIONS: A lentivirus-mediated AEG-1 overexpression in RB cells led in vitro to a growth promotion and an apoptosis inhibition of human RB cells, associated with an upregulation of the Bcl-2 protein, a downregulation of the Bax protein and of cleaved caspase-3 proteins, and with alterations of the cell cycle. AEG-1 may be involved in the development and progression of RB.

Guo L, Bai Y, Ji S, Ma H
MicroRNA‑98 suppresses cell growth and invasion of retinoblastoma via targeting the IGF1R/k‑Ras/Raf/MEK/ERK signaling pathway.
Int J Oncol. 2019; 54(3):807-820 [PubMed] Article available free on PMC after 15/01/2020 Related Publications
Accumulating evidence has indicated that the dysregulation of microRNAs (miRNAs) is involved in the pathogenesis o retinoblastoma (RB); however, the potential role of miR‑98 in RB remains elusive. In the present study, it was demonstrated that miR‑98 is downregulated in RB tissues and cell lines, and its expression significantly associated with clinicopathological features, including differentiation, N classification and largest tumor base; patients with low miR‑98 expression levels exhibited significantly poorer overall survival. Overexpression of miR‑98 was suggested to suppress RB cell growth, migration and invasion. In addition, insulin‑like growth factor‑1 receptor (IGF1R), a well‑reported oncogene, was identified as a potential target of miR‑98 via a luciferase assay, reverse transcription‑quantitative polymerase chain reaction and western blotting. Correlation analysis revealed a significantly negative correlation between miR‑98 and IGF1R expression in tumor tissues (n=60). In addition, the results of the present study demonstrated that IGF1R function as an oncogene by promoting RB cell viability, migration and invasion. Furthermore, restoration of IGF1R was observed to reverse the anticancer effects of miR‑98 on RB cell viability, migration and invasion. Importantly, the findings of the present study indicated that miR‑98 suppressed RB cell growth and metastasis by inhibiting the IGF1R/k‑Ras/Raf/mitogen activated protein kinase kinase/extracellular signal‑regulated kinase signaling pathway. Collectively, the present study proposed that miR‑98 may serve as a novel prognostic biomarker and therapeutic target in the treatment of RB.

Li Z, Qi DL, Singh HP, et al.
A novel thyroid hormone receptor isoform, TRβ2-46, promotes SKP2 expression and retinoblastoma cell proliferation.
J Biol Chem. 2019; 294(8):2961-2969 [PubMed] Article available free on PMC after 22/02/2020 Related Publications
Retinoblastoma is a childhood retinal tumor that develops from cone photoreceptor precursors in response to inactivating

Rojanaporn D, Boontawon T, Chareonsirisuthigul T, et al.
Spectrum of germline
Mol Vis. 2018; 24:778-788 [PubMed] Article available free on PMC after 22/02/2020 Related Publications
Purpose: Retinoblastoma (RB) is a retinal tumor that most commonly occurs in children. Approximately 40% of RB patients carry germline mutations in the
Methods: Genomic DNA was extracted from peripheral blood mononuclear cells isolated from 52 RB patients (27 unilaterally and 25 bilaterally affected probands). Mutations in the
Results: Germline
Conclusions: This study provides a data set of an

Sun Z, Zhang A, Zhang L
Inhibition of microRNA‑492 attenuates cell proliferation and invasion in retinoblastoma via directly targeting LATS2.
Mol Med Rep. 2019; 19(3):1965-1971 [PubMed] Related Publications
Numerous studies have demonstrated that microRNAs (miRNAs) are upregulated or downregulated in retinoblastoma (RB), and that this phenomenon is associated with the modulation of various malignant behaviours during RB occurrence and development. Therefore, the mechanisms that associate deregulated miRNAs with RB initiation and progression must be understood to identify effective therapeutic techniques for patients with RB. In the present study, miR‑492 expression was upregulated in RB tissues and cell lines. The effects of miR‑492 inhibition on the proliferation and invasion of RB cells were examined using Cell Counting kit‑8 and invasion assays. The results revealed that miR‑492 downregulation significantly decreased the proliferation and invasion of RB cells. Bioinformatics analysis predicted that large tumour‑suppressor kinase 2 (LATS2) was a putative target of miR‑492. Luciferase reporter assay, reverse transcription‑quantitative polymerase chain reaction and western blot analysis demonstrated that LATS2 was a direct target gene of miR‑492 in RB cells. In addition, LATS2 expression was downregulated in RB tissues, and its downregulation was inversely correlated with miR‑492 level. Furthermore, LATS2‑knockdown abrogated the effects of miR‑492 downregulation in RB cells. In conclusion, miR‑492 inhibition may impede the malignant behaviour of RB by directly targeting LATS2. Therefore, targeting this miRNA may be an effective therapeutic method for treating patients with RB.

Cao Q, Wang Y, Song X, Yang W
Association between MDM2 rs2279744, MDM2 rs937283, and p21 rs1801270 polymorphisms and retinoblastoma susceptibility.
Medicine (Baltimore). 2018; 97(49):e13547 [PubMed] Article available free on PMC after 22/02/2020 Related Publications
Retinoblastoma (Rb) is the most common intra-ocular malignancy in children. The association of rs2279744, and rs937283 in MDM2 gene, and p21 rs1801270 polymorphism and RB development have been demonstrated. To provide a comprehensive assessment of and to clarify associations between the 3 SNPs (MDM2 rs2279744, MDM2 rs937283, and p21 rs1801270) and the risk of RB, we performed a meta-analysis of all the eligible case-control studies. We searched English databases include PubMed, Embase, Google Scholar, and Cochrane Library, using an upper date limit of January 1, 2018. The association between MDM2 rs2279744, MDM2 rs937283, and p21 rs1801270 polymorphisms and the risk of RB were estimated by calculating a pooled OR and 95% CI under a homozygote comparison, heterozygote comparison, dominant model, and recessive model. The statistical power analysis was performed using G*Power. Our meta-analysis showed a significant association between RB susceptibility and MDM2 rs2279744 recessive model (OR = 1.427, 95%CI: 1.107-1.840, P = .006, I = 0%). Moreover, a significant link was observed between RB risk and MDM2 rs937283 homozygote comparison (OR = 0.471, 95%CI: 0.259-0.858, P = .014, I = 0%) and recessive model (OR = 0.587, 95%CI: 0.410-0.840, P = .004, I = 0%). However, no significant relationship between the p21 rs1801270 polymorphism and RB susceptibility was detected in any of the 4 models (P > .05). In conclusion, we found that significant association between the MDM2 rs2279744 polymorphism and increased RB risk, while MDM2 rs937283 polymorphism was associated with significantly decreased RB risk. However, as to the P21 rs1801270 polymorphism, a statistically significant association was not identified for RB.

Cheng Y, Chang Q, Zheng B, et al.
LncRNA XIST promotes the epithelial to mesenchymal transition of retinoblastoma via sponging miR-101.
Eur J Pharmacol. 2019; 843:210-216 [PubMed] Related Publications
Accumulating evidence demonstrated that abnormal expression of long non-coding RNAs (lncRNAs) was closely associated with cancer development including retinoblastoma (RB). LncRNA X inactive specific transcript (XIST) has been found to function as an oncogene or a tumor suppressor in several cancers. However, the role and underlying mechanism of XIST in RB have not been clarified. The expression of XIST, microRNA (miR)- 101, zinc finger E-box binding homeobox (ZEB) 1, and ZEB2 was detected in human RB tissues and cell lines. The effects of XIST on the proliferation, migration, invasion, epithelial to mesenchymal transition (EMT), and apoptosis of RB cells were evaluated after downregulation of XIST. Furthermore, the mechanism of XIST was mainly focused on miR-101/ZEB1 or ZEB2 signaling. We found the expression of XIST, ZEB1 and ZEB2 was increased, whereas miR-101 was reduced in RB tissues and cells. Knockdown of XIST significantly suppressed the proliferation, migration, invasion and EMT, but promoted the apoptosis and caspase-3 activity. Moreover, we found that XIST functioned as a competing endogenous RNA (ceRNA) for miR-101 to regulate the de-repression of its endogenous targets ZEB1 and ZEB2. In conclusion, these findings suggest that XIST may facilitate the progression of RB through acting as a ceRNA for miR-101 to mediate the expression of ZEB1 and ZEB2. This may provide novel therapeutic options for RB.

Sahoo S, Ravi Kumar RK, Nicolay B, et al.
Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma.
FEBS Lett. 2019; 593(1):23-41 [PubMed] Related Publications
Retinoblastoma (RB) is a childhood eye cancer. Currently, chemotherapy, local therapy, and enucleation are the main ways in which these tumors are managed. The present work is the first study that uses constraint-based reconstruction and analysis approaches to identify and explain RB-specific survival strategies, which are RB tumor specific. Importantly, our model-specific secretion profile is also found in RB1-depleted human retinal cells in vitro and suggests that novel biomarkers involved in lipid metabolism may be important. Finally, RB-specific synthetic lethals have been predicted as lipid and nucleoside transport proteins that can aid in novel drug target development.

Yang G, Fu Y, Lu X, et al.
miR‑34a regulates the chemosensitivity of retinoblastoma cells via modulation of MAGE‑A/p53 signaling.
Int J Oncol. 2019; 54(1):177-187 [PubMed] Related Publications
The present study aimed to explore the combined role of microRNA (miR)-34a, melanoma antigen-A (MAGE‑A) and p53 in altering the chemosensitivity of retinoblastoma (RB) cells. Human RB and adjacent tumor tissues, as well as human RB cell lines (HXO‑Rb44, SO‑Rb50, Y79 and WERI‑Rb-1) were used. In addition, four chemotherapeutic drugs, including carboplatin, etoposide, Adriamycin and vincristine, were used to treat the cell lines, in order to evaluate the sensitivity of RB cells. Furthermore, miR‑34a expression was detected by reverse transcription-quantitative polymerase chain reaction, and western blotting was implemented to quantify expression levels of MAGE‑A and p53. A luciferase reporter gene assay was used to validate the targeted association between miR‑34a and MAGE‑A. The results indicated that SO‑Rb50 cells exhibited the highest resistance to carboplatin, Adriamycin and vincristine (P<0.05), whereas HXO‑Rb44 cells revealed the highest inhibition rate in response to etoposide (P<0.05) out of the four cell lines. Furthermore, reduced miR‑34a expression and increased MAGE‑A expression significantly elevated the survival rate and viability of SO‑Rb50 cells following drug treatment (all P<0.05). miR‑34a was also demonstrated to directly target MAGE‑A, thereby significantly promoting the viability of RB cells and depressing apoptosis (P<0.05). p53, which was subjected to modulation by miR‑34a and MAGE‑A, also significantly reduced the proliferation rate of RB cells (P<0.05). In conclusion, the miR‑34a/MAGE‑A/p53 axis may be conducive to enhancing the efficacies of chemotherapeutic treatments for RB.

Cao Y, Xia F, Wang P, Gao M
MicroRNA‑93‑5p promotes the progression of human retinoblastoma by regulating the PTEN/PI3K/AKT signaling pathway.
Mol Med Rep. 2018; 18(6):5807-5814 [PubMed] Related Publications
Numerous reports have indicated that microRNA‑93‑5p (miR‑93‑5p) is involved in the development and progression of human cancer, including non‑small cell lung, gastric and breast cancer; however, the role of miR‑93‑5p in retinoblastoma (RB) remains unknown. In the present study, it was reported that miR‑93‑5p expression levels were significantly upregulated in RB tissues compared with in normal tissues by reverse transcription‑quantitative polymerase chain reaction. Furthermore, it was demonstrated via cell counting kit‑8 and Transwell assays that knockdown of miR‑93‑5p significantly suppressed the proliferation, migration and invasion of RB cells, but promoted cellular apoptosis. Regarding the underlying mechanism, the present study reported that phosphatase and tensin homolog (PTEN) was a direct target of miR‑93‑5p in RB cells. Overexpression of miR‑93‑5p significantly inhibited the expression of PTEN; opposing results were observed when PTEN expression was downregulated. Furthermore, the present study revealed that PTEN expression levels were downregulated and were inversely correlated with that of miR‑93‑5p in RB tissues. Additionally, the present study demonstrated that knockdown of PTEN in miR‑93‑5p‑depleted RB cells significantly reversed the effects of miR‑93‑5p on cell proliferation, migration and invasion; miR‑93‑5p knockdown was suggested to promote PTEN expression, consequently inhibiting the activation of phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway. Collectively, the results of the present study demonstrated that miR‑93‑5p may serve a role as an oncogene by modulating the PTEN/PI3K/AKT signaling pathway in RB, indicating that miR‑93‑5p may be a potential therapeutic target for the treatment of RB.

Yang Y, Peng XW
The silencing of long non-coding RNA ANRIL suppresses invasion, and promotes apoptosis of retinoblastoma cells through the ATM-E2F1 signaling pathway.
Biosci Rep. 2018; 38(6) [PubMed] Article available free on PMC after 22/02/2020 Related Publications
As one of the most common primary intraocular carcinomas, retinoblastoma generally stems from the inactivation of the retinoblastoma

Delsin LEA, Salomao KB, Pezuk JA, Brassesco MS
Expression profiles and prognostic value of miRNAs in retinoblastoma.
J Cancer Res Clin Oncol. 2019; 145(1):1-10 [PubMed] Related Publications
Current cure rates for retinoblastoma (RB) are very high in developed countries. Nonetheless, in less privileged places worldwide, delayed diagnosis and refusal to adhere to treatment still endure an obstacle to improve overall patient survival. Thus, the access to consistent biomarkers for diagnosis at an earlier stage may facilitate treatment and improve outcomes. Over recent years, much attention has been focused on miRNAs, key post-transcriptional regulators that when altered, largely contribute to carcinogenesis and tumor progression. Many of the ~ 2500 microRNAs described in humans have shown differential expression profiles in tumors. In this review, we summarize current data about the roles of miRNAs in RB along with their value as diagnostic/prognostic factors using electronic databases such as PubMed. We reviewed the importance of miRNA in RB biology and discussed their implications in clinic intervention. Several miRNAs have pointed out reliable diagnostic and prognostic molecular biomarkers. The emergence of targeted therapies has significantly improved cancer treatment. In the near future, the modulation of miRNAs will represent a good treatment strategy.

Huang YX, Nie XG, Li GD, et al.
Downregulation of microRNA‑182 inhibits cell viability, invasion and angiogenesis in retinoblastoma through inhibition of the PI3K/AKT pathway and CADM2 upregulation.
Int J Oncol. 2018; 53(6):2615-2626 [PubMed] Related Publications
Retinoblastoma (RB) is a well‑vascularized tumor dependent on angiogenesis. The present study aimed to explore whether microRNA (miR)‑182 regulates cell viability, invasion and angiogenesis in RB via the phosphatidylinositol‑3‑OH kinase (PI3K)/protein kinase B (AKT) signaling pathway and by targeting cell adhesion molecule 2 (CADM2). The expression levels of miR‑182 and CADM2 were initially detected in RB tissues from patients with RB who underwent ophthalmectomy, and normal retinal tissues collected from other trauma patients who underwent eye enucleation. To determine whether CADM2 was targeted by miR‑182, a dual luciferase reporter assay was conducted. Subsequently, Y79 and WERI‑Rb‑1 RB cells were transfected with a miR‑182 mimic or miR‑182 inhibitor, or small interfering RNA against CADM2, in order to investigate the effects of miR‑182 on viability and invasion, which were detected using MTT and Transwell assays, respectively. In addition, to determine whether the regulatory mechanism underlying the effects of miR‑182 was associated with the PI3K/AKT signaling pathway, the expression levels of associated genes were detected by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. A xenograft tumor model in nude mice was also established, in order to evaluate the effects of miR‑182 on tumor growth and angiogenesis. The results indicated that miR‑182 expression was increased and CADM2 expression was reduced in RB tissues; CADM2 was confirmed to be targeted and negatively regulated by miR‑182. When the expression of miR‑182 was downregulated, cell viability, invasion, tumor volume and angiogenesis were significantly decreased. Furthermore, the expression levels of PI3K/AKT signaling pathway‑associated genes were increased in response to miR‑182 overexpression or CADM2 silencing. Taken together, these results suggested that inhibition of miR‑182 may suppress cell viability, invasion and angiogenesis in RB through inactivation of the PI3K/AKT pathway and CADM2 upregulation. This mechanism may reveal a novel potential therapeutic target.

Schipper L, Kanber D, Steenpass L
Generation of heterozygous and homozygous hESC H9 sublines carrying inactivating mutations in RB1.
Stem Cell Res. 2018; 33:41-45 [PubMed] Related Publications
Inactivation of the tumor suppressor gene RB1 is causal for development of retinoblastoma, a tumor of the neural retina arising in children under the age of five. In addition, secondary RB1 mutations are found in many other tumor types. To investigate retinoblastoma formation in vitro, stem cells with inactivated RB1 can be differentiated into neural retina. To enable such studies, two sublines of hESC line H9 carrying mutations in RB1 exon 3 in heterozygous or homozygous state were generated and characterized. Homozygous mutation led to loss of RB1 protein expression. Resource table.

Liao Y, Yin X, Deng Y, Peng X
MiR-140-5p suppresses retinoblastoma cell growth via inhibiting c-Met/AKT/mTOR pathway.
Biosci Rep. 2018; 38(6) [PubMed] Article available free on PMC after 22/02/2020 Related Publications
MiR-140-5p is low expression and acts as a tumor suppressor in various types of human cancers. However, the potential role of miR-140-5p in retinoblastoma (RB) remains unknown. In the present study, we performed the miRNA microarray analysis to investigate whether miRNAs expression are associated with RB tumorigenesis in RB tissues. We found that a large set of miRNAs were ectopic expressions and miR-140-5p is most significantly down-regulated in human RB tissues compared with normal retinas. In addition, low miR-140-5p expression is associated with clinicopathological features (differentiation, invasion, T classification, N classification, cTNM stage, and largest tumor base) and poor survival in RB patients. Furthermore, our results showed that overexpression of miR-140-5p suppresses proliferation and induces apoptosis and cell cycle arrest in RB cell. Meanwhile, we confirmed that c-Met is the functional target of miR-140-5p in RB cell, and miR-140-5p expression is negatively correlated with c-Met in RB tissues. We also found that inhibition of c-Met also suppresses proliferation and induces apoptosis and cell cycle arrest in RB cell. Interestingly, c-Met can rescue the suppressive effects of miR-140-5p on RB cell growth and cell cycle arrest. More importantly, our findings indicated that miR-140-5p may inhibit cell growth via blocking c-Met/AKT/mTOR signaling pathway. Collectively, these results suggested that miR-140-5p might be a potential biomarker and target in the diagnosis and treatment of RB.

Singh HP, Wang S, Stachelek K, et al.
Developmental stage-specific proliferation and retinoblastoma genesis in RB-deficient human but not mouse cone precursors.
Proc Natl Acad Sci U S A. 2018; 115(40):E9391-E9400 [PubMed] Article available free on PMC after 22/02/2020 Related Publications
Most retinoblastomas initiate in response to the inactivation of the

Torbidoni AV, Sampor C, Laurent VE, et al.
Minimal disseminated disease evaluation and outcome in trilateral retinoblastoma.
Br J Ophthalmol. 2018; 102(11):1597-1601 [PubMed] Related Publications
Trilateral retinoblastoma (TRb) presents a management challenge, since intracranial tumours are seldom times resectable and quickly disseminate. However, there are no risk factors to predict the final outcome in each patient.
OBJECTIVE: To evaluate minimal disseminated disease (MDD) in the bone marrow (BM) and the cerebrospinal fluid (CSF) at diagnosis and during follow-up and reviewing its potential impact in the outcome of patients with TRb.
METHODS AND ANALYSIS: We evaluated MDD in five patients with TRb, detecting the mRNA of
RESULTS: Treatment involved intensive systemic chemotherapy in four patients, one did not receive this treatment and died of progression of the disease. Two patients underwent stem cell rescue. Three patients had leptomeningeal relapse and died. One patient remains disease-free for 84 months.
CONCLUSION: CSF dissemination always concluded in the death of the patient, without concomitant systemic dissemination denoting the importance of increasing treatment directed to the CSF compartment. The MDD presence could indicate a forthcoming relapse.

Shang Y
LncRNA THOR acts as a retinoblastoma promoter through enhancing the combination of c-myc mRNA and IGF2BP1 protein.
Biomed Pharmacother. 2018; 106:1243-1249 [PubMed] Related Publications
Long non-coding RNA (lncRNA) THOR is an extremely conserved lncRNA with specifically expressed in testis while widespreadly exist in human multiple cancer tissues. The high expression of it significantly promotes the occurrence and progression of melanoma, non-small cell lung cancer, osteosarcoma and renal cell carcinoma. However, the expression pattern and effects of lncRNA THOR in the progression of retinoblastoma remain unclear. As a result, this study was conducted to discovery the expression and roles of lncRNA THOR in the malignant phenotype transformation of retinoblastoma cells, as well as its underlying mechanism. Our results demonstrated that lncRNA THOR was over-expressed in the retina tissues from retinoblastoma patients and retinoblastoma Y79 and WERI-Rb1 cell lines. Down-regulation of lncRNA THOR with siRNA significantly repressed cell growth, migration and S phase accumulation, while induced cell apoptosis and G1 phase reduction and reduced the expression of c-myc. Besides, knockdown of c-myc promoted cell apoptosis and suppressed cell proliferation. Furthermore, RNA pull down and PIP assays showed that up-regulation of lncRNA THOR enhanced the combination of IGF2BP1 protein and c-myc RNA. And lncRNA THOR up-regulation obviously increased the tumorigenesis of Y79 cells in vivo. In conclusion, this study makes clear that lncRNA THOR is up-regulated in retinoblastoma, and its over-expression significantly enhances the malignant phenotype transformation of retinoblastoma cells through up-regulating c-myc expression via enhancing its combination with TGF2BP1 protein. Overall, our study illustrates that lncRNA THOR/c-myc molecular cascade might be another potent target for retinoblastoma treatment.

Hu C, Liu S, Han M, et al.
Knockdown of lncRNA XIST inhibits retinoblastoma progression by modulating the miR-124/STAT3 axis.
Biomed Pharmacother. 2018; 107:547-554 [PubMed] Related Publications
Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) was reportedly to be tightly associated with tumorigenesis and progression of multiple cancers. However, the expression, biological function, and action mechanisms of XIST in retinoblastoma (RB) are still unknown. Here, we found that XIST expression was upregulated in RB tissues and cell lines, and that increased XIST expression was positively associated with advanced cTNM stage (III-V) and late differentiation status. We also revealed that knockdown of XIST inhibited RB cell proliferation, promoted cell cycle at G1/G0 phase, and induced cell apoptosis. Mechanistically, XIST directly bound to microRNA (miR)-124 in RB cells. XIST mRNA expression was inversely correlated with miR-124 in RB tissues. Importantly, miR-124 inhibition partially reversed the effect on cell proliferation, cycle arrest and apoptosis by XIST knockdown mediated. In addition, XIST could regulate expression of signal transducer and activator of transcription 3(STAT3), a directly target of miR-124 in RB. These findings implied that XIST promoted RB progression partially by modulating the miR-124/STAT3 axis.

Wang S, Liu J, Yang Y, et al.
PlncRNA-1 is overexpressed in retinoblastoma and regulates retinoblastoma cell proliferation and motility through modulating CBR3.
IUBMB Life. 2018; 70(10):969-975 [PubMed] Related Publications
PlncRNA-1 has been suggested to function as an oncogenic role in prostate cancer, colorectal cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, and gastric cancer. The expression pattern of PlncRNA-1 in retinoblastoma remained unknown. Therefore, the aim of this study was to explore the clinical significance of PlncRNA-1 in retinoblastoma patient and the biological function and molecular mechanism of PlncRNA-1 in regulating retinoblastoma cell proliferation, migration, and invasion. The results showed the level of PlncRNA-1 expression was obviously increased in retinoblastoma tissues and cell lines compared with compared with normal retina tissues and retina cell lines, respectively. Meanwhile, patients with advanced stage retinoblastoma had higher levels of PlncRNA-1 expression than patients with early stage retinoblastoma. There was an inverse correlation between PlncRNA-1 expression and CBR3 expression in retinoblastoma tissues, and PlncRNA-1 negatively regulated mRNA and protein expressions of CBR3. The in vitro experiments showed that down-regulation of PlncRNA-1 expression suppressed retinoblastoma cell proliferation, migration and invasion through up-regulating CBR3. In conclusion, PlncRNA-1 serves as an oncogenic lncRNA in regulating retinoblastoma cell proliferation, migration, and invasion through proliferation, migration, and invasion through up-regulating CBR3. © 2018 IUBMB Life, 70(10):969-975, 2018.

Zhu X, Xue L, Yao Y, et al.
The FoxM1-ABCC4 axis mediates carboplatin resistance in human retinoblastoma Y-79 cells.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(9):914-920 [PubMed] Related Publications
Carboplatin is the most commonly used drug in the first-line treatment of human retinoblastoma (RB), but its clinical application is greatly limited due to acquired drug resistance upon the long-term treatment. Forkhead box protein M1 (FoxM1) is the transcription factor aberrantly expressed in various types of human cancers, which plays an essential role in the regulation of tumorigenesis, tumor metastasis and drug resistance. However, little is known about the role of FoxM1 in chemo-resistance of human RB. In this study, we investigated the regulatory effect of FoxM1 on carboplatin resistance in human RB Y-79 cells and carboplatin-resistant Y-79 (Y-79CR) cells, as well as the possible mechanism. Our results showed that FoxM1 was up-regulated in Y-79CR cells and silencing of FoxM1 promoted carboplatin sensitivity and accumulation, while overexpression of FoxM1 in Y-79 cells performed oppositely. Our study further revealed that FoxM1 enhanced carboplatin resistance in Y-79CR cells through directly up-regulating the transcription of ATP-binding cassette transporter C4 (ABCC4), an important drug efflux transporter. Overall, our study demonstrated the novel role of FoxM1-ABCC4 axis in human RB, which provides insights into the prevention of carboplatin resistance in human RB.

Hudson LE, Mendoza P, Hudson WH, et al.
Distinct Gene Expression Profiles Define Anaplastic Grade in Retinoblastoma.
Am J Pathol. 2018; 188(10):2328-2338 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Morbidity and mortality associated with retinoblastoma have decreased drastically in recent decades, in large part owing to better prediction of high-risk disease and appropriate treatment stratification. High-risk histopathologic features and severe anaplasia both predict the need for more aggressive treatment; however, not all centers are able to assess tumor samples easily for the degree of anaplasia. Instead, identification of genetic signatures that are able to distinguish among anaplastic grades and thus predict high- versus low-risk retinoblastoma would facilitate appropriate risk stratification in a wider patient population. A better understanding of genes dysregulated in anaplasia also would yield valuable insights into pathways underlying the development of more severe retinoblastoma. Here, we present the histopathologic and gene expression analysis of 28 retinoblastoma cases using microarray analysis. Tumors of differing anaplastic grade show clear differential gene expression, with significant dysregulation of unique genes and pathways in severe anaplasia. Photoreceptor and nucleoporin expression in particular are identified as highly dysregulated in severe anaplasia and suggest particular cellular processes contributing to the development of increased retinoblastoma severity. A limited set of highly differentially expressed genes also are able to predict severe anaplasia accurately in our data set. Together, these data contribute to the understanding of the development of anaplasia and facilitate the identification of genetic markers of high-risk retinoblastoma.

Further References

MacCarthy A, Birch JM, Draper GJ, et al.
Retinoblastoma in Great Britain 1963-2002.
Br J Ophthalmol. 2009; 93(1):33-7 [PubMed] Related Publications
AIM: This paper describes the epidemiology and family history status of 1601 children with retinoblastoma in Great Britain diagnosed 1963-2002 and summarises the practical consequences for diagnosis and counselling of developments in molecular genetics.
METHODS: Incidence rates were analysed according to year of diagnosis and tumour laterality. Cases were classified as heritable or non-heritable on the basis of laterality and family history of the disease.
RESULTS: There were 998 unilateral cases, 581 bilateral and 22 of unknown laterality. Bilateral cases tended to be diagnosed at a younger age than unilateral. All bilateral cases are regarded as heritable, and 35% had a family history of the disease. 7% of the unilateral cases had a family history and are therefore heritable. Thus, at least (41%) of our cases are heritable. This is an underestimate, since these data on family history are incomplete. For unilateral cases aged below 1 year, the reported incidence rate increased significantly (p<0.0001) by about 2.5% per year; for the age group 1-4 years, the average increase was about 0.5% per year (not significant).

de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, et al.
Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma.
Pediatr Blood Cancer. 2012; 59(1):39-43 [PubMed] Related Publications
BACKGROUND: Retinoblastoma (RB) accounts for 3% of all childhood malignancies, with different incidences around the world. This malignancy results from loss-of-function of both RB1 alleles although other genes, like MDM2 and MDM4, have been proposed to be involved in tumor development.
PROCEDURE: We genotyped rs2279744T>G and rs937283A>G in MDM2, and rs4252668T>C and rs116197192G>A in MDM4, in 104 unrelated RB patients and 104 controls. Sixty-month survival Kaplan-Meier curves and χ(2)-tests were performed for estimating the putative effect of MDM2 and MDM4 alleles on disease progression and survival of RB patients.
RESULTS: MDM2 rs2279744G was significantly more frequent in controls, indicating an apparently protective effect on RB development. However, survival of patients who carried a constitutional RB1 mutation was significantly lower with rs2279744TG or GG than with rs2279744TT. Presence of rs2279744G and a constitutional RB1 mutation was sixfold more frequent in the 0-12 month age group than other age groups at onset of symptoms (P = 0.0401). MDM4 rs4252668C was present at a significantly higher frequency in controls while the frequency of MDM4 rs116197192G was significantly higher in RB patients, suggesting that this allele might increase the risk of developing RB.
CONCLUSION: Our results indicate that MDM2 and MDM4 polymorphisms may influence development and/or survival in RB.

Castéra L, Sabbagh A, Dehainault C, et al.
MDM2 as a modifier gene in retinoblastoma.
J Natl Cancer Inst. 2010; 102(23):1805-8 [PubMed] Related Publications
Variability in the age of onset and number of tumors is occasionally described among retinoblastoma patients, and possible genetic modifiers might lie in the pRB or p53 pathways, both of which are involved in the development of retinoblastoma. MDM2, which increases p53 and pRB catabolism, is therefore a prominent candidate. The minor allele of MDM2 that includes a 309T>G transversion (single-nucleotide polymorphism rs2279744) in the MDM2 promoter is known to enhance MDM2 expression. Its genetic transmission was studied in 326 individuals including 212 RB1 mutation carriers in 70 retinoblastoma families, and the marker genotype was tested for association with age at diagnosis and disease phenotype. In family-based association analyses, the MDM2 309G allele was found to be statistically significantly associated with incidence of bilateral or unilateral retinoblastoma among members of retinoblastoma families (Z = 3.305, two-sided exact P = .001) under a recessive model (ie, affected patients tend to be homozygous for the G allele); in transmission disequilibrium analyses using the recessive model, the association was also observed (estimated odds ratio = 4.0, 95% confidence interval = 1.3 to 12.0). The strong association of this genotype with retinoblastoma development designates MDM2 as the first modifier gene to be identified among retinoblastoma patients and suggests that enhancement of pRB haploinsufficiency and/or resistance to p53-mediated apoptosis is critical to tumor formation.

Di Fiore R, D'Anneo A, Tesoriere G, Vento R
RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis.
J Cell Physiol. 2013; 228(8):1676-87 [PubMed] Related Publications
Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species-and cell type-specific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107, and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cancer.

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