Retinoblastoma

Overview

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 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (24)

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'.

GeneLocationAliasesNotesTopicPapers
RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 Germline
-RB1 mutation in Retinoblastoma
510
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 Amplification
-MYCN Amplification in Retinoblastoma
85
RBL2 16q12.2 Rb2, P130 -RBL2 and Retinoblastoma
16
MDM2 12q14.3-q15 HDMX, hdm2, ACTFS -MDM2 and Retinoblastoma
15
MDM4 1q32 HDMX, MDMX, MRP1 -MDM4 and Retinoblastoma
13
PRB1 12p13.2 PM, PMF, PMS, PRB1L, PRB1M -PRB1 and Retinoblastoma
10
E2F3 6p22 E2F-3 -E2F3 and Retinoblastoma
10
RBL1 20q11.2 PRB1, p107, CP107 -RBL1 and Retinoblastoma
10
KIF14 1q32.1 -KIF14 and Retinoblastoma
7
CDH11 16q21 OB, CAD11, CDHOB, OSF-4 -CDH11 and Retinoblastoma
7
DEK 6p22.3 D6S231E -DEK and Retinoblastoma
6
PRB2 12p13.2 Ps, cP7, IB-9, PRPPRB1 -PRB2 and Retinoblastoma
6
CDK6 7q21-q22 MCPH12, PLSTIRE -CDK6 and Retinoblastoma
5
CDH13 16q23.3 CDHH, P105 -CDH13 and Retinoblastoma
4
CD82 11p11.2 R2, 4F9, C33, IA4, ST6, GR15, KAI1, SAR2, TSPAN27 -CD82 and Retinoblastoma
3
DDX1 2p24 DBP-RB, UKVH5d Amplification
-DDX1 Amplification in Retinoblastoma cell lines
3
OTX2 14q22.3 CPHD6, MCOPS5 -OTX2 and Retinoblastoma
3
RXRA 9q34.3 NR2B1 -RXRA and Retinoblastoma
2
MIRLET7E 19q13.41 LET7E, let-7e, MIRNLET7E, hsa-let-7e -MicroRNA let-7e and Retinoblastoma
1
CACNA1G 17q22 NBR13, Cav3.1, Ca(V)T.1 -CACNA1G and Retinoblastoma
1
RCVRN 17p13.1 RCV1 -RCVRN and Retinoblastoma
1
NEUROG1 5q23-q31 AKA, ngn1, Math4C, bHLHa6, NEUROD3 -NEUROG1 and Retinoblastoma
1
HLA-C 6p21.3 HLC-C, D6S204, PSORS1, HLA-JY3 -HLA-C and Retinoblastoma
1
HLA-B 6p21.3 AS, HLAB, SPDA1 -HLA-B and Retinoblastoma
1

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

Maris JM, Knudson AG
Revisiting tissue specificity of germline cancer predisposing mutations.
Nat Rev Cancer. 2015; 15(2):65-6 [PubMed] Related Publications

Wu X, Zeng Y, Wu S, et al.
MiR-204, down-regulated in retinoblastoma, regulates proliferation and invasion of human retinoblastoma cells by targeting CyclinD2 and MMP-9.
FEBS Lett. 2015; 589(5):645-50 [PubMed] Related Publications
Aberrant expression of miR-204 had been frequently reported in cancer studies; however, the mechanism of its function in retinoblastoma remained unknown. Here, we reported that miR-204 was frequently downregulated in retinoblastoma tissues and cell lines. Enforced expression of miR-204 inhibited retinoblastoma cells' proliferation and invasion. In vivo study indicated that restoration of miR-204 inhibited tumor growth. CyclinD2 and MMP-9 were identified as potential targets of miR-204. In addition, a reverse correlation between miR-204 and CyclinD2 or MMP-9 expression was noted in retinoblastoma tissues. Taken together, our results identified a crucial tumor suppressive role of miR-204 in the progression of retinoblastoma.

Benavente CA, Dyer MA
Genetics and epigenetics of human retinoblastoma.
Annu Rev Pathol. 2015; 10:547-62 [PubMed] Related Publications
Retinoblastoma is a pediatric tumor of the developing retina from which the genetic basis for cancer development was first described. Inactivation of both copies of the RB1 gene is the predominant initiating genetic lesion in retinoblastoma and is rate limiting for tumorigenesis. Recent whole-genome sequencing of retinoblastoma uncovered a tumor that had no coding-region mutations or focal chromosomal lesions other than in the RB1 gene, shifting the paradigm in the field. The retinoblastoma genome can be very stable; therefore, epigenetic deregulation of tumor-promoting pathways is required for tumorigenesis. This review highlights the genetic and epigenetic changes in retinoblastoma that have been reported, with special emphasis on recent whole-genome sequencing and epigenetic analyses that have identified novel candidate genes as potential therapeutic targets.

Bai H, Li B
[Research advances of animal models of retinoblastoma].
Zhonghua Yan Ke Za Zhi. 2014; 50(10):793-7 [PubMed] Related Publications
Advances in animal models of retinoblastoma have accelerated the research in understanding tumor biology and assessing therapeutic modalities. At present, there are two types of models:transgenic models and xenograft models. The transgenic models have experienced a developmental process from LH-β-Tag models to conditional gene knock-out models. The xenograft models included intraocular transplantation models and subcutaneous transplantation models. The two types of RB models both have their merits and drawbacks. The combination of genetic and xenograft models in retinoblastoma research has and will help to pave way for better understanding tumor progression and searching more effective diagnosis and treatment modalities. In this review, we summarized the recent research progress in animal models of retinoblastoma and their application in assessing therapeutic modalities.

Quintero-Estades JA, Izquierdo NJ
Germline retinoblastoma without inherited gene mutation: a case report.
Bol Asoc Med P R. 2014; 106(3):32-5 [PubMed] Related Publications
Retinoblastoma is the most common primary ocular malignancy in childhood and can occur as a germline or somatic mutation. Recent studies have suggested a higher incidence of retinoblastoma in Hispanic children as compared to non-Hispanic white children of the same ages. We report the ocular findings of a 20 years old Hispanic male with a history of bilateral retinoblastoma. Although screening is currently performed with the red reflex test, analysis of current literature suggests the need to reassess screening recommendations for retinoblastoma.

Rodriguez-Galindo C, Orbach DB, VanderVeen D
Retinoblastoma.
Pediatr Clin North Am. 2015; 62(1):201-23 [PubMed] Related Publications
Retinoblastoma is the most common neoplasm of the eye in childhood, and represents 3% of all childhood malignancies. Retinoblastoma is a cancer of the very young; two-thirds are diagnosed before 2 years of age and 95% before 5 years. Retinoblastoma presents in 2 distinct clinical forms: (1) a bilateral or multifocal, heritable form (25% of all cases), characterized by the presence of germline mutations of the RB1 gene; and (2) a unilateral or unifocal form (75% of all cases), 90% of which are nonhereditary. The treatment of retinoblastoma is multidisciplinary and is designed primarily to save life and preserve vision.

Zhang L, Jia R, Zhao J, et al.
Novel mutations in the RB1 gene from Chinese families with a history of retinoblastoma.
Tumour Biol. 2015; 36(4):2409-20 [PubMed] Related Publications
Retinoblastoma is an aggressive eye cancer that develops during infancy and is divided into two clinical types, sporadic and heritable. RB1 has been identified as the only pathological gene responsible for heritable retinoblastoma. Here, we identified 11 RB1 germline mutations in the Han pedigrees of 17 bilateral retinoblastoma patients from China. Four mutations were nonsense mutations, five were splice site mutations, and two resulted in a frame shift due to an insertion or a deletion. Three of the mutations had not been previously reported, and the p.Q344L mutation occurred in two generations of retinoblastoma patients. We investigated phenotypic-genotypic relationships for the novel mutations and showed that these mutations affected the expression, location, and function of the retinoblastoma protein. Abnormal protein localization was observed after transfection of the mutant genes. In addition, changes in the cell cycle distribution and apoptosis rates were observed when the Saos-2 cell line was transfected with plasmids encoding the mutant RB1 genes. Our findings expand the spectrum of known RB1 mutations and will benefit the investigation of RB1 mutation hotspots. Genetic counseling can be offered to families with heritable RB1 mutations.

Elouarradi H, Daoudi R
[Bilateral retinoblastoma: report of a case].
Pan Afr Med J. 2014; 17:141 [PubMed] Free Access to Full Article Related Publications

Benavente CA, Finkelstein D, Johnson DA, et al.
Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression.
Oncotarget. 2014; 5(20):9594-608 [PubMed] Free Access to Full Article Related Publications
The retinoblastoma (Rb) family of proteins are key regulators of cell cycle exit during development and their deregulation is associated with cancer. Rb is critical for normal retinal development and germline mutations lead to retinoblastoma making retinae an attractive system to study Rb family signaling. Rb coordinates proliferation and differentiation through the E2f family of transcription factors, a critical interaction for the role of Rb in retinal development and tumorigenesis. However, whether the roles of the different E2fs are interchangeable in controlling development and tumorigenesis in the retina or if they have selective functions remains unknown. In this study, we found that E2f family members play distinct roles in the development and tumorigenesis. In Rb;p107-deficient retinae, E2f1 and E2f3 inactivation rescued tumor formation but only E2f1 rescued the retinal development phenotype. This allowed the identification of key target genes for Rb/E2f family signaling contributing to tumorigenesis and those contributing to developmental defects. We found that Sox4 and Sox11 genes contribute to the developmental phenotype and Hells and Uhrf1 contribute to tumorigenesis. Using orthotopic human xenografts, we validated that upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK.

Masaoutis P, Koutsandrea C, Paraskevopoulos T, Georgalas I
White pupillary reflex in a 3 year old boy.
BMJ. 2014; 349:g6081 [PubMed] Related Publications

Astudillo PP, Chan HS, Héon E, Gallie BL
Late-diagnosis retinoblastoma with germline mosaicism in an 8-year-old.
J AAPOS. 2014; 18(5):500-2 [PubMed] Related Publications
We describe bilateral retinoblastoma in an 8-year-old girl presenting with macular tumor in one eye and a small peripheral tumor in the other but no detected RB1 gene mutation. Despite chemotherapy, multiple focal laser, cryotherapy, and periocular chemotherapy, tumor activity persisted and enucleation was performed. Two RB1 mutations were found in the tumor; one RB1 mutation was present in 10% of blood cells, identifying mosaicsm.

Xu XL, Singh HP, Wang L, et al.
Rb suppresses human cone-precursor-derived retinoblastoma tumours.
Nature. 2014; 514(7522):385-8 [PubMed] Free Access to Full Article Related Publications
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, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. 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. 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.

Gao R, Zhou X, Yang Y, Wang Z
Transfection of wtp53 and Rb94 genes into retinoblastomas of nude mice by ultrasound-targeted microbubble destruction.
Ultrasound Med Biol. 2014; 40(11):2662-70 [PubMed] Related Publications
Using ultrasound-targeted microbubble destruction (UTMD), we transfected both wild-type p53 (wtp53) and Rb94 genes into retinoblastomas (RBs) of nude mice to investigate the inhibitory role of these two genes in RB development. The 40 tumor-bearing mice, which had been established by sub-retinal injection of an HXO-Rb44 cell suspension, were randomly divided into five groups: blank control group (C); blank plasmid group (M); wtp53 plasmid group (p53); Rb94 plasmid group (Rb94); wtp53 + Rb94 plasmid group (p53 + Rb94). For preparation of the DNA-loaded microbubbles, a pre-determined amount of blank plasmid, pVIVO1-p53, pVIVO1-Rb94 or pVIVO1-p53-Rb94 was added and mixed with the microbubbles. Then, these DNA-loaded microbubbles were respectively transfected into the animal model by UTMD. Vascular endothelial growth factor level and microvessel density of the tumor were determined by immunohistochemical staining. Apoptosis of tissues was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Expression of wtp53 and Rb94 at both the gene and protein levels was detected by RT-PCR (reverse transcription polymerase chain reaction) and Western blot, respectively. Transfection of both genes had greater inhibitory effects on RB development and resulted in lower levels of vascular endothelial growth factor, lower microvessel density and more obvious apoptosis than single-gene transfection (p < 0.05). The results indicate that the transfection of both genes into the RB by UTMD more strongly inhibited RB growth than transfection of a single gene.

Brodowska K, Theodoropoulou S, Meyer Zu Hörste M, et al.
Effects of metformin on retinoblastoma growth in vitro and in vivo.
Int J Oncol. 2014; 45(6):2311-24 [PubMed] Free Access to Full Article Related Publications
Recent studies suggest that the anti-diabetic drug metformin may reduce the risk of cancer and have anti-proliferative effects for some but not all cancers. In this study, we examined the effects of metformin on human retinoblastoma cell proliferation in vitro and in vivo. Two different human retinoblastoma cell lines (Y79, WERI) were treated with metformin in vitro and xenografts of Y79 cells were established in nu/nu immune-deficient mice and used to assess the effects of pharmacological levels of metformin in vivo. Metformin inhibited proliferation of the retinoblastoma cells in vitro. Similar to other studies, high concentrations of metformin (mM) blocked the cell cycle in G0‑G1, indicated by a strong decrease of G1 cyclins, especially cyclin D, cyclin-dependent kinases (4 and 6), and flow cytometry assessment of the cell cycle. This was associated with activation of AMPK, inhibition of the mTOR pathways and autophagy marker LC3B. However, metformin failed to suppress growth of xenografted tumors of Y79 human retinoblastoma cells in nu/nu mice, even when treated with a maximally tolerated dose level achieved in human patients. In conclusion, suprapharmacological levels (mM) of metformin, well above those tolerated in vivo, inhibited the proliferation of retinoblastoma cells in vitro. However, physiological levels of metformin, such as seen in the clinical setting, did not affect the growth of retinoblastoma cells in vitro or in vivo. This suggests that the potential beneficial effects of metformin seen in epidemiological studies may be limited to specific tumor types or be related to indirect effects/mechanisms not observed under acute laboratory conditions.

Philippeit C, Busch M, Dünker N
Epigenetic control of trefoil factor family (TFF) peptide expression in human retinoblastoma cell lines.
Cell Physiol Biochem. 2014; 34(3):1001-14 [PubMed] Related Publications
BACKGROUND: Recent studies demonstrated that epigenetic mechanisms are involved in the regulation of trefoil factor family (TFF) peptide expression in cancer. In human tissues with endogenous TFF1, TFF2 or TFF3 gene expression, the corresponding promoter is unmethylated and in organs without TFF expression, the promoter of the three genes is highly methylated.
METHODS: Retinoblastoma (Rb) cell lines were treated with the DNA methyltransferase inhibitor 5-Aza-2`deoxycytidine (5-Aza-dC), the histone deacetylase inhibitor 4-Phenylbutyric acid (PBA) or both and analyzed for changes (i) in TFF mRNA expression by Real-time PCR and (ii) in the methylation status of the TFF promoters by genomic bisulfite sequencing.
RESULTS: The degree of promoter methylation correlates with endogenous TFF expression in the retinoblastoma cell lines analyzed. Nearly all Rb cell lines exhibiting high endogenous TFF1 expression displayed low methylation of the CpGs in the corresponding promoter region. Low expression of TFF3 in Rb cell lines is linked with high density methylation of the TFF3 promoter. 5-Aza-dC treatment induced TFF1 and TFF3 expression in nearly all cell lines investigated and combined treatment with PBA further increased this effect. The number of methylated CpG dinucleotides of the TFF promoter is clearly reduced upon treatment with 5-Aza-dC and combined treatment with PBA further extended the degree of demethylation.
CONCLUSION: Our data clearly show that the expression of TFF3 in retinoblastoma cell lines is epigenetically regulated, whereas the level of TFF1 and TFF2 seems to be regulated by other or additional mechanisms.

Wong JR, Morton LM, Tucker MA, et al.
Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy.
J Clin Oncol. 2014; 32(29):3284-90 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
PURPOSE: Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN risks, but less is known about chemotherapy-related risks.
PATIENTS AND METHODS: In a long-term follow-up study of 906 5-year hereditary Rb survivors diagnosed from 1914 to 1996 and observed through 2009, treatment-related SMN risks were quantified using cumulative incidence analyses and multivariable Cox proportional hazards regression models with age as the underlying time scale.
RESULTS: Nearly 90% of Rb survivors were treated with RT, and almost 40% received alkylating agent (AA) -containing chemotherapy (predominantly triethylenemelamine). Median follow-up time to first SMN diagnosis was 26.3 years. Overall SMN risk was not significantly elevated among survivors receiving AA plus RT versus RT without chemotherapy (hazard ratio [HR], 1.27; 95% CI, 0.99 to 1.63). AA-related risks were significantly increased for subsequent bone tumors (HR, 1.60; 95% CI, 1.03 to 2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22 to 5.85) but not for melanoma (HR, 0.74; 95% CI, 0.36 to 1.55) or epithelial tumors (HR, 0.89; 95% CI, 0.48 to 1.64). Leiomyosarcoma risk was significantly increased for survivors who received AAs at age < 1 (HR, 5.17; 95% CI, 1.76 to 15.17) but not for those receiving AAs at age ≥ 1 year (HR, 1.75; 95% CI, 0.68 to 4.51). Development of leiomyosarcoma was significantly more common after AA plus RT versus RT (5.8% v 1.6% at age 40 years; P = .01).
CONCLUSION: This comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors also demonstrates an AA-related contribution to risk. Although triethylenemelamine is no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.

Kumar N, Gangappa D, Gupta G, Karnati R
Chebulagic acid from Terminalia chebula causes G1 arrest, inhibits NFκB and induces apoptosis in retinoblastoma cells.
BMC Complement Altern Med. 2014; 14:319 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
BACKGROUND: Plants are the valuable source of natural products with important medicinal properties. Most of the approved anti cancer drugs have a natural product origin or are natural products. Retinoblastoma is the most common ocular cancer of children. Although chemotherapy is the preferred mode of therapy, a successful treatment for retinoblastoma requires enucleation. Chebulagic acid (CA) from Terminalia chebula was shown to have anti-proliferative properties in the studies on cancerous cell lines. Due to anti cancer properties of CA and due to limitation in treatment options for retinoblastoma, the present study is undertaken to understand the role of CA on the proliferation of retinoblastoma cells.
METHODS: Anti proliferative potential of CA was determined by MTT assay. The expression levels of various cell death mediators in retinoblastoma cells with CA treatment were assessed by Western blotting. Flowcytometer analysis was used to estimate the mitochondrial membrane potential (MMP) and to determine the percentage of cells undergoing apoptosis.
RESULTS: The present study showed CA inhibited the proliferation of retinoblastoma cells in a dose dependent manner. CA modulated MMP, induced release of Cytochrome c, activated caspase 3 and shifted the ratio of BAX and Bcl2 towards cell death. G1 arrest, noticed in CA treated cells, is mediated by the increase in the expression of CDK inhibitor p27. CA treatment also decreased the levels of NFκB in the nucleus. This decrease is mediated by suppression in degradation of IκBα.
CONCLUSION: CA has shown significant anti proliferative potential on retinoblastoma cells. Our findings clearly demonstrate that CA induces G1 arrest, inhibits NFκB and induces apoptosis of retinoblastoma cells.

Thangavel C, Boopathi E, Ciment S, et al.
The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness.
Clin Cancer Res. 2014; 20(21):5468-82 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
PURPOSE: Perturbations in the retinoblastoma pathway are over-represented in advanced prostate cancer; retinoblastoma loss promotes bypass of first-line hormone therapy. Conversely, preliminary studies suggested that retinoblastoma-deficient tumors may become sensitized to a subset of DNA-damaging agents. Here, the molecular and in vivo consequence of retinoblastoma status was analyzed in models of clinical relevance.
EXPERIMENTAL DESIGN: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of retinoblastoma using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts.
RESULTS: Loss of retinoblastoma enhanced the radioresponsiveness of both hormone-sensitive and castrate-resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. Retinoblastoma loss led to alteration in DNA damage repair and activation of the NF-κB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of retinoblastoma-deficient tumors exhibited diminished tumor mass, lower PSA kinetics, and decreased tumor growth after treatment with ionizing radiation (P < 0.05).
CONCLUSIONS: Loss of retinoblastoma confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of retinoblastoma loss, but also credential retinoblastoma status as a putative biomarker for predicting response to radiotherapy.

Miles WO, Korenjak M, Griffiths LM, et al.
Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells.
EMBO J. 2014; 33(19):2201-15 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Inactivation of the retinoblastoma tumor suppressor (pRb) is a common oncogenic event that alters the expression of genes important for cell cycle progression, senescence, and apoptosis. However, in many contexts, the properties of pRb-deficient cells are similar to wild-type cells suggesting there may be processes that counterbalance the transcriptional changes associated with pRb inactivation. Therefore, we have looked for sets of evolutionary conserved, functionally related genes that are direct targets of pRb/E2F proteins. We show that the expression of NANOS, a key facilitator of the Pumilio (PUM) post-transcriptional repressor complex, is directly repressed by pRb/E2F in flies and humans. In both species, NANOS expression increases following inactivation of pRb/RBF1 and becomes important for tissue homeostasis. By analyzing datasets from normal retinal tissue and pRb-null retinoblastomas, we find a strong enrichment for putative PUM substrates among genes de-regulated in tumors. These include pro-apoptotic genes that are transcriptionally down-regulated upon pRb loss, and we characterize two such candidates, MAP2K3 and MAP3K1, as direct PUM substrates. Our data suggest that NANOS increases in importance in pRb-deficient cells and helps to maintain homeostasis by repressing the translation of transcripts containing PUM Regulatory Elements (PRE).

Grossniklaus HE
Retinoblastoma. Fifty years of progress. The LXXI Edward Jackson Memorial Lecture.
Am J Ophthalmol. 2014; 158(5):875-91 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
PURPOSE: To review the progress made in understanding the genetic basis, molecular pathology, and treatment of retinoblastoma since the previous Jackson lecture on the topic was published 50 years ago.
DESIGN: Perspective based on personal experience and the literature.
METHODS: The literature regarding retinoblastoma was reviewed since 1963. Advances in understanding the biology and treatment of retinoblastoma provided context through the author's clinical, pathologic, and research experiences.
RESULTS: Retinoblastoma was first identified in the 1500s and defined as a unique clinicopathologic entity in 1809. Until the mid-1900s, knowledge advanced sporadically, with technological developments of ophthalmoscopy and light microscopy, and with the introduction of surgical enucleation, chemotherapy, and radiation therapy. During the last 50 years, research and treatment have progressed at an unprecedented rate owing to innovations in molecular biology and the development of targeted therapies. During this time period, the retinoblastoma gene was discovered; techniques for genetic testing for retinoblastoma were developed; and plaque brachytherapy, chemoreduction, intra-arterial chemotherapy, and intraocular injections of chemotherapeutic agents were successfully introduced.
CONCLUSIONS: Nearly all patients with retinoblastoma in developed countries can now be cured of their primary cancer--a remarkable achievement for a childhood cancer that once was uniformly fatal. Much of this success is owed to deciphering the role of the Rb gene, and the benefits of targeted therapies, such as chemoreduction with consolidation as well as intra-arterial and intravitreal chemotherapies. Going forward, the main challenge will be ensuring that access to care is available for all children, particularly those in developing countries.

He LQ, Njambi L, Nyamori JM, et al.
Developing clinical cancer genetics services in resource-limited countries: the case of retinoblastoma in Kenya.
Public Health Genomics. 2014; 17(4):221-7 [PubMed] Related Publications
BACKGROUND/AIMS: Clinical cancer genetics is an integral part of cancer control and management, yet its development as an essential medical service has been hindered in many low-and-middle-income countries. We report our experiences in developing a clinical cancer genetics service for retinoblastoma in Kenya.
METHODS: A genetics task force was created from within the membership of the existing Kenyan National Retinoblastoma Strategy group. The task force engaged in multiple in-person and telephone discussions, delineating experiences, opinions and suggestions for an evidence-based, culturally sensitive retinoblastoma genetics service. Discussions were recorded and thematically categorized to develop a strategy for the design and implementation of a national retinoblastoma clinical genetics service.
RESULTS: Discussion among the retinoblastoma genetics task force supported the development of a comprehensive genetics service that rests on 3 pillars: (1) patient and family counseling, (2) community involvement, and (3) medical education.
CONCLUSIONS: A coordinated national retinoblastoma genetics task force led to the creation of a unique and relevant approach to delivering comprehensive and accurate genetic care to Kenyan retinoblastoma patients. The task force aims to stimulate innovative approaches in cancer genetics research, education and knowledge translation, taking advantage of unique opportunities offered in the African context.

Meng B, Wang Y, Li B
Suppression of PAX6 promotes cell proliferation and inhibits apoptosis in human retinoblastoma cells.
Int J Mol Med. 2014; 34(2):399-408 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The aim of this study was to investigate the role of the transcription factor, PAX6, in the development of retinoblastoma. The expression of endogenous PAX6 was knocked down using PAX6-specific lentivirus in two human retinoblastoma cell lines, SO-Rb50 and Y79. Cell proliferation functional assays and apoptotic assays were performed on the cells in which PAX6 was knocked down. The results revealed that PAX6 knockdown efficiency was significant (P<0.01, n=3) in the SO-Rb50 and Y79 cells. The inhibition of PAX6 reduced tumor cell apoptosis (P<0.05, n=3), but induced cell cycle S phase arrest (SO-Rb50; P<0.05, n=3) and G2/M phase arrest (Y79; P<0.05, n=3). Western blot analysis indicated that the inhibition of PAX6 increased the levels of the anti-apoptotic proteins, Bcl-2, proliferating cell nuclear antigen (PCNA) and CDK1, but reduced the levels of the pro-apoptotic proteins, BAX and p21. In conclusion, our data demonstrate that the suppression of PAX6 increases proliferation and decreases apoptosis in human retinoblastoma cells by regulating several cell cycle and apoptosis biomarkers.

Ghazaryan S, Sy C, Hu T, et al.
Inactivation of Rb and E2f8 synergizes to trigger stressed DNA replication during erythroid terminal differentiation.
Mol Cell Biol. 2014; 34(15):2833-47 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Rb is critical for promoting cell cycle exit in cells undergoing terminal differentiation. Here we show that during erythroid terminal differentiation, Rb plays a previously unappreciated and unorthodox role in promoting DNA replication and cell cycle progression. Specifically, inactivation of Rb in erythroid cells led to stressed DNA replication, increased DNA damage, and impaired cell cycle progression, culminating in defective terminal differentiation and anemia. Importantly, all of these defects associated with Rb loss were exacerbated by the concomitant inactivation of E2f8. Gene expression profiling and chromatin immunoprecipitation (ChIP) revealed that Rb and E2F8 cosuppressed a large array of E2F target genes that are critical for DNA replication and cell cycle progression. Remarkably, inactivation of E2f2 rescued the erythropoietic defects resulting from Rb and E2f8 deficiencies. Interestingly, real-time quantitative PCR (qPCR) on E2F2 ChIPs indicated that inactivation of Rb and E2f8 synergizes to increase E2F2 binding to its target gene promoters. Taken together, we propose that Rb and E2F8 collaborate to promote DNA replication and erythroid terminal differentiation by preventing E2F2-mediated aberrant transcriptional activation through the ability of Rb to bind and sequester E2F2 and the ability of E2F8 to compete with E2F2 for E2f-binding sites on target gene promoters.

Dehainault C, Garancher A, Castéra L, et al.
The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion.
Hum Mol Genet. 2014; 23(19):5243-50 [PubMed] Related Publications
Retinoblastoma is a non-hereditary as well as an inherited pediatric tumor of the developing retina resulting from the inactivation of both copies of the RB1 tumor suppressor gene. Familial retinoblastoma is a highly penetrant genetic disease that usually develops by carrying germline mutations that inactivate one allele of the RB1 gene, leading to multiple retinoblastomas. However, large and complete germline RB1 deletions are associated with low or no tumor risk for reasons that remain unknown. In this study, we define a minimal genomic region associated with this low penetrance. This region encompasses few genes including MED4 a subunit of the mediator complex. We further show that retinoblastoma RB1 -/- cells cannot survive in the absence of MED4, both in vitro and in orthotopic xenograft models in vivo, therefore identifying MED4 as a survival gene in retinoblastoma. We propose that the contiguous loss of the adjacent retinoblastoma gene, MED4, explains the low penetrance in patients with large deletions that include both RB1 and MED4. Our findings also point to another synthetic lethal target in tumors with inactivated RB1 and highlight the importance of collateral damage in carcinogenesis.

Dean M, Bendfeldt G, Lou H, et al.
Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala.
Cancer Lett. 2014; 351(1):59-63 [PubMed] Article available free on PMC after 28/08/2015 Related Publications
Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population.

Ayari Jeridi H, Bouguila H, Ansperger-Rescher B, et al.
Genetic testing in Tunisian families with heritable retinoblastoma using a low cost approach permits accurate risk prediction in relatives and reveals incomplete penetrance in adults.
Exp Eye Res. 2014; 124:48-55 [PubMed] Related Publications
Heritable retinoblastoma is caused by oncogenic mutations in the RB1 tumor suppressor gene. Identification of these mutations in patients is important for genetic counseling and clinical management of relatives at risk. In order to lower analytical efforts, we designed a stepwise mutation detection strategy that was adapted to the spectrum of oncogenic RB1 gene mutations. We applied this strategy on 20 unrelated patients with familial and/or de novo bilateral retinoblastoma from Tunisia. In 19 (95%) patients, we detected oncogenic mutations including base substitutions, small length mutations, and large deletions. Further analyses on the origin of the mutations showed mutational mosaicism in one unilaterally affected father of a bilateral proband and incomplete penetrance in two mothers. In a large family with several retinoblastoma patients, the mutation identified in the index patient was also detected in several non-penetrant relatives. RNA analyses showed that this mutation results in an in-frame loss of exon 9. In summary, our strategy can serve as a model for RB1 mutation identification with high analytical sensitivity. Our results point out that genetic testing is needed to reveal or exclude incomplete penetrance specifically in parents of patients with sporadic disease.

Lei Q, Shen F, Wu J, et al.
MiR-101, downregulated in retinoblastoma, functions as a tumor suppressor in human retinoblastoma cells by targeting EZH2.
Oncol Rep. 2014; 32(1):261-9 [PubMed] Related Publications
Accumulating evidence indicates that microRNAs are involved in multiple processes in cancer development and progression, and several miRNAs have emerged as candidate components of oncogene or tumor-suppressor networks in retinoblastoma. miR-101 has been identified as a tumor suppressor in several types of human cancer. However, the specific function of miR-101 in retinoblastoma remains unclear. In the present study, we found that the expression of miR-101 in retinoblastoma tissues was much lower than that in the normal controls. In addition, downregulation of miR-101 more frequently occurred in retinoblastoma specimens with adverse clinicopathological and histopathological features. In addition, miR-101 inhibited cell viability and progression in retinoblastoma cells by promoting cell apoptosis and arresting the cell cycle. Finally, we found that miR-101 directly inhibited EZH2 expression by targeting its 3'-UTR, and EZH2 was upregulated and inversely correlated with miR-101 expression in the retinoblastoma tissues. Thus, for the first time, we provide convincing evidence that downregulation of miR-101 is associated with tumor aggressiveness in retinoblastoma and inhibits cell growth and proliferation of retinoblastoma cells by targeting EZH2. In conclusion, all the evidence supports the tumor-suppressor role of miR-101 in human retinoblastoma.

Xia T, Cheng H, Zhu Y
Knockdown of hypoxia-inducible factor-1 alpha reduces proliferation, induces apoptosis and attenuates the aggressive phenotype of retinoblastoma WERI-Rb-1 cells under hypoxic conditions.
Ann Clin Lab Sci. 2014; 44(2):134-44 [PubMed] Related Publications
BACKGROUND: Hypoxia-inducible factor-1 alpha (HIF-1α) plays a critical role in tumor cell adaption to hypoxia by inducing the transcription of numerous genes. The role of HIF-1α in malignant retinoblastoma remains unclear. We analyzed the role of HIF-1α in WERI-Rb-1 retinoblastoma cells under hypoxic conditions.
METHODS: CoCl2 (125 mmol/L) was added to the culture media to mimic hypoxia. HIF-1α was silenced using siRNA. Gene and protein expression were measured by semi-quantitative RT-PCR and Western blotting. Cell cycle and apoptosis were analyzed by flow cytometry. Cell proliferation, adhesion and invasion were assayed using MTT, Transwell invasion, and cell adhesion assays respectively.
RESULT: Hypoxia significantly upregulated HIF-1α protein expression and the HIF-1α target genes VEGF, GLUT1, and Survivin mRNA. HIF-1α mRNA expression was not affected by hypoxia. Transfection of the siRNA expression plasmid pRNAT-CMV3.2/Neo-HIF-1α silenced HIF-1α by approximately 80% in hypoxic WERI-Rb-1 cells. The knockdown of HIF-1α under hypoxic conditions downregulated VEGF, GLUT1, and Survivin mRNA. It also inhibited proliferation, promoted apoptosis, induced the G0/G1 phase cell cycle arrest, and reduced the adhesion and invasion of WERI-Rb-1 cells.
CONCLUSION: HIF-1α plays a major role in the survival and aggressive phenotype of retinoblastoma cells under hypoxic conditions. Targeting HIF-1α may be a promising therapeutic strategy for human malignant retinoblastoma.

Jehanne M, Brisse H, Gauthier-Villars M, et al.
[Retinoblastoma: recent advances].
Bull Cancer. 2014; 101(4):380-7 [PubMed] Related Publications
Retinoblastoma is the most common intraocular malignancy of infancy with an incidence of 1/15,000 to 1/20,000 births. Sixty percent of retinoblastomas are unilateral, with a median age at diagnosis of two years, and in most cases are not hereditary. Retinoblastoma is bilateral in 40% of cases, with an earlier median age at diagnosis of one year. All bilateral and multifocal unilateral forms are hereditary and are part of a genetic cancer predisposition syndrome. All children with a bilateral or familial form, and 10 to 15% of children with an unilateral form, constitutionally carry an RB1 gene mutation. The two most frequent symptoms revealing retinoblastoma are leukocoria and strabismus. Diagnosis is made by fundoscopy, with ultrasound and magnetic resonance imaging (MRI) contributing both to diagnosis and assessment of the extension of the disease. Treatment of patients with retinoblastoma must take into account the various aspects of the disease (unilateral/bilateral, size, localization…), the risk to vision and the possible hereditary nature of the disease. The main prognostic aspects are still premature detection and adapted coverage by a multi-disciplinary specialized team. Enucleation is still often necessary in unilateral disease; the decision for adjuvant treatment is taken according to the histological risk factors. The most important recent therapeutic advances concern the conservative treatment which is proposed for at least one of the two eyes in most bilateral cases: laser alone or in combination with chemotherapy, cryotherapy or brachytherapy. Recently, the development of new conservative techniques of treatment, such as intra-arterial selective chemotherapy perfusion, aims at preserving visual function in these children and decreasing the number of enucleations and the need for external beam radiotherapy. The vital prognosis related to retinoblatoma is now excellent in industrialized countries, but long-term survival is still related to the development of secondary tumors, mainly secondary sarcoma. Retinoblastoma requires multi-disciplinary care as well as a long term specialized follow-up. Early counseling of patients and their family concerning the risk of transmission of the disease and the risk of development of secondary tumors is necessary.

Chebbi A, Bouguila H, Boussaid S, et al.
[Clinical features of retinoblastoma in Tunisia].
J Fr Ophtalmol. 2014; 37(6):442-8 [PubMed] Related Publications
PURPOSE: To report the relative frequency of presenting signs in Tunisian children with retinoblastoma and to evaluate their prognostic impact.
METHODS: A retrospective study was undertaken of 200 patients with retinoblastoma examined and treated between January 1993 and June 2009.
RESULTS: There were 123 boys and 77 girls. For all cases, mean age at diagnosis was 29.8 months (range, 1 month to 9 years). There were 138 (69%) unilateral cases and 62 (31%) bilateral cases. Nineteen children (9.5%) had a family history of retinoblastoma. The most common signs were leukocoria (80%) and strabismus (28%) followed by proptosis. Orbital inflammation, hyphemia and phthisis are rare presenting findings in retinoblastoma. In our series, 26 children (13%) presented with extraocular retinoblastoma. Leukocoria and proptosis are significantly associated with a worse prognosis.
CONCLUSION: The ability to recognize the presenting signs and symptoms of retinoblastoma can lead to earlier diagnosis and better prognosis.

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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