Gene Summary

Gene:RB1; RB transcriptional corepressor 1
Aliases: RB, pRb, OSRC, pp110, p105-Rb, PPP1R130
Summary:The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:retinoblastoma-associated protein
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

The Retinoblastoma gene (RB1), located on chromosome 13, is a tumour suppressor gene that was discovered in genetic studies of hereditary retinoblastoma. It also has a role in other cancers including osteosarcoma. The RB1 gene is important because it helps regulates cell division, if the gene is absent then cells may proliferate in an uncontrolled way leading to tumour formation. In hereditary retinoblastoma the RB1 gene is lost and children have multiple tumours in both eyes, while in children with sporadic (non-hereditary) retinoblastoma there is usually only one tumour in one eye.

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

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 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
RetinoblastomaRB1 mutation in Retinoblastoma
In an analysis of 192 patients with retinoblastoma with identifiable germline mutations in the RB gene (Harbour, 1998), the DNA alteration was a nonsense mutation in 83 (43%), frameshift in 67 (35%), intron mutation in 23 (12%), missense mutation in 11 (6%), in-frame deletion in 5 (3%), and promoter mutation in 3 (2%).
View Publications588
Acute Lymphocytic Leukaemia (ALL)RB1 and Acute Leukaemias View Publications126
Lung CancerRB1 and Lung Cancer View Publications103
Bladder CancerRB1 and Bladder Cancer View Publications72
Breast CancerRB1 mutations in Breast Cancer
RB1 mutations are found in some breast cancers; there is a non-random relationship between p53 mutation and loss of material from the RB1 locus.
View Publications73
OsteosarcomaRB1 and Osteosarcoma View Publications68
Esophageal CancerRB1 and Esophageal Cancer View Publications12
Adrenocortical CancerRB1 and Adrenocortical Carcinoma View Publications9

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

Latest Publications: RB1 (cancer-related)

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.

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.

Yu W, Liang S, Zhang C
Aberrant miRNAs Regulate the Biological Hallmarks of Glioblastoma.
Neuromolecular Med. 2018; 20(4):452-474 [PubMed] Related Publications
GBM is the highest incidence in primary intracranial malignancy, and it remains poor prognosis even though the patient is gave standard treatment. Despite decades of intense research, the complex biology of GBM remains elusive. In view of eight hallmarks of cancer which were proposed in 2011, studies related to the eight biological capabilities in GBM have made great progress. From these studies, it can be inferred that miRs, as a mode of post-transcriptional regulation, are involved in regulating these malignant biological hallmarks of GBM. Herein, we discuss state-of-the-art research on how aberrant miRs modulate the eight hallmarks of GBM. The upregulation of 'oncomiRs' or the genetic loss of tumor suppressor miRs is associated with these eight biological capabilities acquired during GBM formation. Furthermore, we also discuss the applicable clinical potential of these research results. MiRs may aid in the diagnosis and prognosis of GBM. Moreover, miRs are also therapeutic targets of GBM. These studies will develop and improve precision medicine for GBM in the future.

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.

Parrilla-Vallejo M, Perea-Pérez R, Relimpio-López I, et al.
Retinoblastoma: The importance of early diagnosis.
Arch Soc Esp Oftalmol. 2018; 93(9):423-430 [PubMed] Related Publications
INTRODUCTION: Retinoblastoma is the most frequent malignant intraocular tumour in childhood, and both its cure and the sequelae arising from it, mainly depend on an early diagnosis. There is currently no consensus on its diagnostic and therapeutic management.
PATIENTS AND METHODS: A descriptive, retrospective, and non-randomised study was conducted on a series of cases (39 patients -58 eyes), treated during the period 2006-2013, in the Regional Reference Centre for Tumours of the National Health Service Quality Agency.
RESULTS: The most frequent presentation sign is leukocoria (71.8%), followed by strabismus (17.9%). All cases of bilateral tumour had a germline mutation of the RB1 gene, and 20% had a family history. Stage E was observed in 55% of the patients, and 90% required chemotherapy treatment. The eye was maintained in 57% of those who had mild stages, compared to 43% who maintained it in advanced stages.
CONCLUSIONS: This analysis included 58 eyes. There are no previous studies in our community and there are few series so numerous throughout the country. Based on non-standardised treatment, the most appropriate is chosen according to the characteristics of the tumour. The multidisciplinary management, formed by ophthalmology, paediatric oncology, radiotherapy, and radiophysical oncology, is fundamental for the selection of the most appropriate treatment. Chemo-reduction, along with consolidation treatments, offers encouraging results in the control of these tumours, especially in those of less severity. Enucleation continues to be the method of choice in the most advanced staging with vitreous involvement, with the importance of early diagnosis being highlighted.

Hossain S, Iwasa H, Sarkar A, et al.
The RASSF6 Tumor Suppressor Protein Regulates Apoptosis and Cell Cycle Progression via Retinoblastoma Protein.
Mol Cell Biol. 2018; 38(17) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
RASSF6 is a member of the tumor suppressor Ras association domain family (RASSF) proteins.

Maeda A, Yoshida A, Kawai K, et al.
Development of a molecular diagnostic test for Retinitis Pigmentosa in the Japanese population.
Jpn J Ophthalmol. 2018; 62(4):451-457 [PubMed] Related Publications
PURPOSE: Retinitis Pigmentosa (RP) is the most common form of inherited retinal dystrophy caused by different genetic variants. More than 60 causative genes have been identified to date. The establishment of cost-effective molecular diagnostic tests with high sensitivity and specificity can be beneficial for patients and clinicians. Here, we developed a clinical diagnostic test for RP in the Japanese population.
STUDY DESIGN: Evaluation of diagnostic technology, Prospective, Clinical and experimental study.
METHODS: A panel of 39 genes reported to cause RP in Japanese patients was established. Next generation sequence (NGS) technology was applied for the analyses of 94 probands with RP and RP-related diseases. After interpretation of detected genetic variants, molecular diagnosis based on a study of the genetic variants and a clinical phenotype was made by a multidisciplinary team including clinicians, researchers and genetic counselors.
RESULTS: NGS analyses found 14,343 variants from 94 probands. Among them, 189 variants in 83 probands (88.3% of all cases) were selected as pathogenic variants and 64 probands (68.1%) have variants which can cause diseases. After the deliberation of these 64 cases, molecular diagnosis was made in 43 probands (45.7%). The final molecular diagnostic rate with the current system combining supplemental Sanger sequencing was 47.9% (45 of 94 cases).
CONCLUSIONS: The RP panel provides the significant advantage of detecting genetic variants with a high molecular diagnostic rate. This type of race-specific high-throughput genotyping allows us to conduct a cost-effective and clinically useful genetic diagnostic test.

AlAli A, Kletke S, Gallie B, Lam WC
Retinoblastoma for Pediatric Ophthalmologists.
Asia Pac J Ophthalmol (Phila). 2018 May-Jun; 7(3):160-168 [PubMed] Related Publications
Retinoblastoma can present in 1 or both eyes and is the most common intraocular malignancy in childhood. It is typically initiated by biallelic mutation of the RB1 tumor suppressor gene, leading to malignant transformation of primitive retinal cells. The most common presentation is leukocoria, followed by strabismus. Heritable retinoblastoma accounts for 45% of all cases, with 80% being bilateral. Treatment and prognosis of retinoblastoma is dictated by the disease stage at initial presentation. The 8th Edition American Joint Committee on Cancer (AJCC) TNMH (tumor, node, metastasis, heritable trait) staging system defines evidence-based clinical and pathological staging for overall prognosis for eye(s) and child. Multiple treatment options are available in 2018 for retinoblastoma management with a multidisciplinary team, including pediatric ocular oncology, medical oncology, radiation oncology, genetics, nursing, and social work. Survival exceeds 95% when disease is diagnosed early and treated in centers specializing in retinoblastoma. However, survival rates are less than 50% with extraocular tumor dissemination. We summarize the epidemiology, genetics, prenatal screening, diagnosis, classification, investigations, and current therapeutic options in the management of retinoblastoma.

Jansen RW, de Jong MC, Kooi IE, et al.
MR Imaging Features of Retinoblastoma: Association with Gene Expression Profiles.
Radiology. 2018; 288(2):506-515 [PubMed] Related Publications
Purpose To identify associations between magnetic resonance (MR) imaging features and gene expression in retinoblastoma. Materials and Methods A retinoblastoma MR imaging atlas was validated by using anonymized MR images from referral centers in Essen, Germany, and Paris, France. Images were from 39 patients with retinoblastoma (16 male and 18 female patients [the sex in five patients was unknown]; age range, 5-90 months; inclusion criterion: pretreatment MR imaging). This atlas was used to compare MR imaging features with genome-wide messenger RNA (mRNA) expression data from 60 consecutive patients obtained from 1995 to 2012 (35 male patients [58%]; age range, 2-69 months; inclusion criteria: pretreatment MR imaging, genome-wide mRNA expression data available). Imaging pathway associations were analyzed by means of gene enrichment. In addition, imaging features were compared with a predefined gene expression signature of photoreceptorness. Statistical analysis was performed with generalized linear modeling of radiology traits on normalized log2-transformed expression values. P values were corrected for multiple hypothesis testing. Results Radiogenomic analysis revealed 1336 differentially expressed genes for qualitative imaging features (threshold P = .05 after multiple hypothesis correction). Loss of photoreceptorness gene expression correlated with advanced stage imaging features, including multiple lesions (P = .03) and greater eye size (P < .001). The number of lesions on MR images was associated with expression of MYCN (P = .04). A newly defined radiophenotype of diffuse-growing, plaque-shaped, multifocal tumors displayed overexpression of SERTAD3 (P = .003, P = .049, and P = .06, respectively), a protein that stimulates cell growth by activating the E2F network. Conclusion Radiogenomic biomarkers can potentially help predict molecular features, such as photoreceptorness loss, that indicate tumor progression. Results imply a possible role for radiogenomics in future staging and treatment decision making in retinoblastoma.

McBrayer SK, Olenchock BA, DiNatale GJ, et al.
Autochthonous tumors driven by
Proc Natl Acad Sci U S A. 2018; 115(16):E3741-E3748 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Inactivation of the retinoblastoma gene (

Risi E, Grilli A, Migliaccio I, et al.
A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients.
Breast Cancer Res Treat. 2018; 170(2):329-341 [PubMed] Related Publications
PURPOSE: HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients.
METHODS: We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR.
RESULTS: Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group.
CONCLUSIONS: Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.

Tian X, Doerig K, Park R, et al.
Evolution of telomere maintenance and tumour suppressor mechanisms across mammals.
Philos Trans R Soc Lond B Biol Sci. 2018; 373(1741) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Mammalian species differ dramatically in telomere biology. Species larger than 5-10 kg repress somatic telomerase activity and have shorter telomeres, leading to replicative senescence. It has been proposed that evolution of replicative senescence in large-bodied species is an anti-tumour mechanism counteracting increased risk of cancer due to increased cell numbers. By contrast, small-bodied species express high telomerase activity and have longer telomeres. To counteract cancer risk due to longer lifespan, long-lived small-bodied species evolved additional telomere-independent tumour suppressor mechanisms. Here, we tested the connection between telomere biology and tumorigenesis by analysing the propensity of fibroblasts from 18 rodent species to form tumours. We found a negative correlation between species lifespan and anchorage-independent growth. Small-bodied species required inactivation of Rb and/or p53 and expression of oncogenic H-Ras to form tumours. Large-bodied species displayed a continuum of phenotypes requiring additional genetic 'hits' for malignant transformation. Based on these data we refine the model of the evolution of tumour suppressor mechanisms and telomeres. We propose that two different strategies evolved in small and large species because small-bodied species cannot tolerate small tumours that form prior to activation of the telomere barrier, and must instead use telomere-independent strategies that act earlier, at the hyperplasia stage.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.

Chudasama P, Mughal SS, Sanders MA, et al.
Integrative genomic and transcriptomic analysis of leiomyosarcoma.
Nat Commun. 2018; 9(1):144 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of "BRCAness", including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies.

Freytsis M, Baugh L, Liu Z, et al.
Conditional deletion of RB1 in the Tie2 lineage leads to aortic valve regurgitation.
PLoS One. 2018; 13(1):e0190623 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
OBJECTIVE: Aortic valve disease is a complex process characterized by valve interstitial cell activation, disruption of the extracellular matrix culminating in valve mineralization occurring over many years. We explored the function of the retinoblastoma protein (pRb) in aortic valve disease, given its critical role in mesenchymal cell differentiation including bone development and mineralization.
APPROACH AND RESULTS: We generated a mouse model of conditional pRb knockout (cKO) in the aortic valve regulated by Tie2-Cre-mediated excision of floxed RB1 alleles. Aged pRb cKO animals showed significantly more aortic valve regurgitation by echocardiography compared to pRb het control animals. The pRb cKO aortic valves had increased leaflet thickness without increased cellular proliferation. Histologic studies demonstrated intense α-SMA expression in pRb cKO leaflets associated with disorganized extracellular matrix and increased leaflet stiffness. The pRb cKO mice also showed increased circulating cytokine levels.
CONCLUSIONS: Our studies demonstrate that pRb loss in the Tie2-lineage that includes aortic valve interstitial cells is sufficient to cause age-dependent aortic valve dysfunction.

Featherston J, Arakaki Y, Hanschen ER, et al.
The 4-Celled Tetrabaena socialis Nuclear Genome Reveals the Essential Components for Genetic Control of Cell Number at the Origin of Multicellularity in the Volvocine Lineage.
Mol Biol Evol. 2018; 35(4):855-870 [PubMed] Related Publications
Multicellularity is the premier example of a major evolutionary transition in individuality and was a foundational event in the evolution of macroscopic biodiversity. The volvocine chlorophyte lineage is well suited for studying this process. Extant members span unicellular, simple colonial, and obligate multicellular taxa with germ-soma differentiation. Here, we report the nuclear genome sequence of one of the most morphologically simple organisms in this lineage-the 4-celled colonial Tetrabaena socialis and compare this to the three other complete volvocine nuclear genomes. Using conservative estimates of gene family expansions a minimal set of expanded gene families was identified that associate with the origin of multicellularity. These families are rich in genes related to developmental processes. A subset of these families is lineage specific, which suggests that at a genomic level the evolution of multicellularity also includes lineage-specific molecular developments. Multiple points of evidence associate modifications to the ubiquitin proteasomal pathway (UPP) with the beginning of coloniality. Genes undergoing positive or accelerating selection in the multicellular volvocines were found to be enriched in components of the UPP and gene families gained at the origin of multicellularity include components of the UPP. A defining feature of colonial/multicellular life cycles is the genetic control of cell number. The genomic data presented here, which includes diversification of cell cycle genes and modifications to the UPP, align the genetic components with the evolution of this trait.

Vasaikar SV, Straub P, Wang J, Zhang B
LinkedOmics: analyzing multi-omics data within and across 32 cancer types.
Nucleic Acids Res. 2018; 46(D1):D956-D963 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The LinkedOmics database contains multi-omics data and clinical data for 32 cancer types and a total of 11 158 patients from The Cancer Genome Atlas (TCGA) project. It is also the first multi-omics database that integrates mass spectrometry (MS)-based global proteomics data generated by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) on selected TCGA tumor samples. In total, LinkedOmics has more than a billion data points. To allow comprehensive analysis of these data, we developed three analysis modules in the LinkedOmics web application. The LinkFinder module allows flexible exploration of associations between a molecular or clinical attribute of interest and all other attributes, providing the opportunity to analyze and visualize associations between billions of attribute pairs for each cancer cohort. The LinkCompare module enables easy comparison of the associations identified by LinkFinder, which is particularly useful in multi-omics and pan-cancer analyses. The LinkInterpreter module transforms identified associations into biological understanding through pathway and network analysis. Using five case studies, we demonstrate that LinkedOmics provides a unique platform for biologists and clinicians to access, analyze and compare cancer multi-omics data within and across tumor types. LinkedOmics is freely available at http://www.linkedomics.org.

Samal J, Kandpal M, Vivekanandan P
HBeAg-induced miR-106b promotes cell growth by targeting the retinoblastoma gene.
Sci Rep. 2017; 7(1):14371 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Chronic HBV infection is a major cause of hepatocellular carcinoma (HCC). The association between hepatitis B "e" antigen (HBeAg) and HCC is well-established by epidemiological studies. Nonetheless, the biological role of HBeAg in HCC remains enigmatic. We investigate the role of HBeAg in HBV-related HCC. Our findings suggest that HBeAg enhances cell proliferation and accelerates progression from G0/G1 phase to the S phase of the cell cycle in Huh7 cells. Examination of host gene expression and miRNA expression profiles reveals a total of 21 host genes and 12 host miRNAs that were differentially regulated in cells expressing HBeAg. Importantly, HBeAg induced the expression of miR-106b, an oncogenic miRNA. Interestingly, HBeAg-expression results in a significant reduction in the expression of retinoblastoma (Rb) gene, an experimentally validated target of miR-106b. Inhibition of miR-106b significantly increased the expression of the Rb gene, resulting in reduced cell proliferation and slowing of cell cycle progression from the G0/G1 phase to S phase. These observations suggest that the up-regulation of miR-106b by HBeAg contributes to the pathogenesis of HBV-related HCC by down-regulating the Rb gene. Our results highlight a role for HBeAg in HCC and provide a novel perspective on the molecular mechanisms underlying HBV-related HCC.

Yang Q, Tripathy A, Yu W, et al.
Hypoxia inhibits growth, proliferation, and increases response to chemotherapy in retinoblastoma cells.
Exp Eye Res. 2017; 162:48-61 [PubMed] Related Publications
Retinoblastoma is a malignant tumor of the retina and the most frequent intraocular cancer in children. Low oxygen tension (hypoxia) is a common phenomenon in advanced retinoblastomas, but its biological effect on retinoblastoma growth is not clearly understood. Here we studied how hypoxia altered retinoblastoma gene expression and modulated growth and response to chemotherapy. The hypoxic marker lysyl oxidase (LOX) was expressed in 8 of 12 human retinoblastomas analyzed by immunohistochemistry, suggesting that a hypoxic microenvironment is present in up to two thirds of the cases. WERI Rb1 and Y79 retinoblastoma lines were exposed to 1% or 5% pO

Zhai Y, Wu R, Kuick R, et al.
High-grade serous carcinomas arise in the mouse oviduct via defects linked to the human disease.
J Pathol. 2017; 243(1):16-25 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Recent studies have suggested that the most common and lethal type of 'ovarian' cancer, i.e. high-grade serous carcinoma (HGSC), usually arises from epithelium on the fallopian tube fimbriae, and not from the ovarian surface epithelium. We have developed Ovgp1-iCreER

Meng QY, Huang LZ, Wang B, et al.
[Application of gene capture technology on mutation screening of RB1 gene in retinoblastoma patients].
Zhonghua Yan Ke Za Zhi. 2017; 53(6):455-459 [PubMed] Related Publications

Liu S, Yan G, Zhang J, Yu L
Knockdown of Long Noncoding RNA (lncRNA) Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Inhibits Proliferation, Migration, and Invasion and Promotes Apoptosis by Targeting miR-124 in Retinoblastoma.
Oncol Res. 2018; 26(4):581-591 [PubMed] Related Publications
Evidence suggests that the long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is upregulated in cancer tissues, and its elevated expression is associated with hyperproliferation. However, the underlying mechanisms regarding the role of MALAT1 in retinoblastoma (RB) remain unclear. This study aimed to explore the functional role of MALAT1 in RB by targeting miR-124. The results showed that the expression of MALAT1 was significantly higher in the Y79 cell line than in the ARPE-19 cell line (

Pulitzer M
Merkel Cell Carcinoma.
Surg Pathol Clin. 2017; 10(2):399-408 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Merkel cell carcinoma (MCC) encompasses neuroendocrine carcinomas primary to skin and occurs most commonly in association with clonally integrated Merkel cell polyomavirus with related retinoblastoma protein sequestration or in association with UV radiation-induced alterations involving the TP53 gene and mutations, heterozygous deletion, and hypermethylation of the Retinoblastoma gene. Molecular genetic signatures may provide therapeutic guidance. Morphologic features, although patterned, are associated with predictable diagnostic pitfalls, usually resolvable by immunohistochemistry. Therapeutic options for MCC, traditionally limited to surgical intervention and later chemotherapy and radiation, are growing, given promising early results of immunotherapeutic regimens.

Soliman SE, Racher H, Zhang C, et al.
Genetics and Molecular Diagnostics in Retinoblastoma--An Update.
Asia Pac J Ophthalmol (Phila). 2017 Mar-Apr; 6(2):197-207 [PubMed] Related Publications
Retinoblastoma is the prototype genetic cancer: in one or both eyes of young children, most retinoblastomas are initiated by biallelic mutation of the retinoblastoma tumor suppressor gene, RB1, in a developing retinal cell. All those with bilateral retinoblastoma have heritable cancer, although 95% have not inherited the RB1 mutation. Non-heritable retinoblastoma is always unilateral, with 98% caused by loss of both RB1 alleles from the tumor, whereas 2% have normal RB1 in tumors initiated by amplification of the MYCN oncogene. Good understanding of retinoblastoma genetics supports optimal care for retinoblastoma children and their families. Retinoblastoma is the first cancer to officially acknowledge the seminal role of genetics in cancer, by incorporating "H" into the eighth edition of cancer staging (2017): those who carry the RB1 cancer-predisposing gene are H1; those proven to not carry the familial RB1 mutation are H0; and those at unknown risk are HX. We suggest H0* be used for those with residual <1% risk to carry a RB1 mutation due to undetectable mosaicism. Loss of RB1 from a susceptible developing retinal cell initiates the benign precursor, retinoma. Progressive genomic changes result in retinoblastoma, and cancer progression ensues with increasing genomic disarray. Looking forward, novel therapies are anticipated from studies of retinoblastoma and metastatic tumor cells and the second primary cancers that the carriers of RB1 mutations are at high risk to develop. Here, we summarize the concepts of retinoblastoma genetics for ophthalmologists in a question/answer format to assist in the care of patients and their families.

Wang B, Du R, Xiao X, et al.
Microrna-217 modulates human skin fibroblast senescence by directly targeting DNA methyltransferase 1.
Oncotarget. 2017; 8(20):33475-33486 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
DNA methyltransferase 1 (DNMT1) is a major epigenetic regulator associated with many biological processes. However, the roles and mechanisms of DNMT1 in skin aging are incompletely understood. Here we explored the role of DNMT1 in human skin fibroblasts senescence and its related regulatory mechanisms. DNMT1 expression decreased in passage-aged fibroblasts and DNMT1 silencing in young fibroblasts induced the senescence phenotype. MiR-217 is predicted to target DNMT1 mRNA and miR-217 expression increased in passage-aged fibroblasts. MiR-217 directly targeted the 3'-untranslated region (3'-UTR) of DNMT1 in HEK 293T cells and inhibited DNMT1 expression in fibroblasts. MiR-217 overexpression induced a senescence phenotype in young fibroblasts, and miR-217 downregulation in old HSFs partially reversed the senescence phenotype. However, these effects could be significantly rescued by regulating DNMT1 expression in fibroblasts. After regulating miR-217 levels, we analyzed changes in the promoter methylation levels of 24 senescent-associated genes, finding that 6 genes were significantly altered, and verified p16 and phosphorylated retinoblastoma (pRb) protein levels. Finally, an inverse correlation between DNMT1 and miR-217 expression was observed in skin tissues and different-aged fibroblasts. Together, these findings revealed that miR-217 promotes fibroblasts senescence by suppressing DNMT1-mediated methylation of p16 and pRb by targeting the DNMT1 3'-UTR.

Carvalho IN, Reis AH, Dos Santos AC, Vargas FR
A polymorphism in mir-34b/c as a potential biomarker for early onset of hereditary retinoblastoma.
Cancer Biomark. 2017; 18(3):313-317 [PubMed] Related Publications
BACKGROUND: Retinoblastoma (RB) is a malignant pediatric tumor and, mainly because of late diagnosis, most patients undergo enucleation. The tumor almost always initiates by two inactivation events at the RB1 gene. Single nucleotide polymorphisms (SNPs) in p53 pathway have been found to represent genetic modifiers of RB.
OBJECTIVE: To investigate whether a SNP (rs4938723T > C) in mir-34b/c gene, a key effector of p53, could influence RB risk and patients' age of onset.
METHODS: mir-34b/c rs4938723T > C was sequenced in 130 RB patients and in 105 control individuals. Statistical analysis consisted of χ 2 tests or Fisher's exact, odds ratios (ORs) and Mann-Whitney test.
RESULTS: The presence of the C allele did not change the risk for retinoblastoma. However, in hereditary RB patients, the mean age at diagnosis is much lower (1.4 ± 1.4 months) among CC carriers than when it is compared to TT genotype (13.8 ± 6.4, p = 0.001). Besides, hereditary RB patients with CC genotype are around 4 times more likely to present retinoblastoma under the age of 3 months (OR = 4.44; IC: 2.50-7.90; p = 0.002).
CONCLUSIONS: The C allele together with a germ-line RB1 gene mutation may speed retinoblastoma onset which suggests that mir-34b/c rs4938723T > C may represent a candidate biomarker for hereditary RB.

Dommering CJ, Henneman L, van der Hout AH, et al.
Uptake of prenatal diagnostic testing for retinoblastoma compared to other hereditary cancer syndromes in the Netherlands.
Fam Cancer. 2017; 16(2):271-277 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands. Uptake for retinoblastoma (Rb) was compared with uptake for Von Hippel-Lindau disease (VHL), Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and hereditary breast ovarian cancer (HBOC). A questionnaire was completed by all nine DNA-diagnostic laboratories assessing the number of independent mutation-positive families identified from the start of diagnostic testing until May 2013, and the number of PNDs performed for these syndromes within these families. Of 187 families with a known Rb-gene mutation, 22 had performed PND (11.8%), this was significantly higher than uptake for FAP (1.6%) and HBOC (<0.2%). For VHL (6.5%) and LFS (4.9%) the difference was not statistically significant. PND for Rb started 3 years after introduction of diagnostic DNA testing and remained stable over the years. For the other cancer syndromes PND started 10-15 years after the introduction and uptake for PND showed an increase after 2009. We conclude that uptake of PND for Rb was significantly higher than for FAP and HBOC, but not different from VHL and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences.

Shah PK, Sripriya S, Narendran V, Pandian AJ
Prenatal genetic diagnosis of retinoblastoma and report of RB1 gene mutation from India.
Ophthalmic Genet. 2016; 37(4):430-433 [PubMed] Related Publications
BACKGROUND: Retinoblastoma is the most common intraocular malignancy of childhood. There is a paucity of genetic testing and prenatal genetic diagnosis from India, which has the highest incidence worldwide.
MATERIALS AND METHODS: RB1 gene screening of an 8-month-old female child with bilateral retinoblastoma was accomplished using next generation sequencing. The results were used for prenatal testing in this family.
RESULTS: A heterozygous germline mutation (chr13: 48951119delA; c.1281delA) was detected, which resulted in premature termination of a protein product (p.Glu428Argfs*29). Prenatal testing in maternal DNA revealed carrier status of the mother. Further clinical examination in the family members revealed retinocytomas in both eyes of the mother and maternal grandmother. Prenatal genetic testing of the developing fetus showed positivity for the mutation. As the family preferred to continue the pregnancy, serial 3-D ultrasounds were carried out every 2 weeks in the third trimester. Ten days after delivery, small extrafoveal tumors developed in both eyes, which were then treated successfully with transpupillary thermotherapy.
CONCLUSION: We report the significance of genetic testing in the early detection and management of retinoblastoma from India.

Kommoss S, Gilks CB, du Bois A, Kommoss F
Ovarian carcinoma diagnosis: the clinical impact of 15 years of change.
Br J Cancer. 2016; 115(8):993-999 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Until recently ovarian carcinoma was considered to be a single disease, and treatment decisions were based solely on grade and pre- and postoperative tumour burden. New insights into molecular features, treatment response, and patient demographics led the scientific community to conclude that ovarian carcinoma histotypes are different disease entities.
METHODS: In 2002, the pathology specimens from patients in a clinical trial were reviewed by an experienced gynaecopathologist (pathologist A) for translational research purposes. All cases were typed according to what were then current criteria. The identical cohort was now reassessed by the same expert pathologist and independently reviewed by another gynaecopathologist (pathologist B) applying WHO 2014 diagnostic criteria. Survival analyses were done based on the original as well as the new diagnoses, and historical biomarker study results were recalculated.
RESULTS: Upon re-review, pathologist A rendered the same histotype diagnosis in only 54% of cases. In contrast, pathologists A and B independently rendered the same diagnosis in 98% of cases. Histotype was of prognostic significance when 2014 diagnoses were used, but was not prognostic using the original (2002) histotype diagnoses.
CONCLUSIONS: Our study demonstrates a marked shift in ovarian carcinoma histotype diagnosis over the past 15 years. The new criteria are associated with a very high degree of interobserver reproducibility, allowing for treatment decisions based on histotype. Finally, biomarkers of putative prognostic significance were revealed to be primarily histotype-specific markers, confirming the critical importance of obtaining up-to-date diagnoses rather than accepting archival histotype data in clinical research.

Singh J, Mishra A, Pandian AJ, et al.
Next-generation sequencing-based method shows increased mutation detection sensitivity in an Indian retinoblastoma cohort.
Mol Vis. 2016; 22:1036-47 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: Retinoblastoma (Rb) is the most common primary intraocular cancer of childhood and one of the major causes of blindness in children. India has the highest number of patients with Rb in the world. Mutations in the RB1 gene are the primary cause of Rb, and heterogeneous mutations are distributed throughout the entire length of the gene. Therefore, genetic testing requires screening of the entire gene, which by conventional sequencing is time consuming and expensive.
METHODS: In this study, we screened the RB1 gene in the DNA isolated from blood or saliva samples of 50 unrelated patients with Rb using the TruSight Cancer panel. Next-generation sequencing (NGS) was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform.
RESULTS: We were able to detect germline pathogenic mutations in 66% (33/50) of the cases, 12 of which were novel. We were able to detect all types of mutations, including missense, nonsense, splice site, indel, and structural variants. When we considered bilateral Rb cases only, the mutation detection rate increased to 100% (22/22). In unilateral Rb cases, the mutation detection rate was 30% (6/20).
CONCLUSIONS: Our study suggests that NGS-based approaches increase the sensitivity of mutation detection in the RB1 gene, making it fast and cost-effective compared to the conventional tests performed in a reflex-testing mode.

Mallipatna A, Marino M, Singh AD
Genetics of Retinoblastoma.
Asia Pac J Ophthalmol (Phila). 2016 Jul-Aug; 5(4):260-4 [PubMed] Related Publications
Retinoblastoma is a malignant retinal tumor that affects young children. Mutations in the RB1 gene cause retinoblastoma. Mutations in both RB1 alleles within the precursor retinal cell are essential, with one mutation that may be germline or somatic and the second one that is always somatic. Identification of the RB1 germline status of a patient allows differentiation between sporadic and heritable retinoblastoma variants. Application of this knowledge is crucial for assessing short-term (risk of additional tumors in the same eye and other eye) and long-term (risk of nonocular malignant tumors) prognosis and offering cost-effective surveillance strategies. Genetic testing and genetic counseling are therefore essential components of care for all children diagnosed with retinoblastoma. The American Joint Committee on Cancer has acknowledged the importance of detecting this heritable trait and has introduced the letter "H" to denote a heritable trait of all cancers, starting with retinoblastoma (in publication). In this article, we discuss the clinically relevant aspects of genetic testing and genetic counseling for a child with retinoblastoma.

Further References

Harbour JW
Overview of RB gene mutations in patients with retinoblastoma. Implications for clinical genetic screening.
Ophthalmology. 1998; 105(8):1442-7 [PubMed] Related Publications
OBJECTIVE: This study aimed to determine the distribution of germline mutations in the retinoblastoma (RB) gene in patients with retinoblastoma to design more effective genetic testing.
DESIGN: A meta-analysis.
PARTICIPANTS: 192 cases identified from literature.
METHODS: All identifiable reported cases of bilateral retinoblastoma, which included DNA sequence analysis of the RB gene, were reviewed.
MAIN OUTCOME MEASURE: Type of genetic mutation.
RESULTS: Among 192 patients with retinoblastoma with identifiable germline mutations in the RB gene, the DNA alteration was a nonsense mutation in 83 (43%), frameshift in 67 (35%), intron mutation in 23 (12%), missense mutation in 11 (6%), in-frame deletion in 5 (3%), and promoter mutation in 3 (2%). Mutations were distributed throughout 24 of the 27 exons of the RB gene with no single mutational "hotspot." Exons 8, 17, 18, and 23 were involved most often, and 189 (98%) of the mutations were predicted to affect the RB large pocket domain.
CONCLUSIONS: A single genetic test is unlikely to detect all germline RB gene mutations in patients with retinoblastoma because of the variety of types and locations of mutations that occur. However, a series of complementary tests may be able to rapidly detect mutations based on the observation that most mutations alter the protein size and disrupt the large pocket domain.

Toguchida J, Ishizaki K, Sasaki MS, et al.
Chromosomal reorganization for the expression of recessive mutation of retinoblastoma susceptibility gene in the development of osteosarcoma.
Cancer Res. 1988; 48(14):3939-43 [PubMed] Related Publications
Recent evidence indicates that the mutation of retinoblastoma susceptibility (RB) gene is also involved in the development of osteosarcoma. We studied 30 cases of osteosarcoma for the structural anomalies of the RB gene by Southern hybridization analysis with cDNA probes of the RB gene. Thirteen cases (43%) showed structural anomalies of the RB gene. They included the total or partial deletion, or rearrangement of the RB gene; seven with homozygous deletions and six with hemizygous deletions or rearrangements. By the use of restriction fragment length polymorphism fragments as chromosome markers, those seven tumors having homozygous deletions and four of six tumors having hemizygous anomalies showed the loss of heterozygosity at other loci on chromosome 13. Among those tumors with no apparent structural changes of the RB gene, seven cases showed the loss of heterozygosity on chromosome 13, and altogether the loss of heterozygosity by either homozygosity or hemizygosity was found in 18 (64%) of 28 informative cases. The loss of heterozygosity was also found for nine of 10 other chromosomes, of which chromosome 17 showed the highest frequency (77%). The tumors with loss of chromosome 13 alleles also showed additional losses of alleles on other chromosomes, while tumors retaining heterozygosity of chromosome 13 also retained heterozygosity at the informative loci on other chromosomes. Southern hybridization and karyotype analysis in some selected cases suggest that the concerted loss of heterozygosity at multiple loci may be a consequence of the polyploidization-segregation process.

Miller CW, Aslo A, Won A, et al.
Alterations of the p53, Rb and MDM2 genes in osteosarcoma.
J Cancer Res Clin Oncol. 1996; 122(9):559-65 [PubMed] Related Publications
Molecular defects affecting tumor-suppressor genes are an important step in the genesis of sarcomas. For example, inheritance of a defective Rb or p53 gene predisposes the carrier to develop osteosarcoma, among other malignancies. In this study, we have assessed the occurrence of p53, Rb and MDM2 alterations in the same samples of osteosarcomas, along with representative samples of various other sarcomas. Point mutations of the p53 gene were found in 13 of 42 osteosarcomas and 1 of 8 leiomyosarcomas, and gross rearrangement of the p53 gene was demonstrated in 5 of 37 osteosarcomas. The retinoblastoma susceptibility gene (Rb) was either rearranged or deleted in 7 of 37 osteosarcomas, 1 of 7 soft-tissue sarcomas and 1 of 4 Ewing sarcomas. Remarkably, 5 of the osteosarcomas having Rb alterations also had p53 mutations. Amplification and overexpression of the MDM2 oncogene may lead to increased MDM2-p53 binding resulting in inactivation of p53 function. A two- to threefold increase in the copy number of MDM2 was detected in 7 of 37 samples, 5 of which were osteosarcomas. Amplification of the MDM2 gene occurred independently of p53 mutation; one sample having threefold amplification of MDM2 also had a p53 mutation. In summary, 34 alterations of the p53, Rb and MDM2 genes were found in 26 of 42 (62%) osteosarcomas.

Kelley MJ, Nakagawa K, Steinberg SM, et al.
Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines.
J Natl Cancer Inst. 1995; 87(10):756-61 [PubMed] Related Publications
BACKGROUND: The CDKN2 gene encodes the human cyclin-dependent kinase 4 inhibitor. This inhibitor protein is believed to be a tumor suppressor that plays an essential role in cell cycle regulation. One half of all cancer cell lines and one fourth of lung cancer cell lines examined to date contain homozygous deletions (i.e., both alleles lost) of CDKN2. However, the relative frequency of homozygous CDKN2 deletions in non-small-cell lung cancers (NSCLC) and in small-cell lung cancers (SCLC) has not been determined. Inactivation or loss of another tumor suppressor encoded by the retinoblastoma gene (the Rb protein) is more common in SCLC than in NSCLC.
PURPOSE: We measured the frequency of homozygous CDKN2 deletions in 77 NSCLC and in 93 SCLC tumor cell lines. In addition, possible associations were explored between CDKN2 gene loss, the presence or absence of Rb protein, and the clinical status of lung cancer patients.
METHODS: DNA was isolated from each tumor cell line and from the primary tumor and normal tissue of one NSCLC patient. Sequences corresponding to exons 1 and 2 of the CDKN2 gene were amplified by use of the polymerase chain reaction, and the resulting amplification products were analyzed by agarose gel electrophoresis and DNA blotting. Genomic DNA blotting was also used to evaluate CDKN2 gene deletions. The frequency of homozygous CDKN2 loss and the presence or absence of functional Rb protein (reported previously) in the cell lines were compared.
RESULTS: Homozygous deletion of CDKN2 was detected in 18 (23%) of 77 cell lines established from patients with NSCLC, compared with one (1%) of 93 cell lines established from patients with SCLC (P < .001). No CDKN2 gene loss was observed in the normal tissue of an NSCLC patient whose tumor cell line showed homozygous deletion of the gene; however, the primary tumor from this patient had evidence of CDKN2 loss. Homozygous CDKN2 deletion was detected in 13 (28%) of 46 tumor cell lines from patients with stage III or stage IV NSCLC, compared with zero of 10 tumor cell lines from patients with stage I or stage II NSCLC. Coincident loss of CDKN2 genes and functional Rb protein was rarely observed (in two of 135 cell lines).
CONCLUSION: The frequency of homozygous CDKN2 gene deletion in NSCLC cell lines is greater than that observed for any other known, or candidate, tumor suppressor gene.
IMPLICATION: Further study of the role of CDKN2 gene alteration in the pathogenesis of NSCLC is needed.

Otterson GA, Kratzke RA, Coxon A, et al.
Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB.
Oncogene. 1994; 9(11):3375-8 [PubMed] Related Publications
Cell cycle dependent phosphorylation of the RB tumor suppressor protein is mediated by a family of G1 cyclin dependent kinases (cdks) and cyclins including the activated cdk4:cyclin D complex. The identification of a cdk4 inhibitor, p16INK4, as a target for mutations in cultured tumor lines and primary tumors suggested that RB activity may be affected in these cells. We have examined 88 lung cancer lines for p16INK4 protein expression and have observed a striking inverse correlation between the presence of p16INK4 and wildtype RB. We demonstrated that only 6/55 (11%) of small cell lung cancer (SCLC) samples had absent p16INK4 protein, and all 6 belonged to the rare subset of SCLC with wildtype RB expression. Conversely of 48 SCLC samples with absent or mutant RB, all showed detectable levels of p16INK4 protein. In contrast, we observed that 23/33 (70%) of non-SCLC samples had loss of p16INK4. Twenty-two of 26 non-SCLC lines with wildtype RB had absent p16INK4 while 6 of 7 non-SCLC lines with absent or mutant RB had detectable p16INK4. The inverse correlation of RB and p16INK4 expression and the absence of p16INK4 inactivation in RB (-/-) SCLC lines (0/48) confirms a common p16INK4/RB growth suppressor pathway in human cancers and provides evidence that p16INK4, and not an adjacent gene on chromosome 9p, is a specific target for mutational events.

Harbour JW, Lai SL, Whang-Peng J, et al.
Abnormalities in structure and expression of the human retinoblastoma gene in SCLC.
Science. 1988; 241(4863):353-7 [PubMed] Free Access to Full Article Related Publications
Small cell lung cancer (SCLC) has been associated with loss of heterozygosity at several distinct genetic loci including chromosomes 3p, 13q, and 17p. To determine whether the retinoblastoma gene (Rb) localized at 13q14, might be the target of recessive mutations in lung cancer, eight primary SCLC tumors and 50 cell lines representing all major histologic types of lung cancer were examined with the Rb complementary DNA probe. Structural abnormalities within the Rb gene were observed in 1/8 (13%) primary SCLC tumors, 4/22 (18%) SCLC lines, and 1/4 (25%) pulmonary carcinoid lines (comparable to the 20 to 40% observed in retinoblastoma), but were not detected in other major types of lung cancer. Rb messenger RNA expression was absent in 60% of the SCLC lines and 75% of pulmonary carcinoid lines, including all samples with DNA abnormalities. In contrast, Rb transcripts were found in 90% of non-SCLC lung cancer lines and in normal human lung. The finding of abnormalities of the Rb gene in SCLC and pulmonary carcinoids (both neuroendocrine tumors) suggests that this gene may be involved in the pathogenesis of a common adult malignancy.

Ceccarelli C, Santini D, Chieco P, et al.
Retinoblastoma (RB1) gene product expression in breast carcinoma. Correlation with Ki-67 growth fraction and biopathological profile.
J Clin Pathol. 1998; 51(11):818-24 [PubMed] Free Access to Full Article Related Publications
AIMS: To investigate the expression of retinoblastoma protein (pRb) in invasive breast tumours and compare its expression with the major biopathological prognostic indicators to identify more aggressive subgroups.
MATERIAL: Archival paraffin embedded tissues from 153 consecutive primary breast carcinomas.
METHODS: pRb, Ki-67, and oestrogen receptor/progesterone receptor proteins were identified by immunohistochemistry and score values were recorded by image cytometric analysis; p53 and EGFr expression was also evaluated.
RESULTS: pRb scores correlated strongly with proliferation activity as determined by Ki-67 staining. Positive relations were also observed between pRb scores, tumour size, nuclear and histological grade, and oestrogen receptor/progesterone receptor content, while abnormal p53 accumulation was not associated with pRb expression. Among the high proliferating carcinomas it was possible to identify 13 cases with loss of pRb expression.
CONCLUSIONS: pRb expression paralleled proliferative activity in the majority of breast carcinomas examined, suggesting that in these cases the protein behaves normally in regulating the cell cycle. Conversely in cases with loss of pRb immunostaining, the combined expression of specific highly aggressive factors (EGFr and p53 expression, oestrogen receptor/progesterone receptor negative status, and high K67) seems to characterise a more aggressive phenotype showing growth advantage and cellular "progression" rather than significant nodal involvement.

Eyfjörd JE, Thorlacius S
Genetic changes in breast carcinomas in an Icelandic population.
Pharmacogenetics. 1992; 2(6):309-16 [PubMed] Related Publications
We have examined breast tumour samples from 109 unselected breast cancer patients for genetic changes on chromosomes 13 and 17. We have looked for allelic losses, firstly, at the retinoblastoma locus, RB1, on chromosome 13q, and secondly, on both arms of chromosome 17. We have also studied the same samples for amplification of the erbB2 oncogene. We searched for mutations in four well conserved areas of the p53 gene using constant denaturant gradient electrophoresis (CDGE). Allelic loss or rearrangement was detected in a large proportion of the tumours, affecting 37-51% of cases with different probes. The areas most frequently affected were 17p13.1 and 17p13.3. Point mutations and small deletions in the p53 gene on 17p13.1 were detected in 16% of the tumours. The data on genetic changes were then analyzed for three different correlations: 1) co-operation between different lesions, 2) association with family history of breast cancer, 3) correlation with clinical factors and prognosis. There was association between losses at the retinoblastoma locus and losses on 17p and 17q. We also found an association between p53 mutations and amplification of the erbB2 oncogene. Relatives of patients having deletions at the retinoblastoma locus and/or sites on chromosome 17 in the tumours have a significantly increased relative risk of developing breast cancer. No such correlation is found for p53 mutations or erbB2 amplification. No p53 germline mutations were detected. P53 mutations do, however, appear to be a strong indication of poor prognosis in this population.

Sauerbrey A, Stammler G, Zintl F, Volm M
Expression of the retinoblastoma tumor suppressor gene (RB-1) in acute leukemia.
Leuk Lymphoma. 1998; 28(3-4):275-83 [PubMed] Related Publications
In this report we review current studies concerning the RB-1 gene expression in acute leukemias. The RB-1 gene was analyzed in several studies by protein-, RNA and DNA-techniques in acute lymphoblastic leukemia (ALL) as well as in acute myelogenous leukemia (AML). The frequency of RB-1 inactivation in ALL-patients ranged between 30% and 64% in several studies. Structural abnormalities of the RB-1 gene were reported in 18% of ALL-patients and in 27% of Philadelphia chromosome-positive ALL, respectively. The proportion of AML-patients with absent RB-1 protein expression ranged between 19% and 55%. Structural RB-1-abnormalities in AML were predominantly reported in leukemias with monocytic differentiation. Furthermore, the prognostic value of an abnormal RB-1 gene expression was also estimated in some studies. In childhood ALL RB-1 inactivation was reported to have prognostic significance while in contrast, in another study on adults no prognostic value of RB-1 was found. In 4 out of 5 documented studies AML-patients with RB-1 inactivation generally had a poorer prognosis. In conclusion, RB-1 inactivation is frequently observed in acute leukemia. The prognostic value of low RB-1 expression is controversial but the majority of published studies found low RB-1 expression to be a negative prognostic predictor, in acute leukemia.

Kornblau SM, Andreeff M, Hu SX, et al.
Low and maximally phosphorylated levels of the retinoblastoma protein confer poor prognosis in newly diagnosed acute myelogenous leukemia: a prospective study.
Clin Cancer Res. 1998; 4(8):1955-63 [PubMed] Related Publications
A prior retrospective study suggested that the level of retinoblastoma protein (RB) expression was prognostic for survival in acute myelogenous leukemia (AML). Individuals with no/low RB protein expression were considered to have loss of RB function, and those with maximally phosphorylated (maxphos) RB were also felt to have nonfunctional RB. To confirm this, we prospectively investigated whether the level of RB expression was prognostic in AML in a larger cohort of patients. RB level was measured by Western blot and immunohistochemical analysis on peripheral blood samples from 210 newly diagnosed AML patients. Patients were divided into three groups based on the level of RB protein expression (i.e., no or low, elevated, and maxphos) or into two groups on the basis of presumed RB function, altered function (AF-RB, low and maxphos RB), versus normal function (NF-RB, elevated RB). By combined results of Western blot and immunohistochemical analysis, 20%, 65%, and 15% of patients had low, elevated, and maxphos RB, respectively. Most patients with acute promyelocytic leukemia (APL) with a French-American-British classification of M3 were in the low RB group, likely reflecting a lower proliferative rate of promyelocytes. Analysis was performed with and without these APL patients. The median survival was significantly shorter for both patients with low RB expression (48 weeks, P = 0.05, including APL patients; 34 weeks, corrected P = 0.008, with APL patients excluded) and maxphos RB expression (51 weeks, P = 0.007) compared to those with elevated RB expression (122 weeks including and 98 weeks excluding APL patients). Differences were greatest among patients with nonfavorable prognosis cytogenetics (median survival, 34 weeks versus 85 weeks; corrected P = 0.001 for AF-RB versus NF-RB). Remission duration was also significantly shorter for non-APL patients with AF-RB versus NF-RB (median survival, 36 weeks versus not reached; corrected P = 0.02). In multivariate analyses, including cytogenetics, performance status, age, antecedent hematological disorder, and RB status, with and without APL patients included, no/low and maxphos-RB protein expression were independent predictors for poorer survival. This prospective study confirms that the level of expression of RB is a strong prognostic factor in AML, with an inferior survival experience being associated with no/low RB and maxphos RB expression. Therefore, therapeutic decisions based on the level of RB expression may be indicated, and protocols to incorporate this are currently under development.

Ahuja HG, Jat PS, Foti A, et al.
Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia.
Blood. 1991; 78(12):3259-68 [PubMed] Related Publications
The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.

Cote RJ, Dunn MD, Chatterjee SJ, et al.
Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53.
Cancer Res. 1998; 58(6):1090-4 [PubMed] Related Publications
Rb protein (pRb) expression was evaluated in 185 cases of transitional cell carcinoma of the bladder from patients that underwent radical cystectomy. Tumors were stratified into three categories based on the percentage of nuclei expressing pRb: (a) 0, 0% of tumor cells showing nuclear reactivity; (b) 1+, 1-50% of tumor cells showing nuclear reactivity; and (c) 2+, >50% of tumor cells showing nuclear reactivity. Cases with undetectable (pRb 0) and high (pRb 2+) pRb reactivity had identical rates of recurrence. These cases had significantly higher recurrence (P = 0.0001) and lower survival rates (P = 0.0002) compared to cases with moderate (pRb 1+) pRb reactivity, indicating that high levels of pRb expression may reflect a dysfunctional (altered) Rb pathway. The tumors were also examined for alterations in p53 expression; patients with tumors altered in both p53 and pRb had significantly increased rates of recurrence (P < 0.0001) and survival (P < 0.0001) compared to patients with no alterations in either p53 or pRb; patients with alterations in only one of these proteins had intermediate rates of recurrence and survival. These results suggest that: (a) bladder cancers with high pRb expression do not show the tumor suppressor effects of the protein; and (b) alteration in both p53 and pRb may act in cooperative or synergistic ways to promote tumor progression.

Grossman HB, Liebert M, Antelo M, et al.
p53 and RB expression predict progression in T1 bladder cancer.
Clin Cancer Res. 1998; 4(4):829-34 [PubMed] Related Publications
The optimal clinical management of minimally invasive (stage T1) bladder cancer is controversial. T1 bladder cancers share characteristics of both noninvasive (Ta) papillary cancer and high stage, muscle-invasive bladder cancers. Patients with T1 bladder cancer have a higher risk of cancer progression and death than do patients with Ta bladder cancer. However, this risk is much lower than that of patients with high-stage bladder cancers. Methods of identifying T1 bladder cancer patients at greatest risk for progression may significantly improve clinical management. We retrospectively evaluated two tumor suppressor genes, p53 and RB, as potential prognostic markers for progression in a cohort of 45 patients with pT1 bladder cancer. Median follow-up for these individuals was greater than 3.5 years. Of this group, 58% had altered p53 expression based on positive p53 immunostaining. Three patterns for RB nuclear protein staining were observed: absent, heterogeneous (normal), and strongly homogeneous. Progression-free survival was similar for patients with loss of RB protein expression and those with apparent overexpression of RB protein. Therefore, both staining patterns were considered abnormal. Patients with normal expression of both proteins (i.e., p53 negative and RB heterogeneously positive) had an excellent outcome, with no patient showing disease progression, whereas patients with abnormal expression of either or both proteins had a significant increase in progression (P = 0.04 and P = 0.005, respectively). These data support the stratification of T1 bladder cancer patients based on p53 and RB nuclear protein status and suggest that patients with normal protein expression for both genes can be managed conservatively, whereas patients with alterations in one and particularly both genes require more aggressive treatment.

Niehans GA, Kratzke RA, Froberg MK, et al.
G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder.
Br J Cancer. 1999; 80(8):1175-84 [PubMed] Free Access to Full Article Related Publications
The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16INK4a, are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16INK4a, which occurred in 15/79 cases (19%). One biphenotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16INK4a, or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16INK4a and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16INK4a and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16INK4a can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins.

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