J BUON. 2011 Jan-Mar;16(1):142-6.

1.Linkage analysis and detection of somatic, postzygous RB1 mutations in Serbianretinoblastoma patients.
Kontic M, Palacios I, Kontic M, Alonso J, Pestana A.

Source Institute of Lung Diseases, Clinical Center of Serbia, Belgrade, Serbia. milicakontic@yahoo.com

Abstract
PURPOSE: The etiology of retinoblastoma (RB) is mutational inactivation of two RB1 alleles, the prototype of tumor suppressorgene. The aim of this research was to reveal sporadic, postzygous RB1 gene mutations, in particular loss of heterozygosity (LOH), from formalin-fixed, paraffin-embedded tumor samples in RB patients, as well as tracking RB1 allele inheritance in 10 RB families. METHODS: The mutational studies were carried out in the peripheral blood lymphocytes' DNA of 4 bilateral and 12 unilateral RB patients and DNAs from tumors from 3 bilateral and 10 unilateral patients. Tumor samples were collected from the same patients whose blood was analyzed. DNA was extracted and linkage analysis and microsatellite markers method were performed. LOH for two RB1 intragenic markers was analyzed. RESULTS: Ten LOH were found in the area of two intragene microsatellite loci. Linkage analysis revealed inheritance of RB1alleles in 10 families. LOH was found in 63.16% of tumors. CONCLUSION: Peripheral blood lymphocytes' DNA gives better results as a control group for somatic mutations than DNA isolated from eye tissue outside the tumor. Linkage analysis is essential for identifying the individual risk, offering the possibility of an adequate genetic counseling in familial RB.

Clin Exp Metastasis. 2011 Mar;28(3):319-26. Epub 2011 Jan 21.

2.Alterations of the retinoblastoma gene in metastatic breast cancer.

Berge EO, Knappskog S, Lillehaug JR, Lnning PE.

Source Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway.

Abstract
Germline mutations affecting the retinoblastoma gene (RB1) predispose to inherited retinoblastomas but also other malignancies, including breast cancer. While somatic RB1 mutations have been detected in different malignancies, information about the potential role of RB1 mutations in breast cancer is limited. Recently, we discovered RB1 mutations to be associated with resistance to anthracyclines/mitomycin in primary breast cancer. The

present work is the first report evaluatingRB1 mutation and epigenetic status in metastatic breast cancer. Among 148 breast cancer samples analyzed by MLPA, four samples harbored intragenic deletions/duplications: Thus, exons 1-2 were deleted in two tumors and exons 21-23 in one tumor, while one sample harbored duplication of exons 18-23. The entire RB1 gene was duplicated in two tumors and multiple amplifications were revealed in one sample. Reduced copy number was observed in 17 samples (11.5%). No point mutation or promoter hypermethylation was discovered (n = 38 and 114 tumors analyzed, respectively). Interestingly, among seven tumors expressing lack of response to epirubicin, two samples harbored alterations in RB1, contrasting none out of 16 tumors with stable disease or an objective response (P = 0.08). In summary, the frequency of RB1 alterations in metastatic lesions was not increased when compared to primary breast cancer, indicating that RB1 alterations do not play a major role in metastatic development. While a non-significant association suggesting RB1 alterations to be linked to therapy resistance was observed, our data do not suggest a major role for RB1 alterations explaining acquired drug resistance.

PLoS One. 2011 Feb 22;6(2):e16434.

3.A context-specific role for retinoblastoma proteindependent negative growth control in suppressing mammary tumorigenesis.
Francis SM, Chakrabarti S, Dick FA.

Source London Regional Cancer Program, London, Ontario, Canada.

Abstract
BACKGROUND: The ability to respond to anti-growth signals is critical to maintain tissue homeostasis and loss of this negative growth control safeguard is considered a hallmark of cancer. Negative growth regulation generally occurs during the G0/G1 phase of the cell cycle, yet the redundancy and complexity among components of this regulatory network has made it difficult to discern how negative growth cues protect cells from aberrant proliferation. METHODOLOGY/PRINCIPAL FINDINGS: The retinoblastoma protein (pRB) acts as the final barrier to prevent cells from entering into the cell cycle. By introducing subtle changes in the endogenous mouse Rb1 gene (Rb1(L)), we have previously shown that interactions at the LXCXE binding cleft are necessary for the proper response to anti-growth signals such as DNA damage and TGF-, with minimal effects on overall development. This disrupts the balance of pro- and anti-growth signals in mammary epithelium of Rb1(L/L) mice. Here we show that Rb1(L/L) mice are more prone to mammary tumors in the Wap-p53(R172H) transgenic background indicating that negative growth regulation is important for tumor suppression in these mice. In contrast, the same defect in anti-growth control has no impact on Neu-induced mammary tumorigenesis. CONCLUSIONS/SIGNIFICANCE: Our work demonstrates that negative growth control by pRB acts as a crucial barrier against oncogenic transformation. Strikingly, our data also reveals that this tumor suppressive effect is context-dependent.

Biochem Biophys Res Commun. 2011 Mar 25;406(4):518-23. Epub 2011 Feb 15.

4.miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastomatumor suppressor.
Park JK, Henry JC, Jiang J, Esau C, Gusev Y, Lerner MR, Postier RG, Brackett DJ, Schmittgen TD.

Source College of Pharmacy, Ohio State University, Columbus, OH 43210, United States.

Abstract
Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target theretinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G(2)/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the 2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The 2 adrenergic pathway may play an important role in this novel mechanism.

Genes Chromosomes Cancer. 2011 May;50(5):327-37. doi: 10.1002/gcc.20857. Epub 2011 Feb 8.

5.Loss at chromosome arm 16q in retinoblastoma: confirmation of the association with diffuse vitreous seeding and refinement of the recurrently deleted region.
Gustmann S, Klein-Hitpass L, Stephan H, Weber S, Bornfeld N, Kaulisch M, Lohmann DR, Dnker N.

Source Department of Neuroanatomy, Institute for Anatomy, University of Duisburg-Essen, Hufelandstrasse 55, Essen D-45122, Germany.

Abstract
In addition to mutations in both alleles of the retinoblastoma gene (RB1) alleles, retinoblastomas frequently show additional alterations including loss of chromosome arm 16q. In a previous study, the presence of 16q alterations was found to be associated with diffuse vitreous seeding of this tumor. This growth pattern is clinically important as it determines therapeutic decisions. The present study was designed to test this association and to narrow down the list of candidate genes in the minimal region of genomic loss on chromosome arm 16q. Our data confirm the association of 16q loss and diffuse vitreous seeding and define a minimal region of genomic loss of 6.6 Mb on 16q containing 86 known genes. As retinoblastoma is an embryonic tumor, we assumed that any gene relevant for its progression is likely to show regulated expression during retinogenesis. Microarray expression analysis of RNA from a continuous

developmental series of murine retinas identified murine orthologs with regulated expression and these data helped to narrow the number of candidate genes in minimal region to 35. Analysis of gene expression in retinoblastomas with and without the loss of heterozygosity (LOH) on chromosome 16q further reduced this number to 26 candidate genes. One of these genes is cadherin 13 (CDH13) and notably, downregulation of CHD13 has previously been associated with poorer prognosis in various other cancers. 2011 Wiley-Liss, Inc.

Mol Cancer. 2011 Mar 29;10:31.

6.Expression ratio of CCND1 to CDKN2A mRNA predicts RB1 status of cultured cancer cell lines and clinical tumor samples.
Mizuarai S, Machida T, Kobayashi T, Komatani H, Itadani H, Kotani H.

Source Department of Oncology, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 300-2611, Japan.

Abstract
BACKGROUND: The retinoblastoma product (RB1) is frequently deregulated in various types of tumors by mutation, deletion, or inactivation through association with viral oncoproteins. The functional loss of RB1 is recognized to be one of the hallmarks that differentiate cancer cells from normal cells. Many researchers are attempting to develop anti-tumor agents that are preferentially effective against RB1-negative tumors. However, to identify patients with RB1-negative cancers, it is imperative to develop predictive biomarkers to classify RB1-positive and -negative tumors. RESULTS: Expression profiling of 30 cancer cell lines composed of 16 RB1-positive and 14 RB1-negative cancers was performed to find genes that are differentially expressed between the two groups, resulting in the identification of an RB1signature with 194 genes. Among them, critical RB1 pathway components CDKN2A and CCND1 were included. We found that microarray data of the expression ratio of CCND1 and CDKN2A clearly distinguished the RB1 status of 30 cells lines. Measurement of the CCND1/CDKN2A mRNA expression ratio in additional cell lines by RT-PCR accurately predicted RB1status (12/12 cells lines). The expression of CCND1/CDKN2A also correlated with RB1 status in xenograft tumors in vivo. Lastly, a CCND1/CDKN2A assay with clinical samples showed that uterine cervical and small cell lung cancers known to have a high prevalence of RB1-decifiency were predicted to be 100% RB1-negative, while uterine endometrial or gastric cancers were predicted to be 5-22% negative. All clinically normal tissues were 100% RB1-positive. CONCLUSIONS: We report here that the CCND1/CDKN2A mRNA expression ratio predicts the RB1 status of cell lines in vitro and xenograft tumors and clinical tumor samples in vivo. Given the high predictive accuracy and quantitative nature of the CCND1/CDKN2A expression assay, the assay could be utilized to stratify patients for anti-tumor agents with preferential effects on either RB1-positive or -negative tumors.

Nucleic Acids Res. 2011 Aug;39(15):6669-78. Epub 2011 Apr 21.

7.MicroRNA-192 targeting retinoblastoma 1 inhibits cell proliferation and induces cell apoptosis in lung cancer cells.
Feng S, Cong S, Zhang X, Bao X, Wang W, Li H, Wang Z, Wang G, Xu J, Du B, Qu D, Xiong W, Yin M, Ren X, Wang F, He J,Zhang B.

Source Lab for RNA Chemical Biology at Guangzhou Institutes of Biomedicine and Health, Chinese Academic of Science, Guangzhou 510530, China.

Abstract
microRNAs play an important roles in cell growth, differentiation, proliferation and apoptosis. They can function either as tumor suppressors or oncogenes. We found that the overexpression of miR-192 inhibited cell proliferation in A549, H460 and 95D cells, and inhibited tumorigenesis in a nude mouse model. Both caspase-7 and the PARP protein were activated by the overexpression of miR-192, thus suggesting that miR-192 induces cell apoptosis through the caspase pathway. Further studies showed that retinoblastoma 1 (RB1) is a direct target of miR-192. Over-expression of miR-192 decreased RB1 mRNA and protein levels and repressed RB1-3'-UTR reporter activity. Knockdown of RB1 using siRNA resulted in a similar cell morphology as that observed for overexpression of miR-192. Additionally, RB1-siRNA treatment inhibited cell proliferation and induced cell apoptosis in lung cancer cells. Analysis of miRNA expression in clinical samples showed that miR-192 is significantly downregulated in lung cancer tissues compared to adjacent non-cancerous lung tissues. In conclusion, our results demonstrate that miR-192 is a tumor suppressor that can target the RB1 gene to inhibit cell proliferation and induce cell apoptosis in lung cancer cells. Furthermore, miR-192 was expressed at low levels in lung cancer samples, indicating that it might be a promising therapeutic target for lung cancer treatment.

J Biol Chem. 2011 Jun 3;286(22):19556-64. Epub 2011 Apr 8.

8.Rb1 gene inactivation expands satellite cell and postnatal myoblast pools.
Hosoyama T, Nishijo K, Prajapati SI, Li G, Keller C.

Source Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA.

Abstract
Satellite cells are well known as a postnatal skeletal muscle stem cell reservoir that under injury conditions participate in repair. However, mechanisms controlling satellite cell quiescence and activation are the topic of ongoing inquiry by many laboratories. In this study, we investigated whether loss of the cell cycle regulatory factor, pRb, is associated with the re-entry of quiescent satellite cells into replication and subsequent stem cell expansion. By ablation of Rb1 using a Pax7CreER,Rb1conditional mouse line, satellite cell number was increased 5-fold over 6 months. Furthermore, myoblasts originating from satellite cells lacking Rb1 were also increased 3-fold over 6 months, while terminal differentiation was greatly diminished. Similarly, Pax7CreER,Rb1 mice exhibited muscle fiber hypotrophy in

vivo under steady state conditions as well as a delay of muscle regeneration following cardiotoxin-mediated injury. These results suggest that cell cycle re-entry of quiescent satellite cells is accelerated by lack of Rb1, resulting in the expansion of both satellite cells and their progeny in adolescent muscle. Conversely, that sustained Rb1 loss in the satellite cell lineage causes a deficit of muscle fiber formation. However, we also show that pharmacological inhibition of protein phosphatase 1 activity, which will result in pRb inactivation accelerates satellite cell activation and/or expansion in a transient manner. Together, our results raise the possibility that reversible pRb inactivation in satellite cells and inhibition of protein phosphorylation may provide a new therapeutic tool for muscle atrophy by short term expansion of the muscle stem cells and myoblast pool.

BMC Med Genet. 2011 May 26;12:76.

9.Low penetrance of retinoblastoma for p.V654L mutation of the RB1 gene.

Hung CC, Lin SY, Lee CN, Chen CP, Lin SP, Chao MC, Chiou SS, Su YN.

Source Graduate Institute of Clinical Genomics, National Taiwan University College of Medicine, Taipei, Taiwan.

Abstract
BACKGROUND: Retinoblastoma is caused by compound heterozygosity or homozygosity of retinoblastoma gene (RB1) mutations. In germline retinoblastoma, mutations in the RB1 gene predispose individuals to increased cancer risks during development. These mutations segregate as autosomal dominant traits with high penetrance (90%). METHODS: We screened 30 family members from one family using high resolution melting assay and DNA direct sequencing for mutations in the RB1 gene. We evaluate the phenotype and penetrance of germline mutations of the RB1 gene in a large Taiwanese family. RESULTS: The molecular analysis and clinical details of this family showed phenotypic variability associated with the p.V654L mutation in exon 19 of the RB1 gene in 11 family members. The phenotype varied from asymptomatic to presence of a unilateral tumor. Only four individuals (2 males and 2 females) developed unilateral retinoblastoma, which resulted in calculated low penetrance of 36% (4/11). The four individuals with retinoblastoma were diagnosed before the age of three years. None of their relatives exhibited variable severity or bilateral retinoblastoma. CONCLUSIONS: The diseased-eye ratio for this family was 0.36, which is lower than current estimates. This suggests that theRB1 p.V654L mutation is a typical mutation associated with low penetrance.

Cell Cycle. 2011 May 15;10(10):1563-70. Epub 2011 May 15.

10.RB1 and p53 at the crossroad of EMT and triple-negative breast cancer.

Jiang Z, Jones R, Liu JC, Deng T, Robinson T, Chung PE, Wang S, Herschkowitz JI, Egan SE, Perou CM, Zacksenhaus E.

Source Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.

Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous disease that includes Basal-like and Claudin-low tumors. The Claudin-low tumors are enriched for features associated with epithelial-to-mesenchymal transition (EMT) and possibly for tumor initiating cells. Primary TNBCs respond relatively well to conventional chemotherapy; however, metastatic disease is virtually incurable. Thus, there is a great interest in identifying specific therapeutic targets for TNBC. The tumor suppressorRB1 is frequently lost in Basal-like breast cancer. To test for a causative role of RB1 gene loss in BC and for its effect on specific subtypes, we deleted mouse Rb in mammary stem/bipotent progenitor cells. This led to diverse mammary tumors including TNBC, with a subset of the latter containing p53 mutations and exhibiting features of Basal-like BC or EMT. Combined mutation of Rb and p53 in mammary stem/bipotent progenitors induced EMT type tumors. Here, we review our findings and those of others, which connect Rb and p53 to EMT in TNBC. Furthermore, we discuss how by understanding this circuit and its vulnerabilities, we may identify novel therapy for TNBC.

Int J Cancer. 2011 May 15;128(10):2393-404. doi: 10.1002/ijc.25565.

11.Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1mutation.
Bunin GR, Felice MA, Davidson W, Friedman DL, Shields CL, Maidment A, O'Shea M, Nichols KE, Leahey A, Dunkel IJ, Jubran R, Rodriguez-Galindo C, Schmidt ML, Weinstein JL, Goldman S, Abramson DH, Wilson MW, Gallie BL, Chan HS, Shapiro M,Cnaan A, Ganguly A, Meadows AT.

Source Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. bunin@email.chop.edu

Abstract
Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germlineRB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from nine North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower gastrointestinal (GI) series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child [matched odds ratio (OR) = 3.6, 95% confidence interval (CI) = 1.2-11.2, two-sided p = 0.02], as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI = 1.2-14.4, p = 0.02). Maternal history of lower GI series was also associated with increased risk (OR = 7.6, 95% CI = 2.8-20.7, p < 0.001) as was the estimated total dose (OR for highest dose = 3.0, 95% CI = 1.4-7.0, p = 0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of

gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.

Cancer Genet. 2011 Jun;204(6):316-22.

12.RB1 gene mutations in Iranian patients with retinoblastoma: report of four novel mutations.
Ahani A, Behnam B, Khorshid HR, Akbari MT.

Source Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Abstract
Mutations in the RB1 gene lead to retinoblastoma, which is the most common intraocular tumor in children under the age of 6. In the present survey, the mutations of 18 unrelated Iranian retinoblastoma patients were characterized. Mutation analysis of the RB1 gene was performed in patients by sequencing all coding regions and by multiplex ligation probe-dependent amplification analysis. Clinical signs and symptoms of the retinoblastoma patients were similar to those of previously described patients with retinoblastoma. Eight known mutations and four novel mutations (c.832_833insT, c.1943delC, c.1206C>T, and c.2029delG) were determined. In silico analysis of the c.1206C>T variant showed that exon 12 contained an SC-35 consensus sequence, and this variation disrupted the splicing enhancer element and caused skipping of exon 12. Molecular genetic testing of retinoblastoma patients greatly affects the genetic counseling of the families involved, as well as the management of the disease in patients and atrisk relatives. Copyright 2011 Elsevier Inc. All rights reserved. J Biosci. 2011 Jun;36(2):281-7.

13.Splicing aberrations caused by constitutional RB1 gene mutations in retinoblastoma.

Parsam VL, Ali MJ, Honavar SG, Vemuganti GK, Kannabiran C.

Source
Kallam Anji Reddy Molecular Genetics Laboratory, Hyderabad Eye Research Foundation, LV Prasad Eye Institute, Hyderabad 500034, India.

Abstract

Analysis of RB1 mRNA from blood leukocytes of patients with retinoblastoma identified the effects of mutations involving consensus splice site, exonic substitution and whole-exon deletions identified in genomic DNA of these patients. In addition, this study identified mutations in cases in which no mutations were detectable in the genomic DNA. One proband had mutation at the canonical splice site at +5 position of IVS22, and analysis of the transcripts in this family revealed skipping of exon 22 in three members of this family. In one proband, a missense substitution of c.652T greater than G (g.56897T greater than G; Leu218Val) in exon 7 led to splicing aberrations involving deletions of exons 7 and 8, suggesting the formation of a cryptic splice site. In two probands with no detectable changes in the genomic DNA upon screening of RB1 exons and flanking intronic sequences, transcripts were found to have deletions of exon 6 in one, and exons 21 and 22 in another family. In two probands, RNA analysis confirmed genomic deletions involving one or more exons. This study reveals novel effects of RB1 mutations on splicing and suggests the utility of RNA analysis as an adjunct to mutational screening of genomic DNA in retinoblastoma.

Int J Cancer. 2012 Feb 1;130(3):631-40. doi: 10.1002/ijc.26039. Epub 2011 Jun 10.

14.Analysis of retinoblastoma age incidence data using a fully stochastic cancer model.
Little MP, Kleinerman RA, Stiller CA, Li G, Kroll ME, Murphy MF.

Source Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, DHHS, NIH, Bethesda, MD. mark.little@nih.gov.

Abstract
Retinoblastoma (RB) is an important ocular malignancy of childhood. It has been commonly accepted for some time that knockout of the two alleles of the RB1 gene is the principal molecular target associated with the occurrence of RB. In this article, we examine the validity of the two-hit theory for RB by comparing the fit of a stochastic model with two or more mutational stages. Unlike many such models, our model assumes a fully stochastic stem cell compartment, which is crucial to its behavior. Models are fitted to a population-based dataset comprising 1,553 cases of RB for the period 1962-2000 in Great Britain (England, Scotland and Wales). The population incidence of RB is best described by a fully stochastic model with two stages, although models with a deterministic stem cell compartment yield equivalent fit; models with three or more stages fit much less well. The results strongly suggest that knockout of the two alleles of the RB1 gene is necessary and may be largely sufficient for the development of RB, in support of Knudson's two-hit hypothesis.

Cesk Patol. 2011 Jul;47(3):118-21.

15.Coincidence of chronic lymphocytic leukaemia with Merkel cell carcinoma: deletion of the RB1 gene in both tumors.
Mack J, Dvorckov J, Uvrov M, Kuglk P.

Source
Department of Pathology, Faculty Hospital and Medical Faculty, Masaryk University, Brno, Czech Republic. macak.jirka@seznam.cz

Abstract
The authors report a case of a 64-year-old man with chronic lymphocytic leukaemia (CLL) diagnosed 5 years ago. Recently, the patient was admitted with a tumour of the skin in the left lumbar region. Histological and immunohistochemical examinations established the diagnosis of Merkel cell carcinoma (MCC). Electron-microscopic examination revealed the formation of spherical aggregates of intermediate-sized filaments in the perinuclear region. The coincidence of MCC and CLl is rather rare and in published cases, no cytogenetic examinations were performed. We examined the RB1 gene using the interphase FISH method. A biallelic deletion in CLL tumour cells was detected; in MCC tumour cells, biallelic deletion was found in 33% of the cells and monoallelic deletion in 57% of the cells. In addition, chromosome 6 trisomy and 1p36 deletion were detected. Examination of non-neoplastic cells of the patient's skin showed a biallelic presence of the RB1 gene. According to the relevant literature, examination of the RB1 gene in CLL has informational value as a prognostic factor. The relationship between deletion of the RB1 gene and prognosis in MCC has not yet been determined and needs more research.

Head Neck Pathol. 2011 Mar;5(1):57-62. Epub 2010 Aug 29.

16.Nasal sinus leiomyosarcoma in a patient with history of non-hereditary unilateral treatedretinoblastoma.

Fitzpatrick SG, Woodworth BA, Monteiro C, Makary R.

Source Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL 32610, USA. sfitzpatrick@dental.ufl.edu

Abstract
Hereditary patients with a history of treated retinoblastoma (RB) have a greatly increased risk of a broad spectrum of secondary malignancies appearing many years later, with a high incidence in the head and neck region. Leiomyosarcomas (LMS) account for up to 58% of these tumors. LMS in the sinonasal region generally are uncommon and are associated with a locally aggressive course and have a poor prognosis. RB may occur in two forms. The hereditary form is generally bilateral but can present unilaterally with a positive family history and typically exhibits a germline mutation in the RB1 gene on chromosome 13. The non-hereditary form is usually unilateral but can show the same germline mutation in up to 10% of cases. Patients with hereditary RB have been shown to have a significantly higher cumulative risk of developing secondary malignancies than those with the non-hereditary form (28 vs. 1.44% respectively). Most reported cases of sinonasal LMS are in patients with a history of the bilateral hereditary form of treated RB. We report a case of LMS of the nasal sinus area in a 35-year-old African American male with a history of non-hereditary unilateral RB and radiation therapy. To the best of our knowledge, this is the first reported case of sinonasal LMS arising in a patient with a history of non-hereditary unilateral RB. The clinical history, radiology, and pathology are presented along with a brief discussion of the literature.

Invest Ophthalmol Vis Sci. 2011 Sep 29;52(10):7618-24. Print 2011 Sep.

17.The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated Muller glia with progenitor properties.
Pajovic S, Corson TW, Spencer C, Dimaras H, Orlic-Milacic M, Marchong MN, To KH, Thriault B, Auspitz M, Gallie BL.

Source Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada.

Abstract
PURPOSE: Human retinoblastoma arises from an undefined developing retinal cell after inactivation of RB1. This is emulated in a murine retinoblastoma model by inactivation of pRB by retinal-specific expression of simian virus 40 large T-antigen (TAg-RB). Some mutational events after RB1 loss in humans are recapitulated at the expression level in TAg-RB, supporting preclinical evidence that this model is useful for comparative studies between mouse and human. Here, the characteristics of the TAg-RB cell of origin are defined. METHODS: TAg-RB mice were killed at ages from embryonic day (E)18 to postnatal day (P)35. Tumors were analyzed by immunostaining, DNA copy number PCR, or real-time quantitative RT-PCR for TAg protein, retinal cell type markers, andretinoblastoma-relevant genes. RESULTS: TAg expression began at P8 in a row of inner nuclear layer cells that increased in number through P21 to P28, when clusters reminiscent of small tumors emerged from cells that escaped a wave of apoptosis. Early TAg-expressing cells coexpressed the developmental marker Chx10 and glial markers CRALBP, clusterin, and carbonic anhydrase II (Car2), but not TuJ1, an early neuronal marker. Emerging tumors retained expression of only Chx10 and carbonic anhydrase II. As with human retinoblastoma, TAg-RB tumors showed decreased Cdh11 DNA copy number and gain

of Kif14 and Mycn. It was confirmed that TAg-RB tumors lose expression of tumor suppressor cadherin-11 and overexpress oncogenes Kif14, Dek, and E2f3. CONCLUSIONS: TAg-RB tumors displayed molecular similarity to human retinoblastoma and origin in a cell with features of differentiated Mller glia with progenitor properties.

Fam Cancer. 2011 Sep;10(3):617-21.

18.Low penetrance hereditary retinoblastoma in a family: what should we consider in the genetic counselling process and follow up?
Serrano C, Alonso J, Gmez-Mariano G, Aguirre E, Diez O, Gadea N, Bosch N, Balmaa J, Graa B.

Abstract
Hereditary retinoblastoma (Rb) is a high penetrance autosomal dominant disease showing not only an increased risk of suffering bilateral Rb but also other second neoplasms. However, some families show a low-penetrance phenotype with reduced expressivity and incomplete penetrance of the retinoblastoma gene (RB1). Given the lack of specific guidelines for the follow-up of adult patients with hereditary Rb, the authors present a case report of a family with a low-penetrance phenotype and review the recommended surveillance in this setting, stressing the difficulties found in the genetic counselling process and follow up. Thus, since patients are at an increased risk, lifelong regular medical surveillance to detect any second malignancy at a stage that can be cured is required. In addition, avoidance of DNAdamaging agents and genetic testing should be considered for a throughout management of these families.

Ophthalmic Genet. 2011 Sep 28. [Epub ahead of print]

19.The Bcl-2/Bcl-XL inhibitor ABT-737 promotes death of retinoblastoma cancer cells.

Allaman-Pillet N, Oberson A, Munier F, Schorderet DF.

Source Institute for Research in Ophthalmology , Sion , Switzerland.

Abstract
Purpose: Retinoblastoma is a malignant tumor that usually develops in early childhood. During retinoblastoma spreading,RB1 gene inactivation is followed by additional genomic modifications which progressively lead to resistance of tumor cells to death. Drugs that act at downstream levels of death signaling pathways should therefore be interesting in killingretinoblastoma cells. ABT-737, a BH3 mimetic molecule effective at the mitochondrial level, has been shown to induce apoptosis in different human tumoral cell lines as well as in primary patient-derived cells, and in a mouse xenograph model. Methods: In this report, we analyzed the pro-death effect of ABT-737 on two human retinoblastoma cell lines, Y79 and WERI-Rb, as well as on the mouse photoreceptor cell line 661W. Results: We observed that ABT-737 was very effective as a single agent in inducing human WERI-Rb cells apoptosis without affecting the mouse 661W photoreceptor cells. However human Y79 cells were resistant to ABT-737, as a probable consequence of the absence of Bax. The high sensitivity of WERI-Rb to ABT-737 can be

increased by downregulating Mcl-1 using the proteasome inhibitor MG-132. Preliminary analysis in primary mouse retinoblastoma tumoral cell lines predicts high sensitivity to ABT-737. Conclusion: Our data suggest that ABT737 or related compounds could be a highly effective drug in the treatment of some retinoblastomas.

Curr Top Dev Biol. 2011;94:129-69.

20.RB1, development, and cancer.

Chinnam M, Goodrich DW.

Source Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA.

Abstract
The RB1 gene is the first tumor suppressor gene identified whose mutational inactivation is the cause of a human cancer, the pediatric cancer retinoblastoma. The 25 years of research since its discovery has not only illuminated a general role for RB1 in human cancer, but also its critical importance in normal development. Understanding the molecular function of the RB1encoded protein, pRb, is a long-standing goal that promises to inform our understanding of cancer, its relationship to normal development, and possible therapeutic strategies to combat this disease. Achieving this goal has been difficult, complicated by the complexity of pRb and related proteins. The goal of this review is to explore the hypothesis that, at its core, the molecular function of pRb is to dynamically regulate the location-specific assembly or disassembly of protein complexes on the DNA in response to the output of various signaling pathways. These protein complexes participate in a variety of molecular processes relevant to DNA including gene transcription, DNA replication, DNA repair, and mitosis. Through regulation of these processes, RB1 plays a uniquely prominent role in normal development and cancer. Copyright 2011 Elsevier Inc. All rights reserved.