Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies

Rushlow, Diane; Mol, Berber M.; Kennett, Jennifer Y.; Yee, Stephanie S.; Pajovic, Sanja; Thériault, Brigitte L.; Prigoda-Lee, Nadia L.; Spencer, Clarellen; Dimaras, Helen; Corson, Timothy W.; Pang, Renee; Massey, Christine; Godbout, Roseline; Jiang, Zhe; Zacksenhaus, Eldad; Paton, Katherine; Moll, Annette C.; Houdayer, Claude; Raizis, Anthony; Halliday, William; Lam, Wan L.; Boutros, Paul C.; Lohmann, Dietmar; Dorsman, Josephine C.; Gallie, Brenda L.

doi:10.1016/s1470-2045(13)70045-7

Cited by 317 publications

(309 citation statements)

References 28 publications

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“…Although uncommon, N-myc amplification in retinoblastoma is independent of germline or somatic mutation of the retinoblastoma gene (RB1), and is associated with early onset (median age, 4.5 months), unilateral disease, and clinical aggressiveness (28). Therefore, N-myc-amplified retinoblastomas are thought to represent a distinct molecular subclass of nonfamilial retinoblastoma.…”

Section: N-myc and Human Cancermentioning

confidence: 99%

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Beltran

2014

Molecular Cancer Research

121

109

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N-myc (MYCN), a member of the Myc family of basic-helix-loop-helix-zipper (bHLHZ) transcription factors, is a central regulator of many vital cellular processes. As such, N-myc is well recognized for its classic oncogenic activity and association with human neuroblastoma. Amplification and overexpression of N-myc has been described in other tumor types, particularly those of neural origin and neuroendocrine tumors. This review outlines N-myc's contribution to normal development and oncogenic progression. In addition, it highlights relevant transcriptional targets and mechanisms of regulation. Finally, the clinical implications of N-Myc as a biomarker and potential as a target using novel therapeutic approaches are discussed. Mol Cancer Res; 12(6); 815-22. Ó2014 AACR. IntroductionThe N-myc gene was first reported in 1983, when Schwab and colleagues (1) and Kohl and colleagues (2) discovered that there were a subset of human neuroblastoma cell lines harboring multiple copies of a DNA sequence related to the C-myc oncogene (MYC), and this region was designated Nmyc (MYCN). Genomic amplification of N-myc resulted in overexpression of N-myc at the mRNA level, and rat embryo cells transfected with N-myc demonstrated oncogenic properties. These findings were first to bring attention to N-myc as a putative oncogene.

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Section: N-myc and Human Cancermentioning

confidence: 99%

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Beltran

2014

Molecular Cancer Research

121

109

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“…In hereditary cases, a germline mutation in the RB1 gene predisposes to the development of RB, requiring only one additional somatic hit in the remaining RB1 allele for tumor formation, whereas two independent somatic mutations or epigenetic silencing through methylation is required in nonhereditary cases. About 1% of RB (usually unilateral) is due to somatic MYCN amplification rather than loss of RB1 function (4). Another study demonstrated three RBs with focal chromothripsis in the tumor tissue disrupting the RB1 locus, suggesting that somatic acquisition of these complex structural rearrangements can play a role in RB1 tumor-suppressor inactivation (5).…”

Section: Hereditary Rb: Introductionmentioning

confidence: 99%

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Kamihara

Bourdeaut

Foulkes

et al. 2017

Clinical Cancer Research

172

126

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Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop.

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“…As explained earlier, most retinoblastoma cases are associated with a mutation of the tumorsuppressor gene RB1. [1][2][3] Normally, RB1 functions as a main regulator of the G1 checkpoint, but several recent studies also defined the role for RB1/p105 in a wide range of cellular processes, including maintenance of chromosome stability, induction and maintenance of senescence, apoptosis, differentiation, and angiogenesis. 43 Although more experimental evidence is needed, the main role RB1 plays in angiogenesis seems to be through p21/E2F/Rb pathway, which indirectly represses VEGF expression.…”

Section: Expression Of the Neural Stem Cell Marker Sox2mentioning

confidence: 99%

“…2015;139:1531-1538; doi: 10.5858/arpa.2014-0262-OA) R etinoblastoma is the most common intraocular malignant neoplasm in children, with most cases initiated by a mutation of the tumor-suppressor gene RB1. [1][2][3] Despite extensive research efforts, retinoblastoma-associated mortality rate remains around 70%, especially in lower-income countries. 4 These poor outcomes are, in part, due to delayed tumor detection and lack of effective therapies targeting late-stage disease.…”

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confidence: 99%

Expression of Angiogenic Factors in Invasive Retinoblastoma Tumors Is Associated With Increase in Tumor Cells Expressing Stem Cell Marker Sox2

Garcia

Gombos²,

Prospero³

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

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Context Progression of retinoblastoma is associated with increased tumor angiogenesis. However, a clear relationship between the expression of angiogenic markers in specific regions of the tumor and tumor progression has not been established. This study investigates the association between angiogenic factors in retinoblastomas with choroidal and/or optic nerve invasion (high-risk/invasive retinoblastoma) and expression of Sox2, a stem cell marker. Objective To investigate the association between the expression of angiogenic factors and markers of tumor invasiveness, such as the stem cell marker Sox2, in retinoblastoma tissues. Design Immunohistochemistry was used to evaluate coexpression of the angiogenic growth factors vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR-2), and endoglin (CD105); markers of glial differentiation (vimentin and glial fibrillary acidic protein); and a neural stem cell marker (Sox2). Expression was assessed in nonneoplastic and neoplastic ocular tissues collected from enucleated eyes of patients with retinoblastoma. During qualitative data interpretation, evaluating pathologists were masked to patient grouping. Results Expression of VEGF-A and VEGFR-2 in noninvasive (non–high-risk feature) retinoblastoma tumors was lower than in the invasive, or high-risk feature tumors. Moreover, our data indicate that the tumor cells, and not the surrounding stroma, secrete VEGF-A and that angiogenesis is mostly localized to the iris. Finally, our data showed that the expression of the neural stem cell marker Sox2 is associated with eyes with increased VEGF-A expression and tumor invasiveness. Conclusions Increased expression of angiogenic factors, with a concomitant increase in expression of the stem cell marker Sox2 observed in retinoblastoma tissues, may partially explain the aggressiveness of these tumors. The complex interaction of angiogenic and stem cell–related pathways in these tumors, especially in high-risk feature retinoblastoma, suggests that targeting tumor cells capable of secreting vasculogenic factors, as well as proangiogenic genes and signaling pathways, may be necessary for development of effective antimetastatic retinoblastoma drugs.

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Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies

Cited by 317 publications

References 28 publications

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Expression of Angiogenic Factors in Invasive Retinoblastoma Tumors Is Associated With Increase in Tumor Cells Expressing Stem Cell Marker Sox2

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