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Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach

Oncogene volume 24, pages 5827–5836 (2005)Cite this article

Abstract

Human retinoblastoma occurs in two forms (familial and sporadic) both due to biallelic mutation of the RB1/p105 gene even if its loss is insufficient for malignancy. We have recently reported that loss of expression of the retinoblastoma-related protein pRb2/p130 correlates with low apoptotic index, suggesting that RB2/p130 gene could be involved in retinoblastoma. Mutational analysis of RB2/p130 in primary tumors showed a tight correlation between Exon 1 mutations and pRb2/p130 expression level in sporadic retinoblastoma. These mutations are located within a CpG-enriched region prone to de novo methylation. Analysis of RB2/p130 methylation status revealed that epigenetic events, most probably consequent to the Exon 1 mutations, determined the observed phenotype. Treatment of Weri-Rb1 cell line by 5-Aza-dC induced an increase in expression level of pRb2/p130, E2F1, p73 and p53. Overall, our results highlight a crucial role of epigenetic events in sporadic retinoblastoma, which opens a perspective for new therapeutic approaches.

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Acknowledgements

This work was supported by AIRC, Fondazione MPS, MURST-LAG-CO3 and CNR Italian grants; Sbarro Health Research Organization (www.shro.org) and NIH USA-grants.

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Authors and Affiliations

  1. Department of Ophthalmology and Neurosurgery, University of Siena, Siena, Italy

    Gian Marco Tosi & Aldo Caporossi

  2. Institute of Neuroscience CNR, Pisa, Italy

    Carmela Trimarchi

  3. Sbarro Institute of Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA

    Marcella Macaluso, Antonio Giordano & Caterina Cinti

  4. Department of Human Pathology and Oncology, University of Siena, Siena, Italy

    Dario La Sala, Stefano Lazzi & Antonio Giordano

  5. Institute of Clinical Physiology CNR, Siena, Italy

    Dario La Sala & Caterina Cinti

  6. Institute of Genetics and Biophysics CNR, Napoli, Italy

    Alfredo Ciccodicola

  7. Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA

    Mina Massaro-Giordano

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  1. Gian Marco Tosi
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  2. Carmela Trimarchi
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Correspondence to Caterina Cinti.

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Tosi, G., Trimarchi, C., Macaluso, M. et al. Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach. Oncogene 24, 5827–5836 (2005). https://doi.org/10.1038/sj.onc.1208630

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