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Human Molecular Genetics Advance Access originally published online on January 22, 2008
Human Molecular Genetics 2008 17(10):1363-1372; doi:10.1093/hmg/ddn024
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma

Helen Dimaras1,3,6, Vikas Khetan8,{dagger}, William Halliday7, Marija Orlic1,3,6, Nadia L. Prigoda4, Beata Piovesan4, Paula Marrano6, Timothy W. Corson1,6,{ddagger}, Ralph C. Eagle, Jr9, Jeremy A. Squire5,6 and Brenda L. Gallie1,2,3,4,5,6,8,*

1 Department of Molecular and Medical Genetics 2 Department of Ophthalmology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8 3 Vision Science Research Program, Toronto Western Research Institute 4 Solutions by Sequence, Inc., University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8 5 Department of Medical Biophysics, University of Toronto 6 Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, 610 University Avenue, Toronto, ON, Canada M5G 2M9 7 Department of Pathology 8 Department of Ophthalmology and Visual Science, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8 9 Department of Pathology, Wills Eye Hospital, 840 Walnut Street, Suite 1410, Philadelphia, PA 19107-5109, USA

* To whom correspondence should be addressed at: Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Room 8-514, 610 University Avenue, Toronto, ON, Canada M5G 2M9. Tel: +1 4169462324; Fax: +1 4169464619; Email: gallie{at}attglobal.net

Received November 7, 2007; Revised December 20, 2007; Accepted January 18, 2008

Retinoblastoma clinical observations revealed the role of tumor suppressor genes in human cancer, Knudson's ‘two-hit’ model of cancer induction. We now demonstrate that loss of both RB1 tumor suppressor gene alleles initiates quiescent RB1–/– retinomas with low level genomic instability and high expression of the senescence-associated proteins p16INK4a and p130. Although retinomas can remain unchanged throughout life, highly proliferative, clonal and aneuploid retinoblastomas commonly emerge, exhibiting altered gene copy number and expression of oncogenes (MYCN, E2F3, DEK, KIF14 and MDM4) and tumor suppressor genes (CDH11, p75NTR) and reduced expression of p16INK4a and p130. We suggest that RB1 inactivation in developing retina induces genomic instability, but senescence can block transformation at the stage of retinoma. However, stable retinoma is rarely clinically observed because progressive genomic instability commonly leads to highly proliferative retinoblastoma.

{dagger} Present address: Department of Vitreoretinal and Ocular Oncology, Sankara Nethralaya, 18 College Road, Chennai-6, India.

{ddagger} Present address: Department of Molecular, Cellular and Developmental Biology, Yale University, PO Box 208103, New Haven, CT 06520-8103, USA.


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