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

Helen Dimaras, Vikas Khetan, William Halliday, Marija Orlic, Nadia L. Prigoda, Beata Piovesan, Paula Marrano, Timothy W. Corson, Ralph C. Eagle, Jeremy A. Squire, Brenda L. Gallie

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1363-1372
Number of pages10
JournalHuman molecular genetics
Volume17
Issue number10
DOIs
StatePublished - May 15 2008

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Dimaras, H., Khetan, V., Halliday, W., Orlic, M., Prigoda, N. L., Piovesan, B., Marrano, P., Corson, T. W., Eagle, R. C., Squire, J. A., & Gallie, B. L. (2008). Loss of RB1 induces non-proliferative retinoma: Increasing genomic instability correlates with progression to retinoblastoma. Human molecular genetics, 17(10), 1363-1372. https://doi.org/10.1093/hmg/ddn024