Cross-species genomic and epigenomic landscape of retinoblastoma

Claudia A. Benavente, Justina D. McEvoy, David Finkelstein, Lei Wei, Guolian Kang, Yong Dong Wang, Geoffrey Neale, Ragsdale Susan Ragsdale, Virginia Valentine, Armita Bahrami, Jamshid Temirov, Stanley Pounds, Jinghui Zhang, Michael A. Dyer

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our understanding of tumor initiation and progression as well as for testing novel therapeutics. Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. GEMMs faithfully recapitulate the histopathology, molecular, cellular, morphometric, neuroanatomical and neurochemical features of human retinoblastoma. In this study, we analyzed the genomic and epigenomic landscape of murine retinoblastoma and compared them to human retinoblastomas to gain insight into shared mechanisms of tumor progression across species. Similar to human retinoblastoma, mouse tumors have low rates of single nucleotide variations. However, mouse retinoblastomas have higher rates of aneuploidy and regional and focal copy number changes that vary depending on the genetic lesions that initiate tumorigenesis in the developing murine retina. Furthermore, the epigenetic landscape in mouse retinoblastoma was significantly different from human tumors and some pathways that are candidates for molecular targeted therapy for human retinoblastoma such as SYK or MCL1 are not deregulated in GEMMs. Taken together, these data suggest there are important differences between mouse and human retinoblastomas with respect to the mechanism of tumor progression and those differences can have significant implications for translational research to test the efficacy of novel therapies for this devastating childhood cancer.

Original languageEnglish (US)
Pages (from-to)844-859
Number of pages16
JournalOncotarget
Volume4
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Epigenetics
  • RB1
  • Retinoblastoma

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Benavente, C. A., McEvoy, J. D., Finkelstein, D., Wei, L., Kang, G., Wang, Y. D., Neale, G., Susan Ragsdale, R., Valentine, V., Bahrami, A., Temirov, J., Pounds, S., Zhang, J., & Dyer, M. A. (2013). Cross-species genomic and epigenomic landscape of retinoblastoma. Oncotarget, 4(6), 844-859. https://doi.org/10.18632/oncotarget.1051