Oncotarget

Research Papers:

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, Susan Ragsdale, Virginia Valentine, Armita Bahrami, Jamshid Temirov, Stanley Pounds, Jinghui Zhang, Michael A. Dyer _

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Oncotarget. 2013; 4:844-859. https://doi.org/10.18632/oncotarget.1051

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Abstract

Claudia A. Benavente1, Justina D. McEvoy1, David Finkelstein2, Lei Wei3, Guolian Kang4, Yong-Dong Wang2, Geoffrey Neale2, Susan Ragsdale5, Virginia Valentine5, Armita Bahrami6, Jamshid Temirov7, Stanley Pounds4, Jinghui Zhang3, and Michael A. Dyer1,8

1 Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA.

2 Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital, Memphis, TN, USA.

3 Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA.

4 Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA.

5 Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA.

6 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA.

7 Cell and Tissue Imaging Facility, St Jude Children’s Research Hospital, Memphis, Tennessee, USA

8 Howard Hughes Medical Institute, Chevy Chase, MD

Correspondence:

Michael A. Dyer, email:

Keywords: retinoblastoma, RB1, epigenetics

Received: May 23, 2013 Accepted: May 31, 2013 Published: June 1, 2013

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.


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