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Cross-species genomic and epigenomic landscape of retinoblastoma.

Benavente CA, McEvoy JD, Finkelstein D, Wei L, Kang G, Wang YD, Neale G, Ragsdale S, Valentine V, Bahrami A, Temirov J, Pounds S, Zhang J, Dyer MA - Oncotarget (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.

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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Mouse and Human Integrative Data Analysis for Retinoblastoma Integrative data analysis for mouse retinoblastoma was compared to the human retinoblastoma integrative data from Zhang et al[6](A) Diagram showing the number of genes significantly deregulated in mouse and human retinoblastoma, the subset considered epigenetically deregulated by our integrative data analysis in each specie and those epigenetically deregulated both in mouse and human. (B) Gene expression data of the 131 genes epigenetically deregulated in the RbTKO mouse retinoblastoma model that could be matched to genes in the human retinoblastoma integrative data. (C) Gene expression data of the 111 genes epigenetically deregulated in human retinoblastoma that could be matched to genes in the RbTKO mouse retinoblastoma. Genes up- and down-regulated in both mouse and human are depicted in red and green, respectively. Genes deregulated in opposite directions are colored in gray. Genes found to be epigenetically deregulated in both species are labeled (black dots). (D) Proposed survival pathways for mouse and human retinoblastoma.
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Figure 4: Mouse and Human Integrative Data Analysis for Retinoblastoma Integrative data analysis for mouse retinoblastoma was compared to the human retinoblastoma integrative data from Zhang et al[6](A) Diagram showing the number of genes significantly deregulated in mouse and human retinoblastoma, the subset considered epigenetically deregulated by our integrative data analysis in each specie and those epigenetically deregulated both in mouse and human. (B) Gene expression data of the 131 genes epigenetically deregulated in the RbTKO mouse retinoblastoma model that could be matched to genes in the human retinoblastoma integrative data. (C) Gene expression data of the 111 genes epigenetically deregulated in human retinoblastoma that could be matched to genes in the RbTKO mouse retinoblastoma. Genes up- and down-regulated in both mouse and human are depicted in red and green, respectively. Genes deregulated in opposite directions are colored in gray. Genes found to be epigenetically deregulated in both species are labeled (black dots). (D) Proposed survival pathways for mouse and human retinoblastoma.

Mentions: Analyses of human retinoblastoma genome and epigenome uncovered few genetic lesions and identified epigenetic as the mechanism underlying the rapid progression of human retinoblastoma [6]. To determine if there were any epigenetically deregulated genes in mouse retinoblastoma that were shared with human retinoblastoma, we performed DNA methylation analysis and chromatin immunoprecipitation (ChIP) assays for histone marks of actively transcribed (H3K4me3 and H3K9/14Ac) or silent chromatin (H3K9me3). We integrated data on gene expression, DNA methylation and histone marks for RbTKO tumors and P5 mouse retina to be able to compare our data to the previously published data on integrated epigenetic analysis of human retinoblastoma and human fetal retina. Overall, we found that the epigenetic landscape in mouse retinoblastoma was very different than for human retinoblastoma, with 327 genes being epigenetically deregulated (Figure 4A and Sup. Table 10). Among the 327 epigenetically regulated genes in mouse retinoblastoma, only 23 were also epigenetically deregulated in human retinoblastoma, 17 of which change gene expression in the same direction (Figure 4B,C). In the mouse retinoblastoma, 11 of the epigenetically deregulated genes are cancer genes but none of those were found to be epigenetically deregulated in the human retinoblastomas (Sup. Table 10).


Cross-species genomic and epigenomic landscape of retinoblastoma.

Benavente CA, McEvoy JD, Finkelstein D, Wei L, Kang G, Wang YD, Neale G, Ragsdale S, Valentine V, Bahrami A, Temirov J, Pounds S, Zhang J, Dyer MA - Oncotarget (2013)

Mouse and Human Integrative Data Analysis for Retinoblastoma Integrative data analysis for mouse retinoblastoma was compared to the human retinoblastoma integrative data from Zhang et al[6](A) Diagram showing the number of genes significantly deregulated in mouse and human retinoblastoma, the subset considered epigenetically deregulated by our integrative data analysis in each specie and those epigenetically deregulated both in mouse and human. (B) Gene expression data of the 131 genes epigenetically deregulated in the RbTKO mouse retinoblastoma model that could be matched to genes in the human retinoblastoma integrative data. (C) Gene expression data of the 111 genes epigenetically deregulated in human retinoblastoma that could be matched to genes in the RbTKO mouse retinoblastoma. Genes up- and down-regulated in both mouse and human are depicted in red and green, respectively. Genes deregulated in opposite directions are colored in gray. Genes found to be epigenetically deregulated in both species are labeled (black dots). (D) Proposed survival pathways for mouse and human retinoblastoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757242&req=5

Figure 4: Mouse and Human Integrative Data Analysis for Retinoblastoma Integrative data analysis for mouse retinoblastoma was compared to the human retinoblastoma integrative data from Zhang et al[6](A) Diagram showing the number of genes significantly deregulated in mouse and human retinoblastoma, the subset considered epigenetically deregulated by our integrative data analysis in each specie and those epigenetically deregulated both in mouse and human. (B) Gene expression data of the 131 genes epigenetically deregulated in the RbTKO mouse retinoblastoma model that could be matched to genes in the human retinoblastoma integrative data. (C) Gene expression data of the 111 genes epigenetically deregulated in human retinoblastoma that could be matched to genes in the RbTKO mouse retinoblastoma. Genes up- and down-regulated in both mouse and human are depicted in red and green, respectively. Genes deregulated in opposite directions are colored in gray. Genes found to be epigenetically deregulated in both species are labeled (black dots). (D) Proposed survival pathways for mouse and human retinoblastoma.
Mentions: Analyses of human retinoblastoma genome and epigenome uncovered few genetic lesions and identified epigenetic as the mechanism underlying the rapid progression of human retinoblastoma [6]. To determine if there were any epigenetically deregulated genes in mouse retinoblastoma that were shared with human retinoblastoma, we performed DNA methylation analysis and chromatin immunoprecipitation (ChIP) assays for histone marks of actively transcribed (H3K4me3 and H3K9/14Ac) or silent chromatin (H3K9me3). We integrated data on gene expression, DNA methylation and histone marks for RbTKO tumors and P5 mouse retina to be able to compare our data to the previously published data on integrated epigenetic analysis of human retinoblastoma and human fetal retina. Overall, we found that the epigenetic landscape in mouse retinoblastoma was very different than for human retinoblastoma, with 327 genes being epigenetically deregulated (Figure 4A and Sup. Table 10). Among the 327 epigenetically regulated genes in mouse retinoblastoma, only 23 were also epigenetically deregulated in human retinoblastoma, 17 of which change gene expression in the same direction (Figure 4B,C). In the mouse retinoblastoma, 11 of the epigenetically deregulated genes are cancer genes but none of those were found to be epigenetically deregulated in the human retinoblastomas (Sup. Table 10).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.

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.

Show MeSH
Related in: MedlinePlus