title: Cross-species genomic and epigenomic landscape of retinoblastoma.
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.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Benavente
authors.forename: Justina D
authors.initials: JD
authors.lastname: McEvoy
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Guolian
authors.initials: G
authors.lastname: Kang
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Wang
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Susan
authors.initials: S
authors.lastname: Ragsdale
authors.forename: Virginia
authors.initials: V
authors.lastname: Valentine
authors.forename: Armita
authors.initials: A
authors.lastname: Bahrami
authors.forename: Jamshid
authors.initials: J
authors.lastname: Temirov
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering / Q000379:methods; D023281:Genomics / Q000379:methods; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012175:Retinoblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity
chemical_list: D016160:Retinoblastoma Protein