title: Genomic landscape of retinoblastoma in Rb-/-p130-/-mice resembles human retinoblastoma.
abstract: Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb-/-p107-/-retinoblastomas, somatic copy number alterations (SCNAs) like Mdm2 amplification or Cdkn2a deletion targeting the p53-pathway occur, which is uncommon for human retinoblastoma. In our study, we determined SCNAs in retinoblastomas developing in Rb-/-p130-/-mice and compared this to murine Rb-/-p107-/-tumors and human tumors. Chimeric mice were made by injection of 129/Ola-derived Rb-/-p130-/-embryonic stem cells into wild type C57BL/6 blastocysts. SCNAs of retinoblastoma samples were determined by low-coverage (∼0.5×) whole genome sequencing. In Rb-/-p130-/-tumors, SCNAs included gain of chromosomes 1 (3/23 tumors), 8 (1/23 tumors), 10 (1/23 tumors), 11 (2/23 tumors), and 12 (4/23 tumors), which could be mapped to frequently altered chromosomes in human retinoblastomas. While the altered chromosomes in Rb-/-p130-/-tumors were similar to those in Rb-/-p107-/-tumors, the alteration frequencies were much lower in Rb-/-p130-/-tumors. Most of the Rb-/-p130-/-tumors (16/23 tumors, 70%) were devoid of SCNAs, in strong contrast to Rb-/-p107-/-tumors, which were never (0/15 tumors) SCNA-devoid. Similarly, to human retinoblastoma, increased age at diagnosis significantly correlated with increased SCNA frequencies. Additionally, focal loss of Cdh11 was observed in one Rb-/-p130-/-tumor, which enforces studies in human retinoblastoma that identified CDH11 as a retinoblastoma suppressor. Moreover, based on a comparison of genes altered in human and murine retinoblastoma, we suggest exploring the role of HMGA1 and SRSF3 in retinoblastoma development. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081BT, The Netherlands.
authors.forename: Irsan E
authors.initials: IE
authors.lastname: Kooi
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081BT, The Netherlands.
authors.forename: Saskia E
authors.initials: SE
authors.lastname: van Mil
authors.affiliation: Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109.
authors.forename: David
authors.initials: D
authors.lastname: MacPherson
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081BT, The Netherlands.
authors.forename: Berber M
authors.initials: BM
authors.lastname: Mol
authors.affiliation: Department of Ophthalmology, VU University Medical Center, Amsterdam, 1007 MB, The Netherlands.
authors.forename: Annette C
authors.initials: AC
authors.lastname: Moll
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081BT, The Netherlands.
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, 1081 HV, The Netherlands.
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, 1081 HV, The Netherlands.|Department of Hematology, VU University Medical Center, Amsterdam, 1081 HV, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081BT, The Netherlands.|Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Hein
authors.initials: H
authors.lastname: Te Riele
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081BT, The Netherlands.
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Dorsman
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012175:Retinoblastoma / Q000235:genetics*; D050720:Retinoblastoma-Like Protein p107 / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130 / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130