Genomic landscape of retinoblastoma in Rb−/−p130−/− mice resembles human retinoblastoma

Irsan E. Kooi, Saskia E. van Mil, David MacPherson, Berber M. Mol, Annette C. Moll, Hanne Meijers-Heijboer, Gertjan J.L. Kaspers, Jacqueline Cloos, Hein te Riele, Josephine C. Dorsman

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)231-242
Number of pages12
JournalGenes Chromosomes and Cancer
Volume56
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017

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