Genomic landscape of retinoblastoma in Rb(-/-) p130(-/-) mice resembles human retinoblastoma.

Publication Type:

Journal Article


Genes, chromosomes & cancer, Volume 56, Issue 3, p.231-242 (2017)


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 (∼0.5x) 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. This article is protected by copyright. All rights reserved.