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Genomic landscape of retinoblastoma in Rb -/- p130 -/- mice resembles human retinoblastoma.
- Source :
-
Genes, chromosomes & cancer [Genes Chromosomes Cancer] 2017 Mar; Vol. 56 (3), pp. 231-242. Date of Electronic Publication: 2016 Nov 21. - Publication Year :
- 2017
-
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 <superscript>-/-</superscript> p107 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> p130 <superscript>-/-</superscript> mice and compared this to murine Rb <superscript>-/-</superscript> p107 <superscript>-/-</superscript> tumors and human tumors. Chimeric mice were made by injection of 129/Ola-derived Rb <superscript>-/-</superscript> p130 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> p130 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> p130 <superscript>-/-</superscript> tumors were similar to those in Rb <superscript>-/-</superscript> p107 <superscript>-/-</superscript> tumors, the alteration frequencies were much lower in Rb <superscript>-/-</superscript> p130 <superscript>-/-</superscript> tumors. Most of the Rb <superscript>-/-</superscript> p130 <superscript>-/-</superscript> tumors (16/23 tumors, 70%) were devoid of SCNAs, in strong contrast to Rb <superscript>-/-</superscript> p107 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> p130 <superscript>-/-</superscript> 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.<br /> (© 2016 Wiley Periodicals, Inc.)
- Subjects :
- Animals
Embryonic Stem Cells cytology
Embryonic Stem Cells metabolism
Female
Genome
High-Throughput Nucleotide Sequencing methods
Humans
Male
Mice
Mice, Inbred C57BL
Biomarkers, Tumor genetics
DNA Copy Number Variations genetics
Retinoblastoma genetics
Retinoblastoma-Like Protein p107 physiology
Retinoblastoma-Like Protein p130 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-2264
- Volume :
- 56
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Genes, chromosomes & cancer
- Publication Type :
- Academic Journal
- Accession number :
- 27750399
- Full Text :
- https://doi.org/10.1002/gcc.22429