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

Cite this

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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.",
author = "Kooi, {Irsan E.} and {van Mil}, {Saskia E.} and David MacPherson and Mol, {Berber M.} and Moll, {Annette C.} and Hanne Meijers-Heijboer and Kaspers, {Gertjan J.L.} and Jacqueline Cloos and {te Riele}, Hein and Dorsman, {Josephine C.}",
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Genomic landscape of retinoblastoma in Rb−/−p130−/− mice resembles human retinoblastoma. / Kooi, Irsan E.; van Mil, Saskia E.; MacPherson, David; Mol, Berber M.; Moll, Annette C.; Meijers-Heijboer, Hanne; Kaspers, Gertjan J.L.; Cloos, Jacqueline; te Riele, Hein; Dorsman, Josephine C.

In: Genes Chromosomes and Cancer, Vol. 56, No. 3, 01.03.2017, p. 231-242.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Genomic landscape of retinoblastoma in Rb−/−p130−/− mice resembles human retinoblastoma

AU - Kooi, Irsan E.

AU - van Mil, Saskia E.

AU - MacPherson, David

AU - Mol, Berber M.

AU - Moll, Annette C.

AU - Meijers-Heijboer, Hanne

AU - Kaspers, Gertjan J.L.

AU - Cloos, Jacqueline

AU - te Riele, Hein

AU - Dorsman, Josephine C.

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N2 - 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.

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