Characterisation of retinoblastomas without RB1 mutations: Genomic, gene expression, and clinical studies

Diane E. Rushlow, Berber M. Mol, Jennifer Y. Kennett, Stephanie Yee, Sanja Pajovic, Brigitte L. Thériault, Nadia L. Prigoda-Lee, Clarellen Spencer, Helen Dimaras, Timothy W. Corson, Renée Pang, Christine Massey, Roseline Godbout, Zhe Jiang, Eldad Zacksenhaus, Katherine Paton, Annette C. Moll, Claude Houdayer, Anthony Raizis, William HallidayWan L. Lam, Paul C. Boutros, Dietmar Lohmann, Josephine C. Dorsman, Brenda L. Gallie

Research output: Contribution to journalArticle

151 Scopus citations


Background: Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations. Methods: Of 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations (RB1+/+) with tumours carrying a mutation in both alleles (RB1-/-). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data. Findings: No RB1 mutations (RB1+/+) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1+/+ tumours had high-level MYCN oncogene amplification (28-121 copies; RB1+/+MYCNA), whereas none of 93 RB1-/- primary tumours tested showed MYCN amplification (p<0·0001). RB1+/+MYCNA tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1-/- tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1+/+MYCNA retinoblastoma. One additional MYCNA tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1+/+MYCNA tumours was 4·5 months (IQR 3·5-10), compared with 24 months (15-37) for 79 children with non-familial unilateral RB1-/- retinoblastoma. Interpretation: Amplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1+/+MYCNA retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis. Funding: National Cancer Institute-National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa.

Original languageEnglish (US)
Pages (from-to)327-334
Number of pages8
JournalThe lancet oncology
Issue number4
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Oncology

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    Rushlow, D. E., Mol, B. M., Kennett, J. Y., Yee, S., Pajovic, S., Thériault, B. L., Prigoda-Lee, N. L., Spencer, C., Dimaras, H., Corson, T. W., Pang, R., Massey, C., Godbout, R., Jiang, Z., Zacksenhaus, E., Paton, K., Moll, A. C., Houdayer, C., Raizis, A., ... Gallie, B. L. (2013). Characterisation of retinoblastomas without RB1 mutations: Genomic, gene expression, and clinical studies. The lancet oncology, 14(4), 327-334.