Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies - 04/04/13

Doi : 10.1016/S1470-2045(13)70045-7

Diane E Rushlow, BSc ^a, Berber M Mol, MSc ^k, Jennifer Y Kennett, MSc ^l,^{^{†
Contributed equally}}, Stephanie Yee, MSc ^{^{†
Contributed equally},}^b,^g, Sanja Pajovic, PhD ^{^{†
Contributed equally},}^b, Brigitte L Thériault, PhD ^b, Nadia L Prigoda-Lee, MSc ^a, Clarellen Spencer, BSc ^b, Helen Dimaras, PhD ^d,^e, Timothy W Corson, PhD ^m, Renée Pang, MA ^c, Christine Massey, MSc ^b, Roseline Godbout, ProfPhD ⁿ, Zhe Jiang, BSc ^j, Eldad Zacksenhaus, PhD ^h,^j, Katherine Paton, MD ^l, Annette C Moll, MD ^k, Claude Houdayer, PhD ^o, Anthony Raizis, PhD ^p, William Halliday, MD ^f,ⁱ, Wan L Lam, ProfPhD ^l, Paul C Boutros, PhD ^c, Dietmar Lohmann, ProfMD ^q, Josephine C Dorsman, PhD ^k, Brenda L Gallie, ProfMD ^a,^b,^g,^h,^⁎

^a Impact Genetics and the Toronto Western Hospital Research Institute, University Health Network, Toronto, ON, Canada

^b Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

^c Informatics and Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, ON, Canada

^d Department of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada

^e Department of Ophthalmology and Visual Science, Hospital for Sick Children, Toronto, ON, Canada

^f Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada

^g Departments of Molecular Genetics and Ophthalmology, University of Toronto, Toronto, ON, Canada

^h Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

ⁱ Department of Pathobiology and Lab Medicine, University of Toronto, Toronto, ON, Canada

^j Toronto General Research Institute, University Health Network, Toronto, ON, Canada

^k Departments of Clinical Genetics, Ophthalmology, and Pediatric Oncology/Hematology, VU University Medical Center Amsterdam, Amsterdam, Netherlands

^l British Columbia Cancer Research Centre and Departments of Ophthalmology and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

^m Eugene and Marilyn Glick Eye Institute, Departments of Ophthalmology, Biochemistry and Molecular Biology, Indiana University School of Medicine Indianapolis, IN, USA

ⁿ University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada

^o Service de Génétique Oncologique, Institut Curie and Université Paris Descartes, Paris, France

^p Department of Molecular Pathology, Canterbury Health Laboratories, Christchurch, New Zealand

^q Institut für Humangenetik, Universitätsklinikum, Essen, Germany

^* Correspondence to: Prof Brenda L Gallie, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1M9

Summary

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^+/+MYCN^A), whereas none of 93 RB1^−/− primary tumours tested showed MYCN amplification (p<0·0001). RB1^+/+MYCN^A 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^+/+MYCN^A retinoblastoma. One additional MYCN^A 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^+/+MYCN^A 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^+/+MYCN^A 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.

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Vol 14 - N° 4

P. 327-334 - avril 2013 Retour au numéro

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Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies - 04/04/13

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