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array further detected copy number increase of MYC in 16/20 (80%),
whereas, deletion of 1p localized to a minimal region of deletion on
1p36.22 was seen in 13/20(65%) of the cases.
Conclusions. These results suggest that loss of BAP1 is the most
common genetic abnormality in OM, whereas deletion 1p36.22 &
MYC amplification may be secondary events. In addition, combined
use of these two methodologies is powerful to detect biologically
important abnormalities including copy number changes and
uniparental disomy. The clinical implications of these abnormalities,
specifically hemizygous deletion of BAP1 in relation to metastases,
prognosis and response to therapy are currently being examined.
Financial disclosure. None
1843 RES 16
BAP 1 MUTATION IN TWO FAMILIES WITH UVEAL
MELANOMA
Miguel A. Materin1, Camila Simoes1, Ruth Halaban1, William Harbour 2
(miguel.materin@yale.edu)
1. Yale School of Medicine, New Haven, Conncecticut
2. Washington University, St. Louis, Missouri
Purpose. To describe the potential inheritance of BAP 1 mutation in
patients with uveal melanoma.
Methods. Two different families with history of uveal melanoma
were found to have BAP1 mutation. Family 1, patient had choroidal
melanoma, class 2, BAP1 mutation. Maternal grandfather died
from liver metastases from an eye tumor. Patient’’s mother DNA
was positive for BAP1 mutation. Family 2, two brothers with uveal
melanoma had BAP1 mutation.
Results. We are presenting two different families with uveal
melanoma in two different members of the family and BAP1 mutation.
In one of the family, this mutation was found in a family member with
no uveal melanoma present.
Conclusions. We are presenting two different families with uveal
melanoma in two different members of the family and BAP1 mutation.
In one of the family, this mutation was found in a family member with
no uveal melanoma present.
Financial disclosure. Pfizer consultant: Miguel Materin, however, no commercial interest in this
paper.
103 RES 17
IDENTIFICATION OF MOLECULAR SUBGROUPS OF
RETINOBLASTOMA
M. Parulekar, G. Kapatai, M.A. Brundler, A. Peet, M. Wilson, H. Jenkinson,
C. McConville (manojparulekar@aol.com)
School of Cancer Sciences, University of Birmingham, Dept of
Ophthalmology, Oncology & Histopathology, Birmingham Children’’s
Hospital, UK
Purpose. Survival for retinoblastoma patients is excellent, but invasion
into the optic nerve or choroid is relatively frequent, increasing
the potential for extra-ocular metastasis. Little is known about the
molecular events which influence tumour behaviour. The purpose of
our research is to develop a clinically relevant molecular classification
of retinoblastoma and to translate this into 1H-MRS (1H-magnetic
resonance spectroscopy)-detectable markers for the non-invasive
RESEARCH DAY
Abstracts
23
diagnostic assessment of retinoblastomas.
Methods. Gene expression profiling was carried out on 21
retinoblastomas. Principal component analysis (PCA) was used for
classification of molecular sub-groups. Differentially expressed genes
in each subgroup were identified using SAM (Significance Analysis of
Microarrays). In vitro 1H-MRS was carried out to identify metabolite
spectra specific for molecular subgroups.
Results. Molecular analyses identified 3 distinct groups of
retinoblastomas characterized primarily by differing levels of
photoreceptor differentiation. One group showed expression of many
cone-associated genes, a second group expressed markers of rod,
cone and Müller glial cells, while the third showed down-regulation
of these genes.
Conclusions. Photoreceptor differentiation was inversely associated
with adverse histopathological features (choroid and post-laminar
optic nerve invasion), suggesting that loss of differentiation may
be associated with more aggressive tumour behaviour. Recurrent
chromosomal alterations characteristic of retinoblastoma (1q gain, 6p
gain, 16q loss) were almost entirely restricted to less differentiated
retinoblastomas indicating that genes on these chromosomes may
function in differentiation-related pathways and/or in the regulation of
cell cycle exit. Preliminary 1H-MRS results identified several metabolites
(e.g. glutamate/glutamine, taurine) which may have potential as
markers of retinoblastoma subgroups.
Financial disclosure. None
1820 RES 18
A NEW DISEASE: RETINOBLASTOMA WITH NO
DETECTABLE RB1 MUTATIONS DRIVEN BY MYCN
AMPLIFICATION
Brenda L. Gallie, D.E. Rushlow, S. Yee, J.Y. Kennett, P. Boutros, N.L. Prigoda-
Lee, W. Halliday, S. Pajovic, C. Spencer, B..LThériault, H. Dimaras, A. Raizis,
C. Houdayer, W.L. Lam, T. Corson, D. Lohmann (brenda@gallie.ca)
Retinoblastoma Solutions and the Toronto Western Hospital Research
Institute, University Health Network; Department of Molecular
Genetics, University of Toronto; British Columbia Cancer Research
Centre, Vancouver; The Ontario Institute for Cancer Research, Toronto;
Department of Pathology, Hospital for Sick Children, Toronto; Campbell
Family Cancer Research Institute and Ontario Cancer Institute, University
Health Network, Toronto; Departments of Hematology Oncology and
Ophthalmology and Visual Science, Hospital for Sick Children, Toronto;
Department of Molecular Pathology, Canterbury Health Laboratories,
Christchurch, New Zealand; Service de Génétique Oncologique, Institut
Curie and Université Paris Descartes, Paris, France; Eugene and Marilyn
Glick Eye Institute, Department of Ophthalmology; and Department of
Biochemistry and Molecular Biology, Indiana University School of Medicine,
Indianapolis, Indiana; Institut für Humangenetik, Universitätsklinikum
Essen, Germany; Dept. of Ophthalmology and Medical Biophysics, Univ
of Toronto, Canada.
Purpose. Dogma states that all retinoblastoma tumors have lost both
alleles of the RB1 tumor suppressor gene. We can efficiently identify
95% of RB1 mutant alleles. In 2% of tumors we failed to find any mutant
RB1 allele (RB1+/+).
Methods. In the RB1+/+ tumors, we characterized the RB and other
protein expression, the other genomic changes characteristic of primary
retinoblastoma, aCGH, and clinical features. One RB1+/+ cell line was
studied for growth rate in comparison to RB1-/- cell lines.
Results. In 1% of retinoblastoma tumors we discovered high level