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Chromosomal aberration predicts uveal melanoma
mutation
ECP September 2017 Amsterdam
Robert M. Verdijk
Pathology Department, section Ophthalmic Pathology
Erasmus MC University Medical Center Rotterdam
The Netherlands
Uveal Melanoma (UM)
• Derived from uveal melanocytes
• Localization: iris (5%), ciliairy body (23%), choroid (72%)
• Incidence 7/1.000.000
• Treatment
• Enucleation
• Brachytherapy/SRT/proton beam irr.
>95% local tumor control
• Metastasis: 50% of all patients
• ~90% Liver
• No succesful treatment options for metastatic disease.
Clinical features
• Age
• Tumor thickness
• Basal diameter
Histopathological
• Cell type (epithelioid cells)
• Closed vascular loops
Immunohistochemistry
• BAP1 staining
Genetics
Prognostic markers in uveal melanoma
BAP1 +
BAP1 --
Clinical features
• Age
• Tumor thickness
• Basal diameter
Histopathological
• Cell type (epithelioid cells)
• Closed vascular loops
Genetics
• Chromosomes 1p-, 3-, 6p+, 6q-, 8+
• Genes:
Prognostic markers in uveal melanoma
Clinical features
• Age
• Tumor thickness
• Basal diameter
Histopathological
• Cell type (epithelioid cells)
• Closed vascular loops
Genetica
• Chromosomes 1p-, 3-, 6p+, 6q-, 8+
• Genes: BAP1, SF3B1 en EIF1AX
Prognostic markers in uveal melanoma
Stratification of patients for individual prognosis
Supervised hierarchal clustering
BAP1 chromsome 3p
BRCA associoated protein-1
~40% of UM
Involved in chromatin remodelling
Deubiquitinase (DUB)
DNA-Damage repair
EIF1AX chromosome X
Eukaryotic translation initiation factor
1a, X-linked
~20% of UM
Mutations exon 1 or exon 2 (missense
and in-frame
Almost exclusively in disomy 3
SF3B1 Chromosome 2
Splicing factor 3b, subunit 1
~25% of UM, exclusively with disomy 3
Almost all missense p.R625
Also mutated in other malignancies
Associated with late metastases
Isochromosomes
Short term cultures (max 4wk)
Karyotyping 10-20 metaphases
• 74 % of the BAP1neg tumors (n = 25/34)
• Iso chromosomes : i(6p), i(8q), i(1q), i(2q)
• None in SF3B1mut (n = 12) and EIF1AXmut (n = 6) tumors
• Also in BAP1neg: translocations with breakpoints centromer .
8 8 iso(8q)
Structural Variants
• SF3B1mut has a median of 4 SV
• Complex structural variants
• Chromosome 6, 8, 9, 11
SF3B1mut tumors have significant more structural
anomalies compared to BAP1neg tumors.
Conclusions
UM patients stratified on mutations in BAP1, SF3B1, EIF1AX
• Chromosomal pattern : mutation specific changes
SF3B1mut : significant more CSV than BAP1neg tumors
SF3B1mut : multiple structural often distal rearrangements
BAP1neg : whole chromosome / arms involved, isochromosome
• Prognosis : different outcome predicted ;
BAP1neg worst prognosis (meta’s <4 year)
SF3B1mut: intermediate risk with late meta’s (>7 years)
EIF1AXmut: low risk
Erasmus MC
Ophthalmology and Clinical Genetics
Wojtek Drabarek
Serdar Yavuzyigitoglu
Kyra Smit
Natasha van Poppelen
Jolanda Vaarwater
Askar Obulkasim
Nicole Naus
Emine Kiliç
Erasmus MC
Pathology
Robert M. Verdijk
Hendricus J. Dubbink
Erasmus MC
Cancer Computational Biology Center
Harmen van de Werken
Job van Riet
Prof. dr. henkes stichting
18
Erasmus MC
Clinical Genetics
Bert Eussen
Tom Brands
Berna Beverloo
Annelies de Klein
Rotterdam Eye Hospital
Dion Paridaens
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