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

The authors declare no conflict of interest.

Disclosure/conflict of interest

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

Mutation-specific chromosomal patterns

NRM with LOH BAP1 =?= BAP1-negative group

Size and number of CNVs

SRO ? (Smallest region of overlap)

Karyotyping

Cytogenetics

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.

Survival analyses

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

Genetic model uveal melanoma

Yavuzyigitoglu et al., Ophthalmology 2016

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