Metastatic Disease in Polyploid Uveal Melanoma Patients Is Associated With BAP1 Mutations.
OBJECTIVE
Most of the uvea melanoma (UM) display a near-diploid (normal, -2N) karyotype with only a few chromosomal changes. In contrast to these simple aberrations 18% of the UM samples show a polyploid character (>2N) and this was associated with an unfavorable prognosis. This study attempts to gain insight in the prognostic value of polyploidy in UM.


METHODS
In 202 patients the ploidy status of the UM was determined using cytogenetic analysis, fluorescence-in-situ-hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), and/or single nucleotide polymorphism (SNP) array analysis. Immunohistochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) and the mutation hotspots for the SF3B1, EIF1AX, GNAQ, and GNA11 genes was carried out using Sanger sequencing or whole-exome sequencing.


RESULTS
Twenty-three patients had a polyploid UM karyotype (11.4%). Patients with a polyploid tumor had larger tumors (15.61 vs. 13.13 mm, P = 0.004), and more often loss of heterozygosity of chromosome 3 (P = 0.003). No difference in occurrence of mutations between polyploid and diploid tumors was observed for BAP1, SF3B1, EIF1AX, GNAQ, and GNA11. Polyploidy did not affect survival (P = 0.143). BAP1 deficiency was the only significant independent prognostic predictor for patients with polyploid tumors, with a 16-fold increased hazard ratio (HR 15.90, P = 0.009).


CONCLUSIONS
The prevalence of mutations in the UM related genes is not different in polyploid UM compared with diploid UM. Moreover, similar to patients with diploid UM, BAP1 mutation is the most significant prognostic predictor of metastasis in patients with polyploid UM.
Department of Ophthalmology Erasmus University Medical Center, Rotterdam, The Netherlands 2Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Serdar
S
Yavuzyigitoglu
The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Hanneke W
HW
Mensink
Department of Ophthalmology Erasmus University Medical Center, Rotterdam, The Netherlands 2Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Kyra N
KN
Smit
Department of Ophthalmology Erasmus University Medical Center, Rotterdam, The Netherlands 2Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Jolanda
J
Vaarwater
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Robert M
RM
Verdijk
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Berna
B
Beverloo
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Hennie T
HT
Brüggenwirth
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Ronald
R
van Marion
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Hendrikus J
HJ
Dubbink
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Dion
D
Paridaens
Department of Ophthalmology Erasmus University Medical Center, Rotterdam, The Netherlands.
Nicole C
NC
Naus
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Annelies
A
de Klein
Department of Ophthalmology Erasmus University Medical Center, Rotterdam, The Netherlands.
Emine
E
Kiliç
D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009362:Neoplasm Metastasis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011123:Polyploidy; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000502:physiology; D014604:Uveal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology
C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase