Chromosome 3 and 8q aberrations in Uveal Melanoma show greater impact on survival in patients with light iris versus dark iris color

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.

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Positive Interaction Between Light Iris Color and Ultraviolet Radiation in Relation to the Risk of Uveal Melanoma: A Case-Control Study

Yearbook of Ophthalmology ◽

10.1016/s0084-392x(10)79221-2 ◽

2010 ◽

Vol 2010 ◽

pp. 222-223

Author(s):

C.L. Shields

Keyword(s):

Ultraviolet Radiation ◽

Uveal Melanoma ◽

Case Control Study ◽

Case Control ◽

Positive Interaction ◽

Iris Color ◽

Control Study

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Multiple locations on chromosome 3 are the targets of specific deletions in uveal melanoma

Eye ◽

10.1038/sj.eye.6701906 ◽

2005 ◽

Vol 20 (4) ◽

pp. 476-481 ◽

Cited By ~ 21

Author(s):

N A Cross ◽

A Ganesh ◽

M Parpia ◽

A K Murray ◽

I G Rennie ◽

...

Keyword(s):

Uveal Melanoma ◽

Chromosome 3

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The Heterogeneous Distribution of Monosomy 3 in Uveal Melanomas: Implications for Prognostication Based on Fine-Needle Aspiration Biopsies

Archives of Pathology & Laboratory Medicine ◽

10.5858/2007-131-91-thdomi ◽

2007 ◽

Vol 131 (1) ◽

pp. 91-96 ◽

Cited By ~ 2

Author(s):

Willem Maat ◽

Ekaterina S. Jordanova ◽

Shama L. van Zelderen-Bhola ◽

Ed R. Barthen ◽

Hans W. Wessels ◽

...

Keyword(s):

Uveal Melanoma ◽

Fine Needle Aspiration ◽

Fine Needle Aspiration Biopsy ◽

Needle Aspiration ◽

Chromosome 3 ◽

Fish Analysis ◽

Paraffin Sections ◽

Heterogeneous Distribution ◽

Fine Needle ◽

Monosomy 3

Abstract Context.—The detection of monosomy 3 in uveal melanomas has repeatedly been associated with adverse outcome. Fine-needle aspiration biopsy is being used to detect monosomy 3 in these tumors, based on the assumption that this chromosomal abnormality is distributed homogeneously throughout the tumor. Objective.—To study the distribution of monosomy 3 in primary uveal melanoma by fluorescence in situ hybridization (FISH). Design.—We studied 50 enucleated eyes with uveal melanoma. In all 50 tumors we performed cytogenetic analysis and FISH using a DNA-specific probe for the centromere region of chromosome 3 on cultured tumor cells. In addition, the percentage of tumor cells with monosomy 3 was assessed by FISH on nuclei, isolated from paraffin-embedded tissue and compared to results of FISH on regular histology sections of the paraffin-embedded tissue. Results.—Combining karyotyping and FISH on cultured cells identified monosomy 3 in 19 (38%) of 50 tumors, whereas FISH on nuclei isolated from paraffin-embedded tissue showed 31 (62%) of 50 as having monosomy for chromosome 3. FISH analysis on paraffin sections showed tumor heterogeneity for copy number of chromosome 3 in at least 7 cases. Conclusions.—FISH analysis on paraffin sections shows that heterogeneity of monosomy of chromosome 3 is a frequent phenomenon in uveal melanoma. FISH on nuclei isolated from paraffin-embedded tissue identifies a higher frequency of monosomy 3 than the traditional combination of karyotyping and FISH on cultured uveal melanoma cells. The practice of assigning patients to risk categories based on fine-needle aspiration biopsy samples from primary uveal melanoma may be subject to error based on the heterogeneous distribution of monosomy 3 in these tumors.

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Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.09-5083 ◽

2010 ◽

Vol 51 (10) ◽

pp. 4884 ◽

Cited By ~ 32

Author(s):

Sarah L. Lake ◽

Sarah E. Coupland ◽

Azzam F. G. Taktak ◽

Bertil E. Damato

Keyword(s):

Loss Of Heterozygosity ◽

Uveal Melanoma ◽

Chromosome 3 ◽

Whole Genome ◽

Whole Genome Microarray

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Positive Interaction Between Light Iris Color and Ultraviolet Radiation in Relation to the Risk of Uveal Melanoma

Ophthalmology ◽

10.1016/j.ophtha.2008.09.040 ◽

2009 ◽

Vol 116 (2) ◽

pp. 340-348 ◽

Cited By ~ 44

Author(s):

Andrea Schmidt-Pokrzywniak ◽

Karl-Heinz Jöckel ◽

Norbert Bornfeld ◽

Wolfgang Sauerwein ◽

Andreas Stang

Keyword(s):

Ultraviolet Radiation ◽

Uveal Melanoma ◽

Positive Interaction ◽

Iris Color

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Effect of Heterogeneous Distribution of Monosomy 3 on Prognosis in Uveal Melanoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/2010-0477-oar1 ◽

2011 ◽

Vol 135 (8) ◽

pp. 1042-1047 ◽

Cited By ~ 20

Author(s):

Inge HG Bronkhorst ◽

Willem Maat ◽

Ekaterina S Jordanova ◽

Wilma GM Kroes ◽

Nicoline E Schalij-Delfos ◽

...

Keyword(s):

Uveal Melanoma ◽

Survival Data ◽

Cultured Cells ◽

Cox Proportional Hazards ◽

Chromosome 3 ◽

Likelihood Ratios ◽

Heterogeneous Distribution ◽

Isolated Nuclei ◽

Monosomy 3 ◽

Significant Difference

Context.—Fluorescence in situ hybridization (FISH) analyses on tumor sections and on isolated nuclei showed that even low numbers of cells with monosomy of chromosome 3 adversely affected survival. Objective.—To determine what percentage of uveal melanoma cells with monosomy of chromosome 3 influences patient mortality. Design.—To determine the presence of monosomy 3, karyotyping and FISH on cultured cells and FISH on isolated nuclei were performed on 50 primary uveal melanomas. Clinical and pathologic prognostic factors were assessed and compared with 5-year survival data. Analyses were performed using Cox proportional hazards test, log-rank analysis, sensitivity, specificity, and positive and negative likelihood ratios. Results.—Combined karyotyping and FISH on cultured cells showed monosomy 3 in 19 of 50 cases (38%), whereas determination of the monosomy 3 status by FISH on isolated nuclei with a threshold of 5% assigned 31 of 50 cases (62%) to the monosomy-3 category. When monosomy 3 on isolated nuclei with a cutoff value of 5% was used, a significant difference in 5-year survival was present (hazard ratio, 15.5; P = .007), indicating that monosomy 3 in greater than 5% of tumor cells is related to death due to metastases. Conclusion.—In uveal melanoma, the presence of greater than 5% of cells with monosomy 3, as determined by FISH on isolated nuclei, is associated with the development of metastases within 5 years after enucleation.

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