Correlation of Gene Mutation Status with Copy Number Profile in Uveal Melanoma

Yavuzyigitoglu, Serdar; Drabarek, Wojtek; Smit, Kyra N.; Poppelen, Natasha van; Koopmans, Anna E; Vaarwater, Jolanda; Brands, Tom; Eussen, Bert; Dubbink, Hendrikus J.; Riet, Job van; Werken, Harmen J.G. van de; Beverloo, Berna; Verdijk, Robert M.; Naus, Nicole; Paridaens, Dion; Kılıç, Emine; Klein, Annelies de

doi:10.1016/j.ophtha.2016.10.039

Cited by 27 publications

(50 citation statements)

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“…In our cohort, more than 1 chromosome was affected in 1 tumor. It is noteworthy that the affected chromosomes in this study included chromosomes 3, 6, and 8, since copy number variations in these chromosomes are correlated with mutation status in UM . This is in line with other studies in which chromothripsis occur among known cancer driver genes .…”

Section: Discussionsupporting

confidence: 88%

“…Recurrent chromosomal aberrations have been described in detail in UM, which are strongly correlated to the mutation status . In this paper, another chromosomal aberration, called chromothripsis, is described.…”

Section: Discussionmentioning

confidence: 98%

“…A relation between prognosis and chromothripsis has been reported in several studies on different malignancies. In high risk neuroblastoma, breast cancer and MDS, chromothripsis is correlated with a poor outcome while in metastatic colorectal cancer a better progression free‐survival has been described . Probably metastases with chromothripsis respond better to therapy while the metastatic rate is higher in cancers harboring chromothripsis.…”

Section: Discussionmentioning

confidence: 99%

“…BAP1 ‐mutated UM harbors entire chromosome copy number variations (CNVs) and entire chromosome arm CNV anomalies (isochromosomes). UM with an SF3B1 mutation is characterized by many structural variants, often affecting the terminal ends of chromosomes and thus not entire chromosomes or chromosome arms . Besides these recurrent CNVs, also other cytogenetic patterns are described such as polyploidy of the genome, which occurs in ∼10%‐15% of all UM .…”

Section: Introductionmentioning

confidence: 99%

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Chromosomal rearrangements in uveal melanoma: Chromothripsis

Poppelen

Yavuzyigitoglu

Smit

et al. 2018

Genes Chromosomes & Cancer

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Uveal melanoma (UM) is the most common primary intraocular malignancy in the Western world. Recurrent mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, EIF1AX, and SF3B1 are described as well as non‐random chromosomal aberrations. Chromothripsis is a rare event in which chromosomes are shattered and rearranged and has been reported in a variety of cancers including UM. SNP arrays of 249 UM from patients who underwent enucleation, biopsy or endoresection were reviewed for the presence of chromothripsis. Chromothripsis was defined as ten or more breakpoints per chromosome involved. Genetic analysis of GNAQ, GNA11, BAP1, SF3B1, and EIF1AX was conducted using Sanger and next‐generation sequencing. In addition, immunohistochemistry for BAP1 was performed. Chromothripsis was detected in 7 out of 249 tumors and the affected chromosomes were chromosomes 3, 5, 6, 8, 12, and 13. The mean total of fragments per chromosome was 39.8 (range 12‐116). In 1 UM, chromothripsis was present in 2 different chromosomes. GNAQ, GNA11 or CYSLTR2 mutations were present in 6 of these tumors and 5 tumors harbored a BAP1 mutation and/or lacked BAP1 protein expression by immunohistochemistry. Four of these tumors metastasized and for the fifth only short follow‐up data are available. One of these metastatic tumors harbored an SF3B1 mutation. No EIF1AX mutations were detected in any of the tumors. To conclude, chromothripsis is a rare event in UM, occurring in 2.8% of samples and without significant association with mutations in any of the common UM driver genes.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chromosomal rearrangements in uveal melanoma: Chromothripsis

Poppelen

Yavuzyigitoglu

Smit

et al. 2018

Genes Chromosomes & Cancer

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“…Genetic prognostication can be performed by the evaluation of loss or gain of chromosomes 1p, 3, 6 and 8 (copy number variations), somatic gene mutations of BAP1 , SF3B1 and EIF1AX or by assessing expression (mRNA) levels of multiple genes (Gill & Char ; Yavuzyigitoglu et al. ). Increasing evidence demonstrates functional associations between the genetic alterations and has allowed for a classification of four distinct molecular subtypes with different risk of metastatic disease (Fig.…”

Section: Introductionmentioning

confidence: 99%

Intraocular biopsy of uveal melanoma Risk assessment and identification of genetic prognostic markers

Bagger

2018

Acta Ophthalmologica

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Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma

Patrone

Maric

Rutigliani

et al. 2018

Genes Chromosomes & Cancer

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Uveal melanoma (UM) exhibits recurring chromosomal abnormalities and gene driver mutations, which are related to tumor evolution/progression. Almost half of the patients with UM develop distant metastases, predominantly to the liver, and so far there are no effective adjuvant therapies. An accurate UM genetic profile could assess the individual patient's metastatic risk, and provide the basis to determine an individualized targeted therapeutic strategy for each UM patient. To investigate the presence of specific chromosomal and gene alterations, BAP1 protein expression, and their relationship with distant progression free survival (DPFS), we analyzed tumor samples from 63 UM patients (40 men and 23 women, with a median age of 64 years), who underwent eye enucleation by a single cancer ophthalmologist from December 2005 to June 2016. UM samples were screened for the presence of losses/gains in chromosomes 1p, 3, 6p, and 8q, and for mutations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. BAP1 protein expression was detected by immunohistochemistry (IHC). Multivariate analysis showed that the presence of monosomy 3, 8q gain, and loss of BAP1 protein were significantly associated to DPFS, while BAP1 gene mutation was not, mainly due to the presence of metastatic UM cases with negative BAP1 IHC and no BAP1 mutation detected by Sanger sequencing. Loss of BAP1 protein expression and monosomy 3 represent the strongest predictors of metastases, and may have important implications for implementation of patient surveillance, properly designed clinical trials enrollment, and adjuvant therapy.

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Correlation of Gene Mutation Status with Copy Number Profile in Uveal Melanoma

Cited by 27 publications

References 5 publications

Chromosomal rearrangements in uveal melanoma: Chromothripsis

Chromosomal rearrangements in uveal melanoma: Chromothripsis

Intraocular biopsy of uveal melanoma Risk assessment and identification of genetic prognostic markers

Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma

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