Prognostic Testing in Uveal Melanoma by Transcriptomic Profiling of Fine Needle Biopsy Specimens

Onken, Michael D.; Worley, Lori A.; Dávila, Rosa M.; Char, Devron H.; Harbour, J. William

doi:10.2353/jmoldx.2006.060077

Cited by 78 publications

(64 citation statements)

References 8 publications

(13 reference statements)

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“…We have shown previously that our RNA-based classifier is a more accurate prognostic indicator than monosomy 3 or clinicopathologic factors in uveal melanoma (13,18). Nevertheless, we recognized the need to develop a DNA-based assay both as a supplement to the RNA-based classifier and as an alternative when RNA of sufficient quality for expression profiling is not available.…”

Section: Discussionmentioning

confidence: 99%

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Loss of Heterozygosity of Chromosome 3 Detected with Single Nucleotide Polymorphisms Is Superior to Monosomy 3 for Predicting Metastasis in Uveal Melanoma

Onken

Worley

Person

et al. 2007

Clinical Cancer Research

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114

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Purpose: Loss of chromosome 3 is strongly associated with metastasis in uveal melanoma and has been proposed as the basis for clinical prognostic testing. It is not known whether techniques that identify loss of heterozygosity for chromosome 3 predict metastasis more accurately than those that detect only numerical loss of chromosome 3 (monosomy 3). Experimental Design: Fifty-three uveal melanomas were analyzed by 28 single nucleotide polymorphisms (SNP) across chromosome 3. SNP was compared with fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH) for metastasis prediction by sensitivity, specificity, and Kaplan-Meier survival analysis, using our validated gene expression-based classifier as a reference standard. Results: By Kaplan-Meier analysis, only the gene expression-based classifier (P = 0.001) and SNP-based detection of loss of heterozygosity for chromosome 3 (P = 0.04) were significantly associated with metastasis. Sensitivity and specificity were 95.2% and 80.8%, respectively, for SNP, 77.8% and 64.7%, respectively, for FISH, and 85.0% and 72.0%, respectively, for aCGH. Isodisomy 3 was identified by SNP but undetected by aCGH and FISH in three tumors. Conclusions: Prognostic tests based on SNP platforms, which detect both chromosomal homologues and their subregions, may be superior to techniques that only detect changes in chromosome number. These observations could have important implications for efforts to detect genetic alterations in cancer genomes with CGH-based approaches.Uveal melanoma is the most common primary cancer of the eye and has a strong predilection for hematogenous metastasis, particularly to the liver (1). Up to half of uveal melanoma patients develop metastasis with a median time of 2.4 years from ocular diagnosis, usually leading to death within a few months (2). This has lead some investigators to propose that high-risk patients should be treated with prophylactic systemic therapy (3). However, an accurate prognostic classifier for identifying high-risk patients who may benefit from prophylactic therapy has not been validated.Many clinical and pathologic features have been associated with metastatic disease, but none of these has been shown to have adequate sensitivity and specificity for making personalized clinical decisions. Monosomy 3, detected by cytogenetic analysis, spectral karyotyping, fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), and other techniques, may be more accurate than clinical and pathologic features and has been adopted as a molecular prognostic marker in many centers (4 -12). More recently, two distinct molecular subgroups were identified by gene expression profiling that correlate strongly with metastatic risk (13,14). Tumors with the class 1 expression signature had a low risk, and those with the class 2 signature had a high risk of metastasis. Although there was a strong association between the class 2 signature and monosomy 3, the gene expression-based classifier w...

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Section: Discussionmentioning

confidence: 99%

“…Most of the tumors in this study were analyzed previously by microarray gene expression profiling, dual-color FISH, and/or aCGH (13,17,18). Therefore, we were able to compare the SNP-based LOH assay with these other molecular techniques.…”

Section: Resultsmentioning

confidence: 99%

Loss of Heterozygosity of Chromosome 3 Detected with Single Nucleotide Polymorphisms Is Superior to Monosomy 3 for Predicting Metastasis in Uveal Melanoma

Onken

Worley

Person

et al. 2007

Clinical Cancer Research

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114

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“…Starting a little over a decade ago, investigators around the world began to report that chromosomal and transcriptional features of primary uveal melanoma cells were strongly associated with the pa tient's likelihood of developing subsequent extraophthalmic metastasis and metastatic death (25,(29)(30)(31)(32)(33)(34)(35) Several authors have shown that these chromosomal and transcriptional features can be determined on tumor specimens obtained by FNAB changing the indication for FNAB from purely diagnostic to investigational-prognostic (24,25,(36)(37)(38) . During the past few years, investigators from several of these centers have reported their experience with cytogenetic testing of the obtained FNAB aspirates (25,27,35,37,(39)(40)(41) .…”

Section: Prognostic Implications Of Cytopathologic Classification Of mentioning

confidence: 99%

“…During the past few years, investigators from several of these centers have reported their experience with cytogenetic testing of the obtained FNAB aspirates (25,27,35,37,(39)(40)(41) . In some of these centers, the results of FNAB are already being used clinically to inform patients of their metastatic risk, direct surveillance testing for metastasis, and even identify high risk subgroups for possible future recruitment into clinical trials of adjuvant therapies intended to prevent or delay the onset of metastasis (25,35,40,42) However, in most reported studies of investigational-prognostic testing of uveal melanomas sampled by FNAB, cytopathologic diagnosis of the obtained tumor cells has not been reported.…”

Section: Prognostic Implications Of Cytopathologic Classification Of mentioning

confidence: 99%

Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy

Augsburger¹,

Corrêa²,

Trichopoulos³

2013

Arq. Bras. Oftalmol.

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Purpose: Determine whether cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy (FNAB) is a significant prognostic factor for death from metastasis. Methods: Retrospective analysis of cases of clinically diagnosed uveal melanoma evaluated by fine-needle aspiration biopsy from 1980 to 2006. Main outcome evaluated was death from metastasis. Associations between baseline clinical variables and cytopathologic classification were evaluated using cross-tabulation. Prognostic significance of cytopathologic classification was evaluated by Ka planMeier and Cox proportional hazards analysis. Results: Of 302 studied biopsies, 260 (86.1%) yielded sufficient cells for cytopathologic classification. Eighty of the 260 patients who had a sufficient specimen have already died (P=0.021), 69 from metastatic uveal melanoma. Cell type assigned by cytopathology was strongly associated with metastasis/metastatic death in this series (P=0.0048). Multivariate analysis showed cytopathologic classification to be an independently significant prognostic factor for metastatic death (P=0.0006). None of the 42 patients whose tumor yielded insufficient aspirates (sampled in at least two sites) have developed metastasis or died of metastasis thus far. Conclusion: In this series, cytopathology of fine-needle aspiration biopsy samples obtained from uveal melanomas was strongly prognostic of death from metastasis. Insufficiently aspirates (2 or more sites sampled) proved to be prognostic of a favorable outcome (i.e., not developing metastasis). Keywords

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“…Both monosomy 3 analysis using the microsatellite DNA assay and transcriptome profiling have been successfully performed in fine-needle biopsy uveal melanoma specimens taken prior to radiotherapy, and CISH has been shown to work successfully on fine-needle biopsies from breast and lung cancer patients. [28][29][30][31] Previous studies 16,17,23 have shown epithelioid cells to correlate with loss of 1 copy of chromosome 3. In our study, monosomy 3 was detected in 38% of the epithelioid/mixed cell types (Table 5).…”

Section: Commentmentioning

confidence: 99%

Evaluation of Chromogenic In Situ Hybridization for the Determination of Monosomy 3 in Uveal Melanoma

Gleeson

Larkin

Horgan

et al. 2014

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Loss of 1 copy of chromosome 3 is considered a significant indicator of metastatic dissemination in uveal melanoma. Fresh or paraffin-embedded tumor tissue is most commonly used for current cytogenetic techniques for determining chromosome 3 status in uveal melanoma and often requires referral to an external specialist laboratory for analysis.Objectives.-To assess the chromogenic in situ hybridization assay for detecting chromosome 3 alterations using frozen tumor imprints and to compare the results obtained with those obtained by standard fluorescence in situ hybridization or single-nucleotide polymorphism array techniques.Design.-Chromogenic in situ hybridization was performed on 52 frozen uveal melanoma tumor imprints. The genetic status of 26 of the 52 cases had been determined previously by fluorescence in situ hybridization (group 1); the status of 26 cases had been determined using singlenucleotide polymorphism array (group 2).Results.-Chromogenic in situ hybridization was successfully performed on 48 of 52 tumor imprints. Chromogenic in situ hybridization showed excellent agreement in all 24 cases determined by fluorescence in situ hybridization (100% concordance; j ¼ 1; P , .001; 95% confidence interval, 100%-100%), and disagreed in 4 of the 24 cases previously studied by single-nucleotide polymorphism array (83% concordance; j ¼ 0.67; P , .001; 95% confidence interval, 95%-39%). All 4 discordant cases were classified as disomic for chromosome 3 by chromogenic in situ hybridization and monosomic by SNP array. On histologic examination, the 4 discordant cases corresponded to 2 mixed cell tumors and 2 spindle cell tumors.Conclusions.-Chromogenic in situ hybridization using tumor imprints is a reliable technique for determining chromosome 3 status in uveal melanoma. Furthermore, it can also be easily integrated into a routine histopathology laboratory.

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Prognostic Testing in Uveal Melanoma by Transcriptomic Profiling of Fine Needle Biopsy Specimens

Cited by 78 publications

References 8 publications

Loss of Heterozygosity of Chromosome 3 Detected with Single Nucleotide Polymorphisms Is Superior to Monosomy 3 for Predicting Metastasis in Uveal Melanoma

Loss of Heterozygosity of Chromosome 3 Detected with Single Nucleotide Polymorphisms Is Superior to Monosomy 3 for Predicting Metastasis in Uveal Melanoma

Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy

Evaluation of Chromogenic In Situ Hybridization for the Determination of Monosomy 3 in Uveal Melanoma

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