Transcriptomic versus Chromosomal Prognostic Markers and Clinical Outcome in Uveal Melanoma

Abstract

Purpose:To compare a gene expression^based classifier versus the standard genetic prognostic marker, monosomy 3, for predicting metastasis in uveal melanoma. Experimental Design: Gene expression profiling, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) were done on 67 primary uveal melanomas. Clinical and pathologic prognostic factors were also assessed. Variables were analyzed by Cox proportional hazards, Kaplan-Meier analysis, sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios. Results: The gene expression^based molecular classifier assigned 27 tumors to class 1 (low risk) and 25 tumors to class 2 (high risk). By Cox univariate proportional hazards, class 2 signature (P = 0.0001), advanced patient age (P = 0.01), and scleral invasion (P = 0.007) were the only variables significantly associated with metastasis. Only the class 2 signature was needed to optimize predictive accuracy in a Cox multivariate model. A less significant association with metastasis was observed for monosomy 3 detected by aCGH (P = 0.076) and FISH (P = 0.127). The sensitivity and specificity for the molecular classifier (84.6% and 92.9%, respectively) were superior to monosomy 3 detected by aCGH (58.3% and 85.7%, respectively) and FISH (50.0% and 72.7%, respectively). Positive and negative predictive values (91.7% and 86.7%, respectively) and positive and negative likelihood ratios (11.9 and 0.2, respectively) for the molecular classifier were also superior to those for monosomy 3. Conclusions: Molecular classification based on gene expression profiling of the primary tumor was superior to monosomy 3 and clinicopathologic prognostic factors for predicting metastasis in uveal melanoma.In recent years, there has been increasing interest in individualized management of cancer patients based on predictive molecular testing (1, 2). Uveal (ocular) melanoma represents an ideal cancer for applying this strategy. Uveal melanoma is the most common primary cancer of the eye and has a strong predilection for hematogenous metastasis, particularly to the liver (3). Investigators have searched for clinical and pathologic prognostic factors for over a century and have identified several that are statistically associated with metastasis, including advanced patient age, anterior tumor location, increased tumor size, epithelioid cell type, and local tumor invasion through the sclera. However, predictive accuracy of these factors has not been adequate for making individualized clinical decisions, such as whether a given patient is at sufficiently high risk for metastasis to necessitate more intense and frequent metastatic surveillance or whether prophylactic systemic therapy may be appropriate. More recently, investigators have identified genetic alterations, such as monosomy 3, which are significantly associated with metastasis (4 -6). With the development of more precise techniques for detecting chromosomal alterations, such as spectral karyoty...

Let-7b and microRNA-199a inhibit the proliferation of B16F10 melanoma cells

“…It has been reported that microRNA signatures differentiate melanoma subtypes; seven microRNAs (microRNA-142-3p, microRNA-486, m ic roR NA-214, m ic roR NA-218, m ic roR NA-362, microRNA-650 and microRNA-31) significantly correlated with acral melanoma compared to non-acral melanoma (15). Furthermore, let-7b and microRNA-199a were upregulated in uveal (ocular) melanoma, showing highly significant associations with the high metastatic gene expression signature and loss of chromosome 3, which have been shown to be more accurate predictors of metastasis than any clinical or pathological factors, and have served as surrogate endpoints for the identification of biomarkers in uveal melanoma (16)(17)(18). Similar findings have been found in both skin melanoma and uveal (ocular) melanoma, but it is unclear as to whether this finding is coincidental or whether it is an important indicator of metastasis.…”

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

“…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) .…”

Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond

“…12,24,25 Such an analysis can be performed by charting chromosomal alternations 26,27 or by gene expression profiling. 24,25,28 The latest TNM edition encourages recording of genetic features. 9 A major breakthrough was the observation that many uveal melanomas lack one copy of chromosome 3, and that these monosomic tumours are usually those that metastatise.…”