Genotypic Profiling of 452 Choroidal Melanomas with Multiplex Ligation-Dependent Probe Amplification

Abstract

Purpose: Metastasis from uveal melanoma occurs almost exclusively with tumors showing chromosome 3 loss. We used multiplex ligation-dependent probe amplification (MLPA) to detect chromosome 1p, 3, 6p, 6q, 8p, and 8q abnormalities in uveal melanomas. The purpose of this study was to correlate our MLPA results with other risk factors and metastatic death.Experimental Design: Patients were included if they had a uveal melanoma involving choroid. Correlations between baseline risk factors were analyzed using the chi-square test (without Yates's adjustment) and the Mann-Whitney test, with log-rank analysis for associations with metastatic death.Results: The patients (194 female; 258 male) had a median age of 59.4 years and a median follow-up of 1.89 years. MLPA abnormalities occurred in a wide variety of combinations. Ten-year disease-specific mortality was 0% in 133 tumors with no chromosome 3 loss, 55% in tumors with chromosome 3 loss but no chromosome 8q gain, and 71% in 168 tumors showing combined chromosome 3 loss and 8q gain. In tumors with both these abnormalities, epithelioid melanoma cytomorphology, closed loops, and high mitotic rate correlated with poor survival as did lack of chromosome 6p gain.Conclusions: These results support the use of MLPA for routine clinical prognostication, especially if the genetic data are considered together with clinical and histologic risk factors. We showed a wide variety of MLPA results, which suggests that chromosomal abnormalities in uveal melanoma accumulate in a variable sequence. Clin Cancer Res; 16(24); 6083-92. Ó2010 AACR.

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

“…29,30 Simple determination of monosomy 3 is inaccurate, however, because the chromosomal defect can be masked by: (1) duplication of the remaining copy to produce isodisomy (both chromosomes then derive from the same parent); (2) partial chromosomal deletion, which can be missed by some methods; and (3) modulation of the risk of metastasis by other choromsomal errors, such as 6p gain and 8q gain. [31][32][33] At present, the method of choice for initial chromosomal analysis is multiple ligation probe amplification (MLPA), which probes multiple loci across several chromosomes. [31][32][33][34] If the result contradicts the histopathological grade, reanalysis with methods such as complete genomic hybridization is advisable.…”

“…[31][32][33] At present, the method of choice for initial chromosomal analysis is multiple ligation probe amplification (MLPA), which probes multiple loci across several chromosomes. [31][32][33][34] If the result contradicts the histopathological grade, reanalysis with methods such as complete genomic hybridization is advisable. 31,33 Advantages of MLPA include low cost and data obtained simultaneously from several chromosomes other than chromosome 3.…”

“…[31][32][33][34] If the result contradicts the histopathological grade, reanalysis with methods such as complete genomic hybridization is advisable. 31,33 Advantages of MLPA include low cost and data obtained simultaneously from several chromosomes other than chromosome 3. A disadvantage is that the technique needs to be validated individually for each laboratory.…”

The pathology of ocular cancer

“…15 In addition, class 2 tumors typically have major chromosomal abnormalities such as loss of chromosome 3 (monosomy 3) and/or amplification of the long arm of chromosome 8 (8Q), which are important prognostic indicators. [16][17][18][19][20] They also manifest histopathological markers of malignant behavior such as epithelioid cell morphology and vascular mimicry patterns. Eighty-four percent of class II melanomas harbor inactivating mutations in the BAP1 (breast cancer 1, early onset (BRCA1)-associated protein-1 gene).…”

Personalized treatment of uveal melanoma

“…Metastatic disease occurs almost exclusively in patients whose tumour shows chromosome 3 loss and/or a class 2 gene expression profile. 26,27 With such tumours, clinical tumour stage indicates how long the tumour and any metastases have been growing whereas histological grade of malignancy correlates with rate of tumour growth. Such personalized prognostication has profoundly influenced patient care, at least at our centre.…”