Genotypic profiling of 452 choroidal melanomas with Multiplex Ligation-Dependent Probe Amplification (MLPA) suggests crescendo malignancy


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Bertil Damato1,Justyna Dopierala1,Sarah Coupland1
1School of Cancer Studies, University of Liverpool, Liverpool, United Kingdom

Background

Almost 50% of patients with intraocular melanoma die of metastasis. Mortality correlates strongly with chromosomal abnormalities. We routinely offer patients genetic tumour typing using Multiplex Ligation-Dependent Probe Amplification (MLPA), which assesses chromosomes 1p, 3, 6p and 8q. Our aims were to determine the prevalence of these abnormalities and to correlate them with clinical and histological survival predictors and with mortality.

Method

452 choroidal melanomas were analysed with MLPA. Survival data were obtained automatically from the NHS Cancer Registry so that outcomes analyses were confined to 367 patients resident in mainland Britain.

Results

MLPA abnormality was absent in 18 cases and found in one chromosome in 112 tumours, two chromosomes in 143, three chromosomes in 137 and four chromosomes in 42 cases. Chromosome 3 loss and 8q gain correlated with all clinical and histological risk factors (Chi square, p<0.001) and with increased mortality (Logrank, p<0.001) whereas unequivocal chromosome 6p gain correlated with improved survival (Logrank, p<0.001). The eight-year disease-specific mortality rates were 0% without chromosome 3 or 8q abnormality, 12% with  abnormality of only one of these chromosomes, 35% with abnormality of both chromosomes with 6p gain, and 71% with abnormality of chromosomes 3 and 8q without 6p gain (Logrank, p<0.001). Only three of 189 patients died of metastatic disease in the absence of combined chromosome 3 loss/ 8q gain.

Conclusion

MLPA analysis of uveal melanoma is highly predictive of survival, with mortality occurring almost exclusively when chromosome 3 loss and chromosome 8q gain coincided. The prevalence rates of the chromosomal abnormalities suggest crescendo malignancy culminating in metastatic capability and contradict the hypothesis that lethal and non-lethal melanoma variants are distinct from their inception. Approximately 50% of tumours lacked the lethal combination of chromosome 3 loss/8q gain suggesting that treatment may have prevented the 'second hit' and hence metastatic spread in some patients.