The High Frequency of cMET Over-Expression in Uveal Melanoma Is Likely Through Altered Gene Regulation Rather Than Mutation and Amplification of the cMET Gene

Abstract

Purpose:: It has been suggested that cMET oncogene (Hepatocyte Growth Factor Receptor) may play an important role in the aggressiveness of uveal melanomas and their high affinity to metastatic spread to the liver. However, the mechanism of activation of cMET in uveal melanomas is largely unknown. In the following study we investigated the frequency of cMET over-expression (activation) in primary uveal melanoma as well as potential molecular mechanisms for such activation.

Methods:: cMET expression in primary uveal melanomas was studied using immunohistochemistry in 70 primary uveal melanomas. The frequency of gains/amplification in chromosomal bands 7q31 (chromosomal location of cMET) and loss of chromosomal band 3p25 (chromosomal location of VHL) was studied by either conventional and/or molecular cytogenetics in a subset of tumors. In addition, the frequency of activating mutations in cMET gene was investigated by DNA sequencing in a subset of tumors.

Results:: Strong over-expression of cMET protein was detected in 27/70 (38.6%) tumors, moderate expression in 33/70 (47.1%) tumors, while absent or weak expression in 10/70 (14.3%) tumors. Gains in the 7q31 region (the chromosomal location of cMET) was detected in 4/16 (25%) of tumors while loss of 3p25 (the chromosomal location of VHL) was detected in 10/16 (62.5%) of the tumors studied by either conventional or molecular cytogenetics. This is interesting giving the fact that VHL is an important negative regulator for cMET. Of note, in the majority of tumors (13/16, 81%) alterations in 7q31 and 3p25, were mutually exclusive. Sequence analysis identified activating mutations in cMET in 0/15 of the tumors tested.

Conclusions:: Our study suggests that in the majority of uveal melanomas cMET activation is likely through indirect gene regulation (such as loss of negative regulators as VHL) rather than through activating mutation or gene amplification. Our results also indicate that cMET is activated in a large number of uveal melanomas, which suggest that cMET could be utilized as a potential target for developing novel therapies for uveal melanomas. In light of the existence of therapeutics that target HGF/SF-Met signaling, our results should be very promising for future management of uveal melanomas.

Keywords: tumors • genetics • melanoma