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Last Updated: Feb 19, 2013 - 1:22:36 AM
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Gene mutation immortalizes malignant melanoma

Jan 25, 2013 - 5:00:00 AM
We don't believe that the telomerase gene in melanoma is mutated by pure chance, but that it is a so-called driver mutation that drives carcinogenesis, says Rajiv Kumar. This is also confirmed by the surprising incidence of this alteration: The telomerase gene is the most frequently mutated gene in melanoma. This is something we hadn't expected, because malignant melanoma has been genetically analyzed thoroughly. But this mutation always seems to have been overlooked, says Kumar.

 
[RxPG] About ten percent of all cases of malignant melanoma are familial cases. The genome of affected families tells scientists a lot about how the disease develops. Prof. Dr. Rajiv Kumar of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) together with Prof. Dr. Dirk Schadendorf from Essen University Hospital studied a family where 14 family members were affected by malignant melanoma.

The scientists analyzed the genomes of family members and found an identical mutation in the gene for telomerase, an enzyme often called 'immortality enzyme', in all persons studied. Telomerase protects the ends of chromosomes from being lost in the process of cell division and, thus, prevents that the cell ages and dies. The inherited gene mutation leads to the formation of a binding site for protein factors in the controlling region of the telomerase gene, causing it to become overactive. As a result, mutated cells overproduce telomerase and hence become virtually immortal.

This spectacular finding of the family analysis prompted the scientists to also look for mutated telomerase genes in non-inherited (sporadic) melanoma, which is much more common than the familial variant. In most of the tissue samples of melanomas of all stages they found alterations in the telomerase gene switch, which the researchers clearly identified as typical consequences of sun exposure. Even though these mutations were not identical to those found in the melanoma family, they had the same effect: overactive telomerase.

We don't believe that the telomerase gene in melanoma is mutated by pure chance, but that it is a so-called driver mutation that drives carcinogenesis, says Rajiv Kumar. This is also confirmed by the surprising incidence of this alteration: The telomerase gene is the most frequently mutated gene in melanoma. This is something we hadn't expected, because malignant melanoma has been genetically analyzed thoroughly. But this mutation always seems to have been overlooked, says Kumar.

Rajiv Kumar, Dirk Schadendorf and their teams are hoping that the alterations in the telomerase gene may be a starting point for developing novel treatment methods for malignant melanoma. A very recent development targeting a specific alteration in the B-RAF gene, which characterizes about half of all melanomas, has shown that this is possible. The mutation gave rise to the development of a targeted drug that can arrest cancer growth. Substances inhibiting telomerase have already been developed and some of them have even been tested in phase III clinical trials, said Rajiv Kumar. Inhibition of the immortality enzyme might also be able to arrest growth in melanoma.



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