Mutations in the promoter of a gene that encodes a protein involved in maintaining telomere length have been found in human melanoma, according to two recent studies in Science (doi:10.1126/science.1229259 and doi:10.1126/science.1230062).

To identify previously unknown disease-segregating mutations, Susanne Horn and her colleagues studied members of a melanoma-prone family who were not carriers of two common melanoma-associated mutations. In these individuals, they found mutations in the TERT (telomerase reverse transcriptase) promoter that resulted in a new binding motif for Ets/TCF transcription factors, leading to increased TERT transcription. The authors also found somatic ultraviolet (UV)-signature mutations, albeit different ones from those found in familial melanoma, in the TERT promoter in human cell lines derived from sporadic melanoma at a frequency of 85% in metastatic tissues and 33% in primary tumors. These mutations also created new binding motifs.

Using whole-genome sequencing, Franklin Huang and his colleagues identified two independent and exclusive mutations in the TERT promoter linked to UV damage in 71% of malignant melanomas that increased transcriptional activity. These mutations were much less abundant in human cell lines derived from other cancer types.

Although further investigation is warranted, these studies indicate that mutations in regulatory regions can act as cancer drivers and suggest a potential link between telomerase activity and other common activating mutations in melanoma pathogenesis.