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Highly recurrent TERT promoter mutations in human melanoma.

Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA.

Science. 2013 Feb 22;339(6122):957-9.

Editor's comments:
The groups of the German Cancer Center in Heidelberg Germany and of the Dana Faber Cancer Center Boston, USA have described mutations in the promoter region of the temolerase reverse transcriptase (TERT gene). These mutations are functional, because they cause an up regulation of the TERT and nicely illustrate the relevance of mutations outside of the coding regions of the genome.

Abstract

Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.