TERT promoter mutations are frequent in melanoma and create ETS/TCF binding motifs.

  • Major finding:TERT promoter mutations are frequent in melanoma and create ETS/TCF binding motifs.

  • Concept: Promoter variants increase transcriptional activity of the TERT promoter in reporter assays.

  • Impact: Mutations in regulatory regions may be driver events in melanoma as well as in other cancers.

Sequencing studies have largely focused on the identification of tumor-associated mutations in protein coding regions, including BRAF and NRAS mutations in melanoma. However, mutations in noncoding regions of the genome may also contribute to tumorigenesis. To investigate this possibility, Huang and colleagues used a whole-genome sequencing approach and identified 2 somatic, UV-signature mutations in the promoter of telomerase reverse transcriptase (TERT), which is necessary to maintain telomere length and is frequently activated in cancer, in 71% of melanomas tested. In a complementary study, Horn and colleagues performed linkage analysis followed by high-throughput sequencing of the linked region and found a germline TERT promoter variant in affected individuals from a melanoma-prone family. Horn and colleagues also detected recurrent somatic, UV-signature TERT promoter mutations in sporadic melanoma, including 74% of cell lines, 33% of primary tumors, and 85% of metastatic tumors. Somatic TERT mutations were mutually exclusive and occurred at a higher frequency than those of BRAF or NRAS mutations, supporting the notion that these may be driver events in melanomagenesis. Furthermore, Huang and colleagues found evidence of TERT promoter mutations in bladder and hepatocellular cancer cell lines, suggesting that somatic TERT mutations may be a common tumor-promoting mechanism. Intriguingly, both groups showed that each of these nucleotide substitutions generated a consensus binding motif for ETS transcription factors including members of the ternary complex factor (TCF) subgroup, which are activated by MAPK and BRAF signaling. These mutations increased TERT promoter activity in in vitro reporter assays, suggesting that promoter mutations may enhance TERT transcription and lead to telomerase reactivation in tumors. Moreover, these findings show that somatic mutations in regulatory regions of the genome may play a critical role in promoting tumor growth and progression.

Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science 2013 Jan 24 [Epub ahead of print].

Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science 2013 Jan 24 [Epub ahead of print].

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