TERT Promoter Mutations Promote Immortalization and Genomic Instability

Mutations in the promoter of TERT, which encodes the reverse transcriptase component of telomerase, occur commonly in cancer, including in the majority of cutaneous melanomas, and are associated with a poor prognosis and shortened telomeres despite enhanced telomerase expression. Conversely, patients with constitutionally shorter telomeres have a reduced risk of cancer. These seemingly contradictory observations illustrate that the role of TERT promoter mutations is incompletely understood. Chiba, Lorbeer, and colleagues investigated the role of acquired TERT promoter mutations in four human melanomas arising from adjacent preneoplastic nevi. The telomeres were shorter in melanomas with TERT promoter mutations compared with the associated nevus, indicating that promoter mutations were not sufficient to promote TERT expression to counteract telomere shortening. However, TERT promoter mutations did promote proliferation of fibroblasts and support cellular immortalization. In wild-type fibroblasts, telomeres shortened progressively, whereas in fibroblasts with TERT promoter mutations, telomeres initially shortened but stabilized after approximately 70 population doublings, resulting in preferential maintenance of short telomeres and indicating that TERT promoter mutations do not protect against telomere shortening. In cells with TERT promoter mutations, when telomeres were critically shortened telomerase expression increased, preventing further telomere shortening and promoting immortalization. Further, telomerase activity became rate-limiting when the number of critically short telomeres increased, resulting in an increase in genomic instability that may promote tumorigenesis in cells with TERT promoter mutations. These findings elucidate mechanisms by which TERT promoter mutations may promote tumorigenesis, suggesting that in early tumorigenesis TERT promoter mutations may prevent critical telomere shortening to delay replicative senescence and promote cancer cell immortalization, and later in tumorigenesis may promote genomic instability.

Chiba K, Lorbeer FK, Shain AH, McSwiggen DT, Schruf E, Oh A, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science 2017 Aug 17 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.