Human cancers can be classified into types with high or low TERT promoter mutation frequency.

  • Major finding: Human cancers can be classified into types with high or low TERT promoter mutation frequency.

  • Concept: TERT and ATRX mutations are mutually exclusive and likely to be functionally equivalent.

  • Impact: Telomere-maintaining mutations may not be necessary in tissues in which telomerase is already activated.

Recurrent telomerase reverse transcriptase (TERT) promoter mutations that create de novo transcription factor binding sites and increase TERT expression have recently been identified in over 70% of melanomas, suggesting a selective advantage for mutations that promote telomerase activity in cancer. However, it is unclear if genetic activation of telomerase is a general requirement for tumorigenesis, given that telomerase may not need to be specifically activated in cancers derived from self-renewing progenitor cells in which it is already active. Killela and colleagues hypothesized that TERT mutations would be rare in cancers arising from highly proliferative, self-renewing tissues because telomerase would presumably already be activated but frequent in cancers originating from terminally differentiated cell types that are not constantly self-renewing. After sequencing the TERT promoter in 1,230 tumor samples representing 60 tumor types, the authors found that tumors could be grouped by a low (<15%) or high (>15%) frequency of TERT mutations. Generally, few, if any, TERT mutations were observed in cancers derived from tissues with relatively high cell turnover, such as the bone marrow, colon, breast, and prostate. Tumors with high frequencies of TERT mutations included cancers of the central nervous system, bladder cancers, and hepatocellular carcinomas and tended to originate from tissues with lower rates of self-renewal. Notably, TERT promoter mutations were found in 83% of primary glioblastomas, representing the most common mutation found in this tumor type to date. Furthermore, TERT mutations were mutually exclusive with mutations of ATRX, which induce telomerase-independent telomere lengthening, suggesting that these mutations are functionally equivalent mechanisms to promote telomere maintenance. Together, these findings provide insight into principles underlying the relationship between telomerase activity and tumorigenesis as well as the mechanisms of telomere maintenance in cancer cells.

Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 2013 Mar 25 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013