TERT promoter mutations in clear cell renal cell carcinoma

We screened promoter region of the telomerase reverse transcriptase (TERT) for activating somatic mutations in 188 tumors from patients with clear cell renal cell carcinoma (ccRCC). Twelve tumors (6.4%) carried a mutation within the core promoter region of the gene. The mutations were less frequent in high grade tumors compared to low grade tumors [odds ratio (OR)=0.15, 95% confidence interval (CI)=0.03-0.72, p=0.02]. Multivariate analysis for cause specific survival showed statistically significant poor outcome in patients with TERT promoter mutations [hazard ratio (HR)=2.90, 95% CI=1.13-7.39, p=0.03]. A common polymorphism (rs2853669) within the locus seemed to act as a modifier of the effect of the mutations on patient survival as the noncarriers of the variant allele with the TERT promoter mutations showed worst survival (HR=3.34, 95% CI=1.24-8.98, p=0.02). We also measured relative telomere length (RTL) in tumors and difference between tumors with and without the TERT promoter mutations was not statistically significant. Similarly, no difference in patient survival based on RTL in tumors was observed. Our study showed a relatively low frequency of TERT promoter mutations in ccRCC. Nevertheless, patients with the mutations, particularly in the absence of the rs2853669 variant showed the worst disease-specific survival. Thus, it is possible that the TERT promoter mutations define a small subset of tumors with an aggressive behavior. What's new? The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, a ribonucleoprotein complex that maintains genomic integrity. Activating somatic mutations in the promoter region of the TERT gene have been reported in many cancers. Here, the authors describe new TERT promoter mutations in clear cell renal cell carcinoma. Although present only in a proportion of the tumors, the TERT promoter mutations were independently associated with poor patient survival. The effect was enhanced by a common polymorphism within the core TERT promoter. The TERT promoter mutations may thus define a small subset of tumors with an aggressive behavior.