TERT promoter mutations in clear cell renal cell carcinoma Ismail Hosen 1 , P. Sivaramakrishna Rachakonda 1 , Barbara Heidenreich 1 , Raviprakash T. Sitaram 2 ,B€ orje Ljungberg 2 , G€ oran Roos 3 , Kari Hemminki 1,4 and Rajiv Kumar 1 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany 2 Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea ˚ University, Umea ˚, Sweden 3 Department of Medical Biosciences, Umea ˚ University, Umea ˚, Sweden 4 Center for Primary Health Care Research, Lund University, Malm€ o, Sweden 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) 5 0.15, 95% confidence interval (CI) 5 0.03–0.72, p 5 0.02]. Multivariate analysis for cause specific survival showed stat- istically significant poor outcome in patients with TERT promoter mutations [hazard ratio (HR) 5 2.90, 95% CI 5 1.13–7.39, p 5 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 5 3.34, 95% CI 5 1.24–8.98, p 5 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 sur- vival 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. The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, a ribonucleopro- tein complex that maintains genomic integrity through de novo synthesis of telomere repeat units at chromosomal ends. 1 Activation of telomerase is dependent on a number of factors in which the transcriptional regulation of the TERT gene constitutes a rate limiting step. The TERT promoter harbors binding sites for a number of transcriptional activa- tors and repressors and is considered to be the most impor- tant regulatory element for telomerase expression. 2 Since initial discovery, activating somatic mutations in the pro- moter region in the TERT gene have been reported in many cancers. 3, 4 The promoter mutations result in creation of binding sites for the E-twenty Six (ETS)/ternary complex fac- tors (TCFs) transcription factors located mainly at two resi- dues at 2124C > T (G > A) and 2146C > T (G > A) from the ATG start site in the TERT promoter. The mutations in the TERT promoter result in increased TERT expression and have been shown to be associated with more advanced forms of malignant diseases. In primary cuta- neous melanoma the mutations were associated with increased patient age, increased tumor thickness and tumor ulceration. 5 In bladder cancer and gliomas, the mutations were associated with risk of tumor recurrence and poor survival. 6,7 In thyroid cancer, the TERT promoter mutations were more frequent in advanced tumors. 4 In follicular thyroid cell-derived carcino- mas, the TERT promoter mutations have been shown to be associated with increased age and decreased telomere length. 8 Renal cell carcinoma (RCC) includes different distinct sub-types that differ in genetic aberrations, histology, clinical course and responses to therapy. 9 Clear cell renal carcinoma (ccRCC) is the most frequent renal tumor subtype, compris- ing around 80% of the RCCs. While an earlier study based on a small number of different RCCs found no TERT pro- moter mutations, a subsequent communication reported TERT promoter mutations at a low frequency. 10,11 In order to establish the frequency of TERT promoter mutations, we screened DNA from 188 patients with tumors of different stages and grades, measured relative telomere length (RTL) and analyzed data for the effect of mutations on disease- specific patient survival. Key words: TERT promoter mutations, telomere length, mutations, survival Abbreviations: ccRCC: clear cell renal cell carcinoma; ETS: E-twenty Six; HR: hazard ratio; OR: odds ratio; RTL: relative telomere length; TERT: telomerase reverse transcriptase Additional Supporting Information may be found in the online version of this article. DOI: 10.1002/ijc.29279 History: Received 1 Sep 2014; Accepted 7 Oct 2014; Online 21 Oct 2014 Correspondence to: Rajiv Kumar, Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany, Tel.: 149-62-21-42-18-06, Fax: 149-62-21–42-18-10, E-mail: r.kumar@dkfz.de Short Report Int. J. Cancer: 00, 00–00 (2014) V C 2014 UICC International Journal of Cancer IJC