Telomerase reverse transcriptase promoter alterations across cancer types as detected by next‐generation sequencing: A clinical and molecular analysis of 423 patients. Issue 6 (6th December 2017)

• Record Type: Journal Article
• Authors: Schwaederle, Maria; Krishnamurthy, Nithya; Daniels, Gregory A.; Piccioni, David E.; Kesari, Santosh; Fanta, Paul T.; Schwab, Richard B.; Patel, Sandip P.; Parker, Barbara A.; Kurzrock, Razelle
• Is Part Of: Cancer. Volume 124:Issue 6(2018)
• Page Start: 1288
• Page End: 1296
• Publication Date: 2017-12-06
• Subjects: BRAF -- glioblastoma -- melanomas -- next‐generation sequencing -- survival -- telomerase reverse transcriptase (TERT) promoter mutations; Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.31175
• Languages: English
• ISSNs: 0008-543X

Abstract

Abstract : BACKGROUND: Telomerase reverse transcriptase ( TERT ) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. METHODS: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next‐generation sequencing was performed between August 2014 and July 2015. RESULTS: Of the 423 patients, 61 (14.4%) had TERT promoter mutations, and this placed TERT promoter alterations among the most prevalent aberrations after tumor protein 53 ( TP53 ; 39%) and KRAS and cyclin‐dependent kinase inhibitor 2A/B ( CDKN2A/B ) alterations (15% each) in this population. TERT promoter alterations were more frequent in men ( P = .031) and were associated with brain cancers ( P = .001), skin cancers/melanoma ( P = .001), and a higher number of aberrations ( P = .0001). A co‐alteration analysis found that TERT promoter alterations were significantly correlated with CDKN2A/B ( P = .001) and BRAF abnormalities ( P = .0003). Patients harboring TERT promoter alterations or TP53 or CDKN2A/B alterations and those with 4 or more alterations demonstrated shorter survival (hazard ratio for normal TERT promoters vs aberrant ones, 0.44; P = .017). However, only a higher number of alterations remained significant in the multivariate analysis. CONCLUSIONS: Overall, TERT promoter alterations were among the most prevalent aberrations in this population, with very high rates in brain cancers (48% of patients) and melanomas (56% of patients). These aberrations frequently coexist with a high number of other aberrations, with the latter feature also significantly associated with poorer overall survival. Therapeutic options for targeting tumors with TERT promoter mutations are currently limited, although a variety of novel approaches are under development. Cancer 2018;124:1288‐96. © 2017 American Cancer Society . Abstract : A high frequency of telomerase reverse transcriptase promoter alterations has been identified in this study's population. These aberrations frequently coexist with a high number of other aberrations, and this highlights the need to develop novel approaches for targeting telomerase reverse transcriptase, preferably with combinations.