TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR.

Kun Wang,Tiantian Liu,Li Liu,Sanyuan Hu,Nan Ge,Magnus Björkholm,Chang Wang,Feng Kong,Keqiang Yan,Zhonghua Xu,Jikai Liu,Xiaotian Yuan,Shengtian Zhao,Cheng Liu,Hongbo Ren,Yidong Fan,Dawei Xu

doi:10.18632/oncotarget.2660

Abstract

TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies.

Highlights

The cancer-specific expression of telomerase reverse transcriptase (TERT) and telomerase activation play a pivotal role in malignant transformation and progression, and the underlying mechanism has been extensively investigated [1,2,3]
The identification of recurrent TERT promoter mutations in human malignancies has significantly contributed to the understanding of the cancer-specific www.impactjournals.com/oncotarget
The present study shows a high rate of TERT promoter mutations in upper tract urothelial carcinomas (UTUCs) tumors, in renal pelvic carcinoma (RPC) where the mutation frequency reached 43%

Summary

Introduction

The cancer-specific expression of telomerase reverse transcriptase (TERT) and telomerase activation play a pivotal role in malignant transformation and progression, and the underlying mechanism has been extensively investigated [1,2,3]. Hotspot mutations in the TERT promoter namely C228T and C250T were identified in various human malignancies including urological tumors and the mutations create de novo ETS1 binding motifs, thereby facilitating TERT transcription and telomerase activation in cancer cells [4,5,6,7,8,9,10,11,12,13,14,15,16]. Up to 84% of bladder cancer (BC) carry TERT promoter mutations and the mutant sequence is detectable in voided urine from mutation-positive BC patients [7, 8, 11]. The presence of TERT promoter mutations has been demonstrated to be associated with poor patient outcome in several types of cancer including BC [12, 13, 17, 18]. The accumulated data have collectively suggested that the detection of TERT promoter mutations has important clinical implications

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Conclusion