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

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.

The association between the TERT rs2736100 AC genotype and reduced risk of upper tract urothelial carcinomas in a Han Chinese population

“…Because a higher frequency of the TERT promoter mutation was previously observed in UTUCs and this genetic event plays a key part in activating telomerase [2, 3, 39], we further sought to determine whether there is a link between this mutation and rs2736100 variants. The TERT promoter was sequenced in UTUC tumors and 56 of 189 evaluable patients (30%) carried a C228T or C250T mutation.…”

“…The hotspot TERT promoter mutations named C228T and C250T were recently identified as a key genetic event to activate telomerase in different types of cancer including urothelial cell carcinomas [2, 3, 38, 39]]. The mutations create extra ETS binding motifs in the proximal TERT promoter and thereby activate the TERT gene transcription.…”

“…Upper tract urothelial carcinomas (UTUCs) are originated from urothelium, and consist predominantly of renal pelvic carcinomas (RPCs) and ureter carcinomas (UTs) [1, 2]. Although not common, UTUC incidence has increased over the past two decades, and importantly, most of them have become invasive when diagnosed, mainly due to lack of early clinical symptoms and of useful screening and diagnostic tools [1–3].…”

“…We found that approximately 50% of RPCs and 20% of UCs carried TERT promoter mutations [2, 3, 39]. Because the cancer-risk alleles of the TERT SNPs may contribute to cancer susceptibility by their regulatory effect on TERT expression and telomerase activity [26, 40], it is worth assessing a relationship between TERT risk-alleles and TERT promoter mutations, which likely provides insights into cooperative roles of germline variants and somatic mutations of the TERT gene in oncogenesis.…”

Detection of EGFR and BRAF mutations by competitive allele-specific TaqMan polymerase chain reaction in lung adenocarcinoma

“…Compared with ARMS, the most commonly used method in clinical practice in China, CastPCR has improved sensitivity and specificity owing to its oligonucleotide blocker that suppresses the wild-type allele, which does not exist in ARMS (28). Previous studies have demonstrated this in multiple types of malignant tumor (22,38,39). Two previous studies used CastPCR technology to validate detected mutation results obtained by NGS (31,40).…”