Diagnostic potential of TERT promoter and FGFR3 mutations in urinary cell‐free DNA in upper tract urothelial carcinoma

Abstract

Most upper tract urothelial carcinomas ( UTUC ) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non‐invasive test for detecting UTUC , but its sensitivity is low. A novel non‐invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell‐free DNA (cf DNA ) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cf DNA from 153 individuals, including 56 patients with localized UTUC , and carried out droplet digital PCR assay for TERT promoter and FGFR 3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR 3 S249C in 9/56 (16.1%) patients. FGFR 3 mutation was detected only in ≤ pT 1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger‐scale cohort, mutation analysis of TERT promoter and FGFR 3 in urinary cf DNA has the potential to be a non‐invasive diagnostic marker and reliable factor for tumor staging.

TERT Promoter Mutation C228T Increases Risk for Tumor Recurrence and Death in Head and Neck Cancer Patients

“…Studies validating these results should be performed in order to confirm the predictive value of this marker for prognosis. In addition, minimally invasive approaches to detect TERT promoter mutations could be performed in head and neck samples in order to evaluate the feasibility of this marker, and since oral cavity is the most affected site, saliva could possibly be a good source, taking into consideration previous data in other tumors: FNA (Fine-Needle Aspiration) in thyroid tumors (51)(52)(53) and cell-free DNA (cfDNA) from urine in urothelial tumors (54)(55)(56), which were able to detect the mutation in fluids.…”

Mutational Landscape and Environmental Effects in Bladder Cancer

“…These mutations are identified in both the normal tissues, which may be precancerous lesion, and the tumor samples of bladder cancer including various rare histological variants (micropapillary, plasmacytoid, adenocarcinoma, squamous cell carcinoma) [ 21 , 22 , 23 , 24 , 25 , 26 ]. These mutations can also be detected with ease in both the pellet and cell-free DNA from patient urine samples, promising application in urine-based disease detection and prediction of progression [ 27 , 28 , 29 , 30 ].…”

Activating Telomerase TERT Promoter Mutations and Their Application for the Detection of Bladder Cancer

“…Two hotspot mutations of the TERT promoter have been detected with high frequency in bladder cancer but not in neighboring normal tissues [ 43 , 46 , 47 ]. These mutations occur at two positions upstream of the transcription starting site, at −124 bp (nucleotide polymorphism G > A, g.1295228 (chr5, 1, 295, 228 assembly GRCh37) or g.1295113 (chr5, 1, 295, 113 assembly GRCh38)) and −146 bp (nucleotide polymorphism G > A, g.1295250 (chr5, 1, 295, 250, assembly GRCh37) or g.1295135 (chr5, 1, 295, 135 assembly GRCh38)) in a GC-rich genome region, which specifies its alternative organization ( Figure 1 ).…”