TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers

Abstract

Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions (−57, −124 or −146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.

Prognostic impact of molecular muscle-invasive bladder cancer subtyping approaches and correlations with variant histology in a population-based mono-institutional cystectomy cohort

“…The prevalence of variant histology in our cohort is higher than in previously reported cohorts. This might be caused by a lack of neoadjuvant treatment (NAC) with well-preserved residual tumors after TURB, by full embedding of the complete tumor mass according to standardized mapping methodologies applied in our institution [ 18 , 19 ], and potentially due to a higher awareness of variant histology based on our primary research interest in bladder pathology.…”

“…No patient was treated with neoadjuvant chemotherapy. All cases were routinely mapped for approximately 23 standardized positions as described previously [ 18 , 19 ]. All cases were systematically reviewed by two experienced uropathologists (A.H., M.E.)…”

YY1 Promotes Telomerase Activity and Laryngeal Squamous Cell Carcinoma Progression Through Impairment of GAS5-Mediated p53 Stability

“…In addition, Weyerer et al. confirmed that TERT promoter mutation may have a significant correlation in the early occurrence of bladder cancer ( 20 ). Therefore, it is of great importance to explore whether telomerase is abnormally activated in LSCC.…”

“…Published documents have confirmed that the promoter mutation upstream of TERT may promote the abnormal activation of telomerase in tumor cells; Cheng et al found the presence of promoter mutation upstream of TERT in 60-80% of conventional urothelial carcinomas and variant urothelial carcinomas (19). In addition, Weyerer et al confirmed that TERT promoter mutation may have a significant correlation in the early occurrence of bladder cancer (20). Therefore, it is of great importance to explore whether telomerase is abnormally activated in LSCC.…”

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

“…detectable telomerase activity are present in premalignant lesions or even benign tumors (41,(65)(66)(67). Weyerer et al performed TERT promoter mutation analyses on different sites in bladder organs from UCB patients, and they identified the mutation in not only tumor tissues, but also non-invasive urothelial lesion as well as adjacent nontumor (normal) tissues (68). A recent analysis of UCB patients showed that the mutated TERT promoter could be detected in urine even 10 years prior to clinical diagnosis of the disease (39).…”