Telomerase Reverse Transcriptase (TERT) Promoter Mutations in Primary Adenocarcinoma of Bladder and Urothelial Carcinoma with Glandular Differentiation - Expert Commentary

Primary adenocarcinoma of the bladder is a rare tumor. It is common in the sixth and seventh decades of life and usually has aggressive behavior. Advanced presentation with or without lymph node metastases is common at the time of diagnosis. Furthermore, pathological diagnosis can be challenging, especially in small biopsy specimens. The molecular landscape of this disease is not well understood.


Telomerase reverse transcriptase (TERT) promoter mutations play a part in tumorigenesis by promoting replicative immortality and genomic instability. TERT promoter mutations have been identified as a key driver of urothelial carcinogenesis and are present in 60–80% of conventional urothelial carcinoma. However, the role of TERT promoter mutations has not been systemically evaluated in primary adenocarcinoma of the bladder.

Recently, Cheng et al. conducted a PCR-based analysis of the C228T and C250T hotspot mutations of the TERT promoter. The results of this study were published in Modern Pathology. The authors investigated the prevalence of TERT promoter mutations in 46 cases of bladder nonurachal adenocarcinoma, 30 cases of urothelial carcinoma with glandular differentiation, and other benign histologies, including nephrogenic adenoma (n=24), villous adenoma (n=8), florid cystitis glandularis (n=31), and intestinal metaplasia of the bladder (n=20).

Urothelial carcinoma with glandular differentiation patients were more likely to be males (ratio 5.2:1.1, P = 0.00021) and older (73 vs. 64 years; P = 0.0065) compared to patients with primary adenocarcinoma of the bladder. TERT promoter mutations were detected in 33% of adenocarcinomas of the bladder and 67% of urothelial carcinomas with glandular differentiation. This difference was statistically significant (33% vs 67%, P =0.0048).

Similar TERT promoter mutations were found in both the urothelial carcinoma and the glandular differentiation components across all tested samples, indicating a common clonal origin. It noteworthy that TERT promoter mutations were absent in benign histologies.

According to this analysis, TERT promoter mutation testing serves as a promising tool in the differential diagnosis of glandular lesions of the urinary bladder. In addition, it showed high organ specificity differentiating metastatic adenocarcinoma of the bladder from cancers originating from prostate, colorectal, breast, and lung as they rarely harbor TERT promoter mutations.

Previous studies showed a range of different prevalence rates of TERT promoter mutations in the primary adenocarcinoma of the bladder. This could be partly due to differences in patient population, tumor location (urachal vs. nonurachal), sample size, methodology divergence, tumorigenesis, and biology. Further large-scale multi-center studies are needed to dissect the role of TERT promoter mutations in patients with mixed variant urothelial carcinoma or pure histological variants. Recent methods that allow direct sequencing and reconstruction of Telomeres can shed light on the impact of Telomerase promoter mutations on Telemore structure and function in these patients.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Cheng L, Lopez-Beltran A, Wang M, Montironi R, Kaimakliotis HZ, Zhang S. Telomerase reverse transcriptase (TERT) promoter mutations in primary adenocarcinoma of Bladder and urothelial carcinoma with glandular differentiation: pathogenesis and diagnostic implications. Mod Pathol. 2021; doi. 10.1038/s41379-021-00776-z. PMID: 33674765
  2. Vail E, Zheng X, Zhou M, Yang X, Fallon JT, Epstein JI, et al. Telomerase reverse transcriptase promoter mutations in glandular lesions of the urinary bladder. Ann Diagn Pathol. 2015;19:301–5. PMID: 26239299
  3. Cowan ML, Springer S, Nguyen D, Taheri D, Guner G, Mendoza Rodriguez MA, et al. Detection of TERT promoter mutations in primary adenocarcinoma of the urinary bladder. Hum Pathol. 2016;53:8–13. PMID: 26980028 

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