Targeted sequencing of Plasmacytoid urothelial carcinoma reveals frequent TERT promoter mutations

Activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract. While the cadherin 1 (CDH1) gene is commonly mutated in the clinically aggressive plasmacytoid variant of urothelial carcinoma (PUC), little is known about their TERT promoter mutation status. A retrospective search of our archives for PUC and UC with plasmacytoid and/or signet ring cell features (2007-2014) was performed. Ten specimens from 10 patients had archived material available for DNA analysis and were included in the study. Intratumoral areas of non-plasmacytoid histology were also evaluated when present. Samples were analyzed for TERT promoter mutations with Safe-SeqS, a sequencing error-reduction technology, and sequenced using a targeted panel of the 10 most commonly mutated genes in bladder cancer on the Illumina MiSeq platform. TERT promoter mutations were detected in specimens with pure and focal plasmacytoid features (6 of 10). Similar to conventional UC, the predominant mutation identified was g.1295228C>T. In heterogeneous tumors with focal variant histology, concordant mutations were found in plasmacytoid and corresponding conventional, glandular, or sarcomatoid areas. Co-occurring mutations in tumor protein p53 (TP53, 2 cases) and kirsten rat sarcoma (KRAS) viral proto-oncogene (1 case) were also detected. TERT promoter mutations are frequently present in PUC, which provides further evidence that TERT promoter mutations are common events in bladder cancer, regardless of histologic subtype, and supports their inclusion in any liquid biopsy assay for bladder cancer.

Human pathology. 2018 Nov 14 [Epub ahead of print]

Doreen N Palsgrove, Diana Taheri, Simeon U Springer, Morgan Cowan, Gunes Guner, Maria A Mendoza Rodriguez, Maria Del Carmen Rodriguez Pena, Yuxuan Wang, Isaac Kinde, Bernardo F P Ricardo, Isabela Cunha, Kazutoshi Fujita, Dilek Ertoy, Kenneth W Kinzler, Trinity J Bivalacqua, Nickolas Papadopoulos, Bert Vogelstein, George J Netto

Department of Pathology, Johns Hopkins University, Baltimore, MD, United States 21287., Department of Pathology, Johns Hopkins University, Baltimore, MD, United States 21287; Department of Pathology, Isfahan University of Medical Sciences, Isfahan, Kidney Diseases Research Center, Isfahan, Iran 81746 73461., Department of Oncology, Johns Hopkins University, Baltimore, MD, United States 21287; The Ludwig Center for Cancer Genetics and Therapeutics and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States 21287., Department of Pathology, Johns Hopkins University, Baltimore, MD, United States 21287; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States 35249., The Ludwig Center for Cancer Genetics and Therapeutics and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States 21287., Department of Pathology, Rede D'OR São Luiz, São Paulo, Brazil 03313-000., Department of Urology, Osaka University, Osaka, Japan 565-0871., Department of Pathology, Koç University, İstanbul, Turkey 34450., Department of Urology, Johns Hopkins University, Baltimore, MD, United States 21287., Department of Pathology, Johns Hopkins University, Baltimore, MD, United States 21287; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States 35249. Electronic address: .