Somatic 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. Little is known, however, about TERT-mutation status in the relatively uncommon but clinically aggressive micropapillary (MPC) variant. We evaluated the presence of TERT promoter mutations in MPC of the bladder and upper urinary tract. A retrospective search of our archives for MPC and UC with micropapillary features (2005-2014) was performed. All slides were reviewed to confirm the histologic diagnosis. Thirty-three specimens from 31 patients had FFPE blocks available for DNA analysis and were included in the study. Intratumoral areas of non-micropapillary histology were also evaluated when present. Samples were analyzed with Safe-SeqS, a sequencing error reduction technology, and sequenced using the Illumina MiSeq platform. TERT promoter mutations were detected in all specimens with pure MPC (18 of 18) and UC with focal micropapillary features (15 of 15). Similar to conventional UC, the predominant mutations identified occurred at positions -124 (C228T) (85 %) and -146 (C250T) (12 %) bp upstream of the TERT ATG start site. In heterogeneous tumors with focal variant histology, intratumoral concordant mutations were found in variant (MPC and non-MPC) and corresponding conventional UC. We found TERT promoter mutations, commonly found in conventional UC, to be frequently present in MPC. Our finding of concordant intratumoral mutational alterations in cases with focal variant histology lends support to the common oncogenesis origin of UC and its variant histology.
Virchows Archiv : an international journal of pathology. 2016 Aug 12 [Epub ahead of print]
Doreen Nguyen, Diana Taheri, Simeon Springer, Morgan Cowan, Gunes Guner, Maria Angelica Mendoza Rodriguez, Yuxuan Wang, Isaac Kinde, Christopher J VandenBussche, Matthew T Olson, 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, 21287, USA., Department of Oncology, Johns Hopkins University, Baltimore, MD, 21287, USA., The Ludwig Center for Cancer Genetics and Therapeutics and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21231, USA., AC Camargo Cancer Centre, Sao Paulo, Brazil., Department of Urology, Osaka University, Osaka, Japan., Department of Pathology, Hacettepe University, Ankara, Turkey., Department of Urology, Johns Hopkins University, Baltimore, MD, 21287, USA., Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA. .