title: High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma.
abstract: 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.
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors: Doreen
authors: D
authors: Nguyen
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.|Department of Pathology, Isfahan University of Medical Sciences, Isfahan Kidney Diseases Research Center, Isfahan, Iran.
authors: Diana
authors: D
authors: Taheri
authors: 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.
authors: Simeon
authors: S
authors: Springer
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors: Morgan
authors: M
authors: Cowan
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors: Gunes
authors: G
authors: Guner
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors: Maria Angelica
authors: MA
authors: Mendoza Rodriguez
authors: The Ludwig Center for Cancer Genetics and Therapeutics and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21231, USA.
authors: Yuxuan
authors: Y
authors: Wang
authors: The Ludwig Center for Cancer Genetics and Therapeutics and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21231, USA.
authors: Isaac
authors: I
authors: Kinde
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors: Christopher J
authors: CJ
authors: VandenBussche
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors: Matthew T
authors: MT
authors: Olson
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors: Bernardo F P
authors: BF
authors: Ricardo
authors: AC Camargo Cancer Centre, Sao Paulo, Brazil.
authors: Isabela
authors: I
authors: Cunha
authors: Department of Urology, Osaka University, Osaka, Japan.
authors: Kazutoshi
authors: K
authors: Fujita
authors: Department of Pathology, Hacettepe University, Ankara, Turkey.
authors: Dilek
authors: D
authors: Ertoy
authors: 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.
authors: Kenneth W
authors: KW
authors: Kinzler
authors: Department of Urology, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors: Trinity J
authors: TJ
authors: Bivalacqua
authors: 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.
authors: Nickolas
authors: N
authors: Papadopoulos
authors: 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.
authors: Bert
authors: B
authors: Vogelstein
authors: Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA. gnetto1@jhmi.edu.|Department of Urology, Johns Hopkins University, Baltimore, MD, 21287, USA. gnetto1@jhmi.edu.|Department of Pathology, The Johns Hopkins Hospital, 401 North Broadway Street, Weinberg 2242, Baltimore, MD, 21231, USA. gnetto1@jhmi.edu.
authors: George J
authors: GJ
authors: Netto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000453:epidemiology* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D015995:Prevalence; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D019098:Telomerase
keywords: Micropapillary; Mutation; TERT; Telomerase reverse transcriptase; Urothelial carcinoma