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01-12-2017 | Original Article

Spectrum of genetic mutations in de novo PUNLMP of the urinary bladder

Authors: Maria Del Carmen Rodriguez Pena, Aline C. Tregnago, Marie-Lisa Eich, Simeon Springer, Yuxuan Wang, Diana Taheri, Dilek Ertoy, Kazutoshi Fujita, Stephania M. Bezerra, Isabela W. Cunha, Maria Rosaria Raspollini, Lijia Yu, Trinity J. Bivalacqua, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, George J. Netto

Published in: Virchows Archiv | Issue 6/2017

Abstract

Our group and others have previously demonstrated the presence of TERT promoter mutations (TERT-mut) in 60–80% of urothelial carcinomas and some of their histologic variants. Five other genes have been frequently implicated in bladder cancer: FGRF3, TP53, PIK3CA, HRAS, and CDKN2A. In the current study, we sought to determine the prevalence of mutations in TERT and these five other genes in de novo papillary urothelial neoplasms of low malignant potential (PUNLMP) of the urinary bladder. A retrospective search of our archives for PUNLMP was performed and 30 de novo cases were identified and included in the study. We found mutations in TERT (TERT-mut) and FGFR3 (FGFR3-mut) to be the most common alterations in the cohort (63 and 60%, respectively). The majority of the TERT-mut-positive tumors (84%) had a g.1295228C > T alteration with the remaining tumors demonstrating g.1295250C > T. Approximately one fourth of tumors had TP53 mutations. These findings support the potential utility of a uniform genetic mutation panel to detect bladder cancers of various subtypes.

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Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30CrossRefPubMed

Netto GJ (2013) Clinical applications of recent molecular advances in urologic malignancies: no longer chasing a “mirage”? Adv Anat Pathol 20:175–203CrossRefPubMed

Kinde I, Munari E, Faraj SF, Hruban RH, Schoenberg M, Bivalacqua T, Allaf M, Springer S, Wang Y, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N, Netto GJ (2013) TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res 73:7162–7167CrossRefPubMedPubMedCentral

Sullivan PS, Chan JB, Levin MR, Rao J (2010) Urine cytology and adjunct markers for detection and surveillance of bladder cancer. Am J Transl Res 2:412–440PubMedPubMedCentral

Busch C, Algaba F (2002) The WHO/ISUP 1998 and WHO 1999 systems for malignancy grading of bladder cancer. Scientific foundation and translation to one another and previous systems. Virchows Arch 441:105–108CrossRefPubMed

Zhou M, Netto GJ, Epstein JI (2012) Uropathology: a volume in the high yield pathology series. Saunders

International Agency for Research on Cancer (2016) WHO Classification of Tumours of the Urinary System and Male Genital Organs. World Health Organization; 4 edition

Holmang S, Hedelin H, Anderstrom C, Holmberg E, Busch C, Johansson SL (1999) Recurrence and progression in low grade papillary urothelial tumors. J Urol 162:702–707CrossRefPubMed

Epstein JI, Netto GJ (2014) 3.9 Urothelial papilloma vs. papillary urothelial neoplasm of low malignant potential (PUNLMP). In: Epstein JI (ed) Differential Diagnosis in Surgical Pathology: Genitourinary System. Wolters Kluwer, pp 286

10.

Lu W, Zhang Y, Liu D, Songyang Z, Wan M (2013) Telomeres-structure, function, and regulation. Exp Cell res 319:133–141CrossRefPubMed

11.

Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–959CrossRefPubMedPubMedCentral

12.

Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih I, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 110:6021–6026CrossRefPubMedPubMedCentral

13.

Scott GA, Laughlin TS, Rothberg PG (2014) Mutations of the TERT promoter are common in basal cell carcinoma and squamous cell carcinoma. Mod Pathol 27:516–523CrossRefPubMed

14.

Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, Schadendorf D, Kumar R (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339:959–961CrossRefPubMed

15.

Allory Y, Beukers W, Sagrera A, Flandez M, Marques M, Marquez M, van der Keur KA, Dyrskjot L, Lurkin I, Vermeij M, Carrato A, Lloreta J, Lorente JA, Carrillo-de Santa Pau E, Masius RG, Kogevinas M, Steyerberg EW, van Tilborg AA, Abas C, Orntoft TF, Zuiverloon TC, Malats N, Zwarthoff EC, Real FX (2014) Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome. Eur Urol 65:360–366CrossRefPubMed

16.

Cowan ML, Springer S, Nguyen D, Taheri D, Guner G, Mendoza Rodriguez MA, Wang Y, Kinde I, Del Carmen Rodriguez Pena M, CJ VB, Olson MT, Cunha I, Fujita K, Ertoy D, Kinzler K, Bivalacqua T, Papadopoulos N, Vogelstein B, Netto GJ (2016) Detection of TERT promoter mutations in primary adenocarcinoma of the urinary bladder. Hum Pathol 53:8–13CrossRefPubMedPubMedCentral

17.

Nguyen D, Taheri D, Springer S, Cowan M, Guner G, Mendoza Rodriguez MA, Wang Y, Kinde I, VandenBussche CJ, Olson MT, Ricardo BF, Cunha I, Fujita K, Ertoy D, Kinzler KW, Bivalacqua TJ, Papadopoulos N, Vogelstein B, Netto GJ (2016) High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma. Virchows Arch 469:427–434CrossRefPubMedPubMedCentral

18.

Netto GJ (2011) Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? Nat Rev Urol 9:41–51CrossRefPubMed

19.

Mo L, Zheng X, Huang HY, Shapiro E, Lepor H, Cordon-Cardo C, Sun TT, Wu XR (2007) Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. J Clin Invest 117:314–325CrossRefPubMedPubMedCentral

20.

Sarkis AS, Dalbagni G, Cordon-Cardo C, Zhang ZF, Sheinfeld J, Fair WR, Herr HW, Reuter VE (1993) Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 85:53–59CrossRefPubMed

21.

Lin HH, Ke HL, Huang SP, Wu WJ, Chen YK, Chang LL (2010) Increase sensitivity in detecting superficial, low grade bladder cancer by combination analysis of hypermethylation of E-cadherin, p16, p14, RASSF1A genes in urine. Urol Oncol 28:597–602CrossRefPubMed

22.

Sarkis AS, Dalbagni G, Cordon-Cardo C, Melamed J, Zhang ZF, Sheinfeld J, Fair WR, Herr HW, Reuter VE (1994) Association of P53 nuclear overexpression and tumor progression in carcinoma in situ of the bladder. J Urol 152:388–392CrossRefPubMed

23.

Sarkis AS, Bajorin DF, Reuter VE, Herr HW, Netto G, Zhang ZF, Schultz PK, Cordon-Cardo C, Scher HI (1995) Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol 13:1384–1390CrossRefPubMed

24.

Wang Y, Sundfeldt K, Mateoiu C, Shih I, Kurman RJ, Schaefer J, Silliman N, Kinde I, Springer S, Foote M, Kristjansdottir B, James N, Kinzler KW, Papadopoulos N, Diaz LA, Vogelstein B (2016) Diagnostic potential of tumor DNA from ovarian cyst fluid. Elife 5: doi: 10.7554/eLife.15175

25.

Cheng L, Montironi R, Lopez-Beltran A (2017) TERT promoter mutations occur frequently in urothelial papilloma and papillary urothelial neoplasm of low malignant potential. Eur Urol 71:497–498CrossRefPubMed

26.

Kompier LC, Lurkin I, van der Aa MN, van Rhijn BW, van der Kwast TH, Zwarthoff EC (2010) FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS One 5:e13821CrossRefPubMedPubMedCentral

27.

Lopez-Knowles E, Hernandez S, Malats N, Kogevinas M, Lloreta J, Carrato A, Tardon A, Serra C, Real FX (2006) PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer res 66:7401–7404CrossRefPubMed

Title: Spectrum of genetic mutations in de novo PUNLMP of the urinary bladder
Authors: Maria Del Carmen Rodriguez Pena
Aline C. Tregnago
Marie-Lisa Eich
Simeon Springer
Yuxuan Wang
Diana Taheri
Dilek Ertoy
Kazutoshi Fujita
Stephania M. Bezerra
Isabela W. Cunha
Maria Rosaria Raspollini
Lijia Yu
Trinity J. Bivalacqua
Nickolas Papadopoulos
Kenneth W. Kinzler
Bert Vogelstein
George J. Netto
Publication date: 01-12-2017
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 6/2017
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-017-2164-5

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Spectrum of genetic mutations in de novo PUNLMP of the urinary bladder

Abstract

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Abstract

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