Skip to main content

Advertisement

SpringerLink
Log in

High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Fig. 2

Similar content being viewed by others

References

  1. Allory Y, Beukers W, Sagrera A, Flandez M, Marques M, Marquez M, van d, Keur KA, Dyrskjot L, Lurkin I, Vermeij M, Carrato A, Lloreta J, Lorente JA, Carrillo-de Santa Pau E, RG M, Kogevinas M, EW S, AA v T, Abas C, TF O, TC Z, Malats N, EC Z, 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 65:360–366. doi:10.1016/j.eururo.2013.08.052

    Article  CAS  PubMed  Google Scholar 

  2. Amin MB, Ro JY, el-Sharkawy T, Lee KM, Troncoso P, Silva EG, Ordonez NG, Ayala AG (1994) Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol 18:1224–1232

    Article  CAS  PubMed  Google Scholar 

  3. MB A, SC S, Reuter VE, Epstein JI, DJ G, DE H, Lin O, JK MK, Montironi R, GP P, HA A-A, Algaba F, Ali S, Alvarado-Cabrero I, Bubendorf L, Cheng L, JC C, Kristiansen G, RJ C, Delahunt B, JN E, EM G, Gulmann C, Hartmann A, Langner C, Lopez-Beltran A, Magi-Galluzzi C, Merce J, GJ N, Oliva E, Rao P, JY R, JR S, SK T, Tsuzuki T, SA U, der Kwast T V, RH Y, MS S (2015) Update for the practicing pathologist: the international consultation on urologic disease-European association of urology consultation on bladder cancer modern pathology. An Official Journal of the United States and Canadian Academy of Pathology, Inc 28:612–630. doi:10.1038/modpathol.2014.158

    Article  Google Scholar 

  4. Bell RJ, Rube HT, Kreig A, Mancini A, Fouse SD, Nagarajan RP, Choi S, Hong C, He D, Pekmezci M, Wiencke JK, Wrensch MR, Chang SM, Walsh KM, Myong S, Song JS, Costello JF (2015) Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 348:1036–1039. doi:10.1126/science.aab0015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Black PC, Brown GA, Dinney CP (2009) The impact of variant histology on the outcome of bladder cancer treated with curative intent. Urol Oncol 27:3–7. doi:10.1016/j.urolonc.2007.07.010

    Article  PubMed  Google Scholar 

  6. Chiba K, Johnson JZ, Vogan JM, Wagner T, Boyle JM, Hockemeyer D (2015) Cancer-associated TERT promoter mutations abrogate telomerase silencing Elife 4. doi: 10.7554/eLife.07918

  7. Comperat E, Roupret M, Yaxley J, Reynolds J, Varinot J, Ouzaid I, Cussenot O, Samaratunga H (2010) Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 72 cases. Pathology 42:650–654. doi:10.3109/00313025.2010.522173

    Article  PubMed  Google Scholar 

  8. 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 339:959–961. doi:10.1126/science.1230062

    Article  CAS  PubMed  Google Scholar 

  9. Huang DS, Wang Z, He XJ, Diplas BH, Yang R, Killela PJ, Meng Q, Ye ZY, Wang W, Jiang XT, Xu L, He XL, Zhao ZS, Xu WJ, Wang HJ, Ma YY, Xia YJ, Li L, Zhang RX, Jin T, Zhao ZK, Xu J, Yu S, Wu F, Liang J, Wang S, Jiao Y, Yan H, Tao HQ (2015) Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer 51:969–976. doi:10.1016/j.ejca.2015.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kamat AM, Dinney CP, Gee JR, Grossman HB, Siefker-Radtke AO, Tamboli P, Detry MA, Robinson TL, Pisters LL (2007) Micropapillary bladder cancer: a review of the University of Texas M. D. Anderson cancer center experience with 100 consecutive patients. Cancer 110:62–67. doi:10.1002/cncr.22756

    Article  PubMed  Google Scholar 

  11. Kar A, Gutierrez-Hartmann A (2013) Molecular mechanisms of ETS transcription factor-mediated tumorigenesis. Crit Rev Biochem Mol Biol 48:522–543. doi:10.3109/10409238.2013.838202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 Ie M, 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 110:6021–6026. doi: 10.1073/pnas.1303607110

  13. Kinde I, Bettegowda C, Wang Y, Wu J, Agrawal N, Shih Ie M, Kurman R, Dao F, Levine DA, Giuntoli R, Roden R, Eshleman JR, Carvalho JP, Marie SK, Papadopoulos N, Kinzler KW, Vogelstein B, Diaz LA, Jr. (2013) Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers. Sci Transl Med 5:167ra164. doi:10.1126/scitranslmed.3004952

  14. 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 73:7162–7167. doi:10.1158/0008-5472.CAN-13-2498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B (2011) Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A 108:9530–9535. doi:10.1073/pnas.1105422108

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lopez-Beltran A, Montironi R, Blanca A, Cheng L (2010) Invasive micropapillary urothelial carcinoma of the bladder. Hum Pathol 41:1159–1164. doi:10.1016/j.humpath.2009.11.018

    Article  PubMed  Google Scholar 

  17. Maida Y, Kyo S, Kanaya T, Wang Z, Yatabe N, Tanaka M, Nakamura M, Ohmichi M, Gotoh N, Murakami S, Inoue M (2002) Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway. Oncogene 21:4071–4079. doi:10.1038/sj.onc.1205509

    Article  CAS  PubMed  Google Scholar 

  18. Meeks JJ, Taylor JM, Matsushita K, Herr HW, Donat SM, Bochner BH, Dalbagni G (2013) Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int 111:E325–E330. doi:10.1111/j.1464-4×.2012.11751.x

    Article  PubMed  Google Scholar 

  19. Monn MF, Kaimakliotis HZ, Pedrosa JA, Cary KC, Bihrle R, Cheng L, Koch MO (2015) Contemporary bladder cancer: variant histology may be a significant driver of disease. Urol Oncol 33(18):e15–e20. doi:10.1016/j.urolonc.2014.10.001

    PubMed  Google Scholar 

  20. Montironi R, Lopez-Beltran A (2005) The 2004 WHO classification of bladder tumors: a summary and commentary. Int J Surg Pathol 13:143–153

    Article  PubMed  Google Scholar 

  21. Raghavan D, Russell PJ, JL B (1992) Experimental models of histogenesis and tumor cell heterogeneity in bladder cancer. Semin Surg Oncol 8:279–284

    Article  CAS  PubMed  Google Scholar 

  22. Sangoi AR, Beck AH, Amin MB, Cheng L, Epstein JI, Hansel DE, Iczkowski KA, Lopez-Beltran A, Oliva E, Paner GP, Reuter VE, Ro JY, Shah RB, Shen SS, Tamboli P, McKenney JK (2010) Interobserver reproducibility in the diagnosis of invasive micropapillary carcinoma of the urinary tract among urologic pathologists. Am J Surg Pathol 34:1367–1376. doi:10.1097/PAS.0b013e3181ec86b3

    Article  PubMed  Google Scholar 

  23. Spaliviero M, Dalbagni G, Bochner BH, Poon BY, Huang H, Al-Ahmadie HA, Donahue TF, Taylor JM, Meeks JJ, Sjoberg DD, Donat SM, Reuter VE, Herr HW (2014) Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder. J Urol 192:702–707. doi:10.1016/j.juro.2014.02.2565

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sung HH, Cho J, Kwon GY, Jeon HG, Jeong BC, Seo SI, Jeon SS, Choi HY, HM L (2014) Clinical significance of micropapillary urothelial carcinoma of the upper urinary tract. J Clin Pathol 67:49–54. doi:10.1136/jclinpath-2013-201799

    Article  PubMed  Google Scholar 

  25. Vinagre J, Almeida A, Populo H, Batista R, Lyra J, Pinto V, Coelho R, Celestino R, Prazeres H, Lima L, Melo M, da Rocha AG, Preto A, Castro P, Castro L, Pardal F, Lopes JM, Santos LL, Reis RM, Cameselle-Teijeiro J, Sobrinho-Simoes M, Lima J, Maximo V, Soares P (2013) Frequency of TERT promoter mutations in human cancers. Nat Commun 4:2185. doi:10.1038/ncomms3185

    Article  PubMed  Google Scholar 

  26. Wang K, Liu T, Liu L, Liu J, Liu C, Wang C, Ge N, Ren H, Yan K, Hu S, Bjorkholm M, Fan Y, Xu D (2014) TERT promoter mutations in renal cell carcinomas and upper tract urothelial carcinomas. Oncotarget 5:1829–1836

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang X, Zhou P, Sun X, Zheng J, Wei G, Zhang L, Wang H, Yao J, S L, Jia P (2015) Acidified bile acids increase hTERT expression via c-myc activation in human gastric cancer cells. Oncol Rep 33:3038–3044. doi:10.3892/or.2015.3908

    PubMed  Google Scholar 

  28. Yang ZF, Mott S, AG R (2007) The Ets transcription factor GABP is required for cell-cycle progression. Nat Cell Biol 9:339–346. doi:10.1038/ncb1548

    Article  PubMed  Google Scholar 

  29. Zheng X, Zhuge J, Bezerra SM, Faraj SF, Munari E, Fallon JT 3rd, Yang XJ, Argani P, Netto GJ, Zhong M (2014) High frequency of TERT promoter mutation in small cell carcinoma of bladder, but not in small cell carcinoma of other origins. J Hematol Oncol 7:47. doi:10.1186/s13045-014-0047-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhong M, Tian W, Zhuge J, Zheng X, Huang T, Cai D, Zhang D, Yang XJ, Argani P, Fallon JT, JI E (2015) Distinguishing nested variants of urothelial carcinoma from benign mimickers by TERT promoter mutation. Am J Surg Pathol 39:127–131. doi:10.1097/PAS.0000000000000305

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Johns Hopkins Greenberg Bladder Cancer Institute, the Virginia and D.K. Ludwig Fund for Cancer Research, the Commonwealth Fund, the Conrad R. Hilton Foundation, and the Sol Goldman Sequencing Facility at Johns Hopkins.

Author information

Authors and Affiliations

  1. Department of Pathology, Johns Hopkins University, Baltimore, MD, 21287, USA

    Doreen Nguyen, Diana Taheri, Morgan Cowan, Gunes Guner, Maria Angelica Mendoza Rodriguez, Christopher J. VandenBussche, Matthew T. Olson, Bernardo F. P. Ricardo & George J. Netto

  2. Department of Urology, Johns Hopkins University, Baltimore, MD, 21287, USA

    Trinity J. Bivalacqua & George J. Netto

  3. Department of Oncology, Johns Hopkins University, Baltimore, MD, 21287, USA

    Simeon Springer, Kenneth W. Kinzler, Nickolas Papadopoulos & Bert Vogelstein

  4. The Ludwig Center for Cancer Genetics and Therapeutics and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21231, USA

    Simeon Springer, Yuxuan Wang, Isaac Kinde, Kenneth W. Kinzler, Nickolas Papadopoulos & Bert Vogelstein

  5. Department of Pathology, Isfahan University of Medical Sciences, Isfahan Kidney Diseases Research Center, Isfahan, Iran

    Diana Taheri

  6. AC Camargo Cancer Centre, Sao Paulo, Brazil

    Isabela Cunha

  7. Department of Urology, Osaka University, Osaka, Japan

    Kazutoshi Fujita

  8. Department of Pathology, Hacettepe University, Ankara, Turkey

    Dilek Ertoy

  9. Department of Pathology, The Johns Hopkins Hospital, 401 North Broadway Street, Weinberg 2242, Baltimore, MD, 21231, USA

    George J. Netto

Authors
  1. Doreen Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diana Taheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simeon Springer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morgan Cowan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gunes Guner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Angelica Mendoza Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuxuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Isaac Kinde
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christopher J. VandenBussche
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Matthew T. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bernardo F. P. Ricardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Isabela Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kazutoshi Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Dilek Ertoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kenneth W. Kinzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Trinity J. Bivalacqua
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Nickolas Papadopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Bert Vogelstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. George J. Netto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George J. Netto.

Ethics declarations

Disclosure/conflict of interest

KWK, NP, and BV are founders of Personal Genome Diagnostics, Inc. and PapGene Inc. and advise Sysmex-Inostics. These companies and others have licensed technologies from Johns Hopkins, of which BV, KWK, and NP are inventors and receive royalties from these licenses. The terms of these arrangements are being managed by the university in accordance with its conflict of interest policies.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nguyen, D., Taheri, D., Springer, S. et al. High prevalence of TERT promoter mutations in micropapillary urothelial carcinoma. Virchows Arch 469, 427–434 (2016). https://doi.org/10.1007/s00428-016-2001-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-016-2001-2

Keywords

Search

Navigation