Skip to main content

Advertisement

SpringerLink
Log in

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

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

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.

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.

Fig. 1
Fig. 2

Similar content being viewed by others

References

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 2:412–440

    PubMed  PubMed Central  Google Scholar 

  5. 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 441:105–108

    Article  PubMed  Google Scholar 

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

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

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

    Article  CAS  PubMed  Google Scholar 

  9. 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 319:133–141

    Article  CAS  PubMed  Google Scholar 

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

    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 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 110:6021–6026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 27:516–523

    Article  CAS  PubMed  Google Scholar 

  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 339:959–961

    Article  CAS  PubMed  Google Scholar 

  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 65:360–366

    Article  CAS  PubMed  Google Scholar 

  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 53:8–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 469:427–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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 117:314–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 85:53–59

    Article  CAS  PubMed  Google Scholar 

  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 28:597–602

    Article  CAS  PubMed  Google Scholar 

  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 152:388–392

    Article  CAS  PubMed  Google Scholar 

  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 13:1384–1390

    Article  CAS  PubMed  Google Scholar 

  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 71:497–498

    Article  CAS  PubMed  Google Scholar 

  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:e13821

    Article  PubMed  PubMed Central  Google Scholar 

  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 66:7401–7404

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Maria Del Carmen Rodriguez Pena, Aline C. Tregnago, Marie-Lisa Eich, Diana Taheri & George J. Netto

  2. The Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21231, USA

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

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

    Dilek Ertoy

  4. Department of Pathology, Osaka University, Osaka, Japan

    Kazutoshi Fujita

  5. Department of Pathology, AC Camargo Cancer Center, Sao Paulo, Brazil

    Stephania M. Bezerra & Isabela W. Cunha

  6. Department of Pathology, University of Florence, Florence, Italy

    Maria Rosaria Raspollini

  7. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35249, USA

    Lijia Yu & George J. Netto

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

    Trinity J. Bivalacqua

  9. Department of Pathology, The University of Alabama at Birmingham, WP Building, Suite P230, 619 19th Street South, Birmingham, AL, 35249-7331, USA

    George J. Netto

Authors
  1. Maria Del Carmen Rodriguez Pena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aline C. Tregnago
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-Lisa Eich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simeon Springer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuxuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Diana Taheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dilek Ertoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazutoshi Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephania M. Bezerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Isabela W. Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maria Rosaria Raspollini
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lijia Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Trinity J. Bivalacqua
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nickolas Papadopoulos
    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. Bert Vogelstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. 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

Conflict of interest

K. K., N. P., and B. V. are founders of Personal Genome Diagnostics and PapGene and advise Sysmex-Inostics. These companies and others have licensed technologies from Johns Hopkins, of which B. V., K. K., and N. P. are inventors and receive royalties. The terms of these arrangements are managed by the university in accordance with its conflict of interest policies.

Funding/support

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.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodriguez Pena, M.D.C., Tregnago, A.C., Eich, ML. et al. Spectrum of genetic mutations in de novo PUNLMP of the urinary bladder. Virchows Arch 471, 761–767 (2017). https://doi.org/10.1007/s00428-017-2164-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-017-2164-5

Keywords

Search

Navigation