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Pathology and Staging: Genetics and Molecular Biology

  • Sean McAdams
  • Michael C. RiskEmail author
Chapter

Abstract

Urothelial cell cancer of the bladder is a multifactorial disease with well-established links to environmental factors and a clear demonstration of a genetic component in its development. Despite a twofold increase in incidence in first-degree relatives, a mode of inheritance, genetic site specificity, or an ethnic predilection has yet to be discovered. Specific chromosomal deletions, gene mutations, genetic pathways, epigenetic changes, and genetic susceptibility loci have been correlated with the development and staging of urothelial cell cancer. Two distinct clinical and molecular pathways to the development of bladder cancer have emerged, namely the pathway to non-invasive stage Ta disease and the CIS pathway that leads to muscle invasive disease. In this chapter we will discuss these two pathways in detail, along with the evolving approach to using genetics and molecular biology for predicting development of bladder cancer, effect on stage and grade, as well as prognosis.

Keywords

Urothelial carcinoma Bladder cancer Molecular carcinogenesis Epigenetics Gene expression 

References

  1. 1.
    American Cancer Society. Cancer facts & figures 2013. Atlanta, GA: American Cancer Society; 2013.Google Scholar
  2. 2.
    Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist. 2007;12(1):20–37.PubMedCrossRefGoogle Scholar
  3. 3.
    Parkin DM. The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl. 2008;218:12–20.PubMedCrossRefGoogle Scholar
  4. 4.
    Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306(7):737–45.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Aben KK, Witjes JA, Schoenberg MP, Hulsbergen-van de Kaa C, Verbeek AL, Kiemeney LA. Familial aggregation of urothelial cell carcinoma. Int J Cancer. 2002;98(2):274–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Kiemeney LA, Schoenberg M. Familial transitional cell carcinoma. J Urol. 1996;156(3):867–72.PubMedCrossRefGoogle Scholar
  7. 7.
    Mueller CM, Caporaso N, Greene MH. Familial and genetic risk of transitional cell carcinoma of the urinary tract. Urol Oncol. 2008;26(5):451–64.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Fletcher O, Easton D, Anderson K, Gilham C, Jay M, Peto J. Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst. 2004;96(5):357–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Guo Z, Linn JF, Wu G, Anzick SL, Eisenberger CF, Halachmi S, et al. CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer. Nat Med. 2004;10(4):374–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Sijmons RH, Kiemeney LA, Witjes JA, Vasen HF. Urinary tract cancer and hereditary nonpolyposis colorectal cancer: risks and screening options. J Urol. 1998;160(2):466–70.PubMedCrossRefGoogle Scholar
  11. 11.
    Watson P, Lynch HT. The tumor spectrum in HNPCC. Anticancer Res. 1994;14(4B):1635–9.PubMedGoogle Scholar
  12. 12.
    Geary J, Sasieni P, Houlston R, Izatt L, Eeles R, Payne SJ, et al. Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Fam Cancer. 2008;7(2):163–72.PubMedCrossRefGoogle Scholar
  13. 13.
    van der Post RS, Kiemeney LA, Ligtenberg MJ, Witjes JA, Hulsbergen-van de Kaa CA, Bodmer D, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010;47(7):464–70.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Barrow PJ, Ingham S, O’Hara C, Green K, McIntyre I, Lalloo F, et al. The spectrum of urological malignancy in Lynch syndrome. Fam Cancer. 2013;12(1):57–63.PubMedCrossRefGoogle Scholar
  15. 15.
    Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X, Figueroa JD, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42(11):978–84.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Kiemeney LA, Thorlacius S, Sulem P, Geller F, Aben KK, Stacey SN, et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet. 2008;40(11):1307–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Wu X, Ye Y, Kiemeney LA, Sulem P, Rafnar T, Matullo G, et al. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat Genet. 2009;41(9):991–5.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Wu X, Hildebrandt MA, Chang DW. Genome-wide association studies of bladder cancer risk: a field synopsis of progress and potential applications. Cancer Metastasis Rev. 2009;28(3–4):269–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science. 1992;258(5083):818–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Chow NH, Cairns P, Eisenberger CF, Schoenberg MP, Taylor DC, Epstein JI, et al. Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer. Int J Cancer. 2000;89(6):514–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Cordon-Cardo C, Cote RJ, Sauter G. Genetic and molecular markers of urothelial premalignancy and malignancy. Scand J Urol Nephrol Suppl. 2000;205:82–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Knowles MA. Bladder cancer subtypes defined by genomic alterations. Scand J Urol Nephrol Suppl. 2008;218:116–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Spruck 3rd CH, Ohneseit PF, Gonzalez-Zulueta M, Esrig D, Miyao N, Tsai YC, et al. Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res. 1994;54(3):784–8.PubMedGoogle Scholar
  24. 24.
    Bakkar AA, Wallerand H, Radvanyi F, Lahaye JB, Pissard S, Lecerf L, et al. FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res. 2003;63(23):8108–12.PubMedGoogle Scholar
  25. 25.
    Neuzillet Y, Paoletti X, Ouerhani S, Mongiat-Artus P, Soliman H, de The H, et al. A meta-analysis of the relationship between FGFR3 and TP53 mutations in bladder cancer. PLoS One. 2012;7(12):e48993.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Knowles MA, Habuchi T, Kennedy W, Cuthbert-Heavens D. Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Res. 2003;63(22):7652–6.PubMedGoogle Scholar
  27. 27.
    Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007;213(1):91–8.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Adar R, Monsonego-Ornan E, David P, Yayon A. Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization. J Bone Miner Res. 2002;17(5):860–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Gomez-Roman JJ, Saenz P, Molina M, Cuevas Gonzalez J, Escuredo K, Santa Cruz S, et al. Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Cancer Res. 2005;11(2 Pt 1):459–65.PubMedGoogle Scholar
  30. 30.
    van Rhijn BW, Montironi R, Zwarthoff EC, Jobsis AC, van der Kwast TH. Frequent FGFR3 mutations in urothelial papilloma. J Pathol. 2002;198(2):245–51.PubMedCrossRefGoogle Scholar
  31. 31.
    Obermann EC, Junker K, Stoehr R, Dietmaier W, Zaak D, Schubert J, et al. Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses. J Pathol. 2003;199(1):50–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Pollard C, Smith SC, Theodorescu D. Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC). Expert Rev Mol Med. 2010;12:e10.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Billerey C, Chopin D, Aubriot-Lorton MH, Ricol D, Gil Diez de Medina S, Van Rhijn B, et al. Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol. 2001;158(6):1955–9.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Bernard-Pierrot I, Brams A, Dunois-Larde C, Caillault A, Diez de Medina SG, Cappellen D, et al. Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. Carcinogenesis. 2006;27(4):740–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Tomlinson DC, Hurst CD, Knowles MA. Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene. 2007;26(40):5889–99.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Qing J, Du X, Chen Y, Chan P, Li H, Wu P, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J Clin Invest. 2009;119(5):1216–29.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Kompier LC, Lurkin I, van der Aa MN, van Rhijn BW, van der Kwast TH, Zwarthoff EC. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS One. 2010;5(11):e13821.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Lopez-Knowles E, Hernandez S, Malats N, Kogevinas M, Lloreta J, Carrato A, et al. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 2006;66(15):7401–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Wu X, Obata T, Khan Q, Highshaw RA, De Vere WR, Sweeney C. The phosphatidylinositol-3 kinase pathway regulates bladder cancer cell invasion. BJU Int. 2004;93(1):143–50.PubMedCrossRefGoogle Scholar
  40. 40.
    Rebouissou S, Herault A, Letouze E, Neuzillet Y, Laplanche A, Ofualuka K, et al. CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma. J Pathol. 2012;227(3):315–24.PubMedCrossRefGoogle Scholar
  41. 41.
    Chatterjee SJ, Datar R, Youssefzadeh D, George B, Goebell PJ, Stein JP, et al. Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma. J Clin Oncol. 2004;22(6):1007–13.PubMedCrossRefGoogle Scholar
  42. 42.
    Rosin MP, Cairns P, Epstein JI, Schoenberg MP, Sidransky D. Partial allelotype of carcinoma in situ of the human bladder. Cancer Res. 1995;55(22):5213–6.PubMedGoogle Scholar
  43. 43.
    Hopman AH, Kamps MA, Speel EJ, Schapers RF, Sauter G, Ramaekers FC. Identification of chromosome 9 alterations and p53 accumulation in isolated carcinoma in situ of the urinary bladder versus carcinoma in situ associated with carcinoma. Am J Pathol. 2002;161(4):1119–25.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Dyrskjot L, Kruhoffer M, Thykjaer T, Marcussen N, Jensen JL, Moller K, et al. Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res. 2004;64(11):4040–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Mallofre C, Castillo M, Morente V, Sole M. Immunohistochemical expression of CK20, p53, and Ki-67 as objective markers of urothelial dysplasia. Mod Pathol. 2003;16(3):187–91.PubMedCrossRefGoogle Scholar
  46. 46.
    Han H, Wolff EM, Liang G. Epigenetic alterations in bladder cancer and their potential clinical implications. Adv Urol. 2012;2012:546917.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, Wang X, Shen TH, Matos T, et al. Inactivation of p53 and Pten promotes invasive bladder cancer. Genes Dev. 2009;23(6):675–80.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Di Pierro GB, Gulia C, Cristini C, Fraietta G, Marini L, Grande P, et al. Bladder cancer: a simple model becomes complex. Curr Genomics. 2012;13(5):395–415.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Wolff EM, Chihara Y, Pan F, Weisenberger DJ, Siegmund KD, Sugano K, et al. Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue. Cancer Res. 2010;70(20):8169–78.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Salem C, Liang G, Tsai YC, Coulter J, Knowles MA, Feng AC, et al. Progressive increases in de novo methylation of CpG islands in bladder cancer. Cancer Res. 2000;60(9):2473–6.PubMedGoogle Scholar
  51. 51.
    Vallot C, Stransky N, Bernard-Pierrot I, Herault A, Zucman-Rossi J, Chapeaublanc E, et al. A novel epigenetic phenotype associated with the most aggressive pathway of bladder tumor progression. J Natl Cancer Inst. 2011;103(1):47–60.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Dyrskjot L, Ostenfeld MS, Bramsen JB, Silahtaroglu AN, Lamy P, Ramanathan R, et al. Genomic profiling of microRNAs in bladder cancer: miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res. 2009;69(11):4851–60.PubMedCrossRefGoogle Scholar
  53. 53.
    Catto JW, Miah S, Owen HC, Bryant H, Myers K, Dudziec E, et al. Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res. 2009;69(21):8472–81.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Dip N, Reis ST, Timoszczuk LS, Viana NI, Piantino CB, Morais DR, et al. Stage, grade and behavior of bladder urothelial carcinoma defined by the microRNA expression profile. J Urol. 2012;188(5):1951–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Dyrskjot L, Zieger K, Real FX, Malats N, Carrato A, Hurst C, et al. Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study. Clin Cancer Res. 2007;13(12):3545–51.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang R, Morris DS, Tomlins SA, Lonigro RJ, Tsodikov A, Mehra R, et al. Development of a multiplex quantitative PCR signature to predict progression in non-muscle-invasive bladder cancer. Cancer Res. 2009;69(9):3810–8.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of UrologyUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of UrologyMinneapolis VA Medical CenterMinneapolisUSA

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