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Molecular Pathology of Genitourinary Cancers: Translating the Cancer Genome to the Clinic

  • Martin J. Magers
  • Joshua I. Warrick
  • Scott A. TomlinsEmail author
Chapter

Abstract

Genitourinary malignancies, including cancers of the prostate, urinary bladder, kidney, testis, and penis, are major causes of cancer morbidity and mortality. Molecular classification and predictive and prognostic assays have historically lagged other cancer types. Nevertheless, high-throughput technologies combined with large international efforts to comprehensively interrogate cancer genomes and transcriptomes have dramatically increased our molecular knowledge of these tumors. In parallel, novel treatments have been approved for several advanced genitourinary cancers, further driving need to identify prognostic and predictive biomarkers. The shift toward precision medicine, selecting the right therapy for the molecular alterations driving a patient’s particular cancer, portends a rise in clinical demand for routine cancer genome/transcriptome assessment. Here, we provide an overview of the range of driving genetic alterations in common genitourinary cancers. We focus on salient single genes, multigene panels, and findings from exome−/genome-wide interrogation and discuss their potential for translation into clinical assays in the context of available therapies.

Keywords

Prostate Kidney Bladder Testis Penis Immunohistochemistry Next-generation sequencing qRT-PCR Molecular subtyping TMPRSS2:ERG PTEN HOXB13 BRCA1 BRCA2 Liquid biopsy Circulating tumor cells Cell-free DNA FGFR3 TP53 VHL 

Notes

Acknowledgments

S.A.T. is a co-inventor on a patent issued to the University of Michigan on ETS fusions in prostate cancer. The diagnostic field of use has been licensed to Gen-Probe, Inc., who has sublicensed certain rights to Ventana Medical Systems. S.A.T. is a co-inventor on a patent filed by the University of Michigan on SPINK1 in prostate cancer. The diagnostic field of use has been licensed to Gen-Probe, Inc., who has sublicensed certain rights to Ventana Medical Systems. S.A.T. is a consultant for and has received honoraria from Ventana Medical Systems, Almac Diagnostics, Astellas/Medivation, Janssen and Sanofi, and has had research sponsored by Astellas/Medivation and GenomeDX. S.A.T. is a co-founder of, consultant for, and the Laboratory Director of Strata Oncology.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep. 1966;50(3):125–8.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016;40(2):244–52.Google Scholar
  4. 4.
    Epstein JI, Amin MB, Reuter VE, Humphrey PA. Contemporary Gleason grading of prostatic carcinoma: an update with discussion on practical issues to implement the 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol. 2017;41(4):e1–7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Epstein JI, Zelefsky MJ, Sjoberg DD, et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol. 2016;69(3):428–35.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Pettersson A, Graff RE, Bauer SR, et al. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2012;21(9):1497–509.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Tomlins SA, Laxman B, Dhanasekaran SM, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007;448(7153):595–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science (New York, NY). 2005;310(5748):644–8.CrossRefGoogle Scholar
  9. 9.
    Tomlins SA, Bjartell A, Chinnaiyan AM, et al. ETS gene fusions in prostate cancer: from discovery to daily clinical practice. Eur Urol. 2009;56(2):275–86.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yoshimoto M, Joshua AM, Chilton-Macneill S, et al. Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement. Neoplasia. 2006;8(6):465–9.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Braun M, Goltz D, Shaikhibrahim Z, et al. ERG protein expression and genomic rearrangement status in primary and metastatic prostate cancer–a comparative study of two monoclonal antibodies. Prostate Cancer Prostatic Dis. 2012;15(2):165–9.CrossRefGoogle Scholar
  12. 12.
    Furusato B, Tan SH, Young D, et al. ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. Prostate Cancer Prostatic Dis. 2010;13(3):228–37.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Park K, Tomlins SA, Mudaliar KM, et al. Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia. 2010;12(7):590–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    van Leenders GJ, Boormans JL, Vissers CJ, et al. Antibody EPR3864 is specific for ERG genomic fusions in prostate cancer: implications for pathological practice. Mod Pathol. 2011;24(8):1128–38.CrossRefGoogle Scholar
  15. 15.
    Minner S, Enodien M, Sirma H, et al. ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin Cancer Res. 2011;17(18):5878–88.CrossRefGoogle Scholar
  16. 16.
    Young A, Palanisamy N, Siddiqui J, et al. Correlation of urine TMPRSS2:ERG and PCA3 to ERG+ and total prostate cancer burden. Am J Clin Pathol. 2012;138(5):685–96.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Shah RB, Tadros Y, Brummell B, Zhou M. The diagnostic use of ERG in resolving an “atypical glands suspicious for cancer” diagnosis in prostate biopsies beyond that provided by basal cell and alpha-methylacyl-CoA-racemase markers. Hum Pathol. 2013;44(5):786–94.CrossRefGoogle Scholar
  18. 18.
    Epstein JI, Egevad L, Humphrey PA, Montironi R. Best practices recommendations in the application of immunohistochemistry in the prostate: report from the international society of urologic pathology consensus conference. Am J Surg Pathol. 2014;38(8):e6–e19.CrossRefGoogle Scholar
  19. 19.
    Park K, Dalton JT, Narayanan R, et al. TMPRSS2:ERG gene fusion predicts subsequent detection of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. J Clin Oncol. 2014;32(3):206–11.CrossRefGoogle Scholar
  20. 20.
    Grupp K, Diebel F, Sirma H, et al. SPINK1 expression is tightly linked to 6q15- and 5q21-deleted ERG-fusion negative prostate cancers but unrelated to PSA recurrence. Prostate. 2013;73(15):1690–8.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Tomlins SA, Rhodes DR, Yu J, et al. The role of SPINK1 in ETS rearrangement-negative prostate cancers. Cancer Cell. 2008;13(6):519–28.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Smith SC, Tomlins SA. Prostate cancer SubtyPINg biomarKers and outcome: is clarity emERGing? Clin Cancer Res. 2014;20(18):4733–6.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Bhalla R, Kunju LP, Tomlins SA, et al. Novel dual-color immunohistochemical methods for detecting ERG-PTEN and ERG-SPINK1 status in prostate carcinoma. Mod Pathol. 2013;26(6):835–48.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fontugne J, Davis K, Palanisamy N, et al. Clonal evaluation of prostate cancer foci in biopsies with discontinuous tumor involvement by dual ERG/SPINK1 immunohistochemistry. Mod Pathol. 2016;29(2):157–65.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011–25.CrossRefGoogle Scholar
  26. 26.
    Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44(6):685–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487(7406):239–43.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhang P, Wang D, Zhao Y, et al. Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nat Med. 2017;23(9):1055–62.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Dai X, Gan W, Li X, et al. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat Med. 2017;23(9):1063–71.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Janouskova H, El Tekle G, Bellini E, et al. Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. Nat Med. 2017;23(9):1046–54.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Palanisamy N, Ateeq B, Kalyana-Sundaram S, et al. Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med. 2010;16(7):793–8.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wang XS, Shankar S, Dhanasekaran SM, et al. Characterization of KRAS rearrangements in metastatic prostate cancer. Cancer Discov. 2011;1(1):35–43.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3(6):636–47.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Beltran H, Yelensky R, Frampton GM, et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol. 2013;63(5):920–6.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Shen Y, Lu Y, Yin X, Zhu G, Zhu J. KRAS and BRAF mutations in prostate carcinomas of Chinese patients. Cancer Genet Cytogenet. 2010;198(1):35–9.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ren G, Liu X, Mao X, et al. Identification of frequent BRAF copy number gain and alterations of RAF genes in Chinese prostate cancer. Genes Chromosomes Cancer. 2012;51(11):1014–23.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–28.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Qian J, Jenkins RB, Bostwick DG. Detection of chromosomal anomalies and c-myc gene amplification in the cribriform pattern of prostatic intraepithelial neoplasia and carcinoma by fluorescence in situ hybridization. Mod Pathol. 1997;10(11):1113–9.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Lotan TL, Carvalho FL, Peskoe SB, et al. PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod Pathol. 2015;28(1):128–37.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lotan TL, Wei W, Ludkovski O, et al. Analytic validation of a clinical-grade PTEN immunohistochemistry assay in prostate cancer by comparison with PTEN FISH. Mod Pathol. 2016;29(8):904–14.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Lotan TL, Wei W, Morais CL, et al. PTEN loss as determined by clinical-grade immunohistochemistry assay is associated with worse recurrence-free survival in prostate cancer. Eur Urol Focus. 2016;2(2):180–8.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Krohn A, Diedler T, Burkhardt L, et al. Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. Am J Pathol. 2012;181(2):401–12.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Chaux A, Peskoe SB, Gonzalez-Roibon N, et al. Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer. Mod Pathol. 2012;25(11):1543–9.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Tosoian JJ, Almutairi F, Morais CL, et al. Prevalence and prognostic significance of PTEN loss in African-American and European-American men undergoing radical prostatectomy. Eur Urol. 2017;71(5):697–700.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Guedes LB, Tosoian JJ, Hicks J, Ross AE, Lotan TL. PTEN loss in Gleason score 3 + 4 = 7 prostate biopsies is associated with nonorgan confined disease at radical prostatectomy. J Urol. 2017;197(4):1054–9.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Suzuki H, Freije D, Nusskern DR, et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res. 1998;58(2):204–9.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69(7):2912–8.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sowalsky AG, Ye H, Bubley GJ, Balk SP. Clonal progression of prostate cancers from Gleason grade 3 to grade 4. Cancer Res. 2013;73(3):1050–5.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kattan MW. Judging new markers by their ability to improve predictive accuracy. J Natl Cancer Inst. 2003;95(9):634–5.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Lennartz M, Minner S, Brasch S, et al. The combination of DNA ploidy status and PTEN/6q15 deletions provides strong and independent prognostic information in prostate cancer. Clin Cancer Res. 2016;22(11):2802–11.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Gudmundsson J, Besenbacher S, Sulem P, et al. Genetic correction of PSA values using sequence variants associated with PSA levels. Sci Transl Med. 2010;2(62):62ra92.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Benafif S, Eeles R. Genetic predisposition to prostate cancer. Br Med Bull. 2016;120(1):75–89.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ewing CM, Ray AM, Lange EM, et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med. 2012;366(2):141–9.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Gudmundsson J, Sulem P, Gudbjartsson DF, et al. A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet. 2012;44(12):1326–9.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443–53.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Penney KL, Sinnott JA, Fall K, et al. mRNA expression signature of Gleason grade predicts lethal prostate cancer. J Clin Oncol. 2011;29(17):2391–6.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Cuzick J, Berney DM, Fisher G, et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer. 2012;106(6):1095–9.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Cuzick J, Swanson GP, Fisher G, et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol. 2011;12(3):245–55.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol. 2014;66(3):550–60.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Karnes RJ, Bergstralh EJ, Davicioni E, et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol. 2013;190(6):2047–53.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Klein EA, Haddad Z, Yousefi K, et al. Decipher genomic classifier measured on prostate biopsy predicts metastasis risk. Urology. 2016;90:148–52.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Knudsen BS, Kim HL, Erho N, et al. Application of a clinical whole-transcriptome assay for staging and prognosis of prostate cancer diagnosed in needle core biopsy specimens. J Mol Diagn. 2016;18(3):395–406.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Saad F, Latour M, Lattouf JB, et al. Biopsy based proteomic assay predicts risk of biochemical recurrence after radical prostatectomy. J Urol. 2017;197(4):1034–40.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Fraser M, Sabelnykova VY, Yamaguchi TN, et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature. 2017;541(7637):359–64.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Baca SC, Prandi D, Lawrence MS, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153(3):666–77.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Berger MF, Lawrence MS, Demichelis F, et al. The genomic complexity of primary human prostate cancer. Nature. 2011;470(7333):214–20.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Kumar A, Coleman I, Morrissey C, et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 2016;22(4):369–78.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Hovelson DH, McDaniel AS, Cani AK, et al. Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors. Neoplasia. 2015;17(4):385–99.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Kron KJ, Murison A, Zhou S, et al. TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer. Nat Genet. 2017;49(9):1336–45.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Chua MLK, Lo W, Pintilie M, et al. A prostate cancer “nimbosus”: genomic instability and SChLAP1 dysregulation underpin aggression of intraductal and cribriform subpathologies. Eur Urol. 2017;72(5):665–74.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Mehra R, Shi Y, Udager AM, et al. A novel RNA in situ hybridization assay for the long noncoding RNA SChLAP1 predicts poor clinical outcome after radical prostatectomy in clinically localized prostate cancer. Neoplasia. 2014;16(12):1121–7.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Mehra R, Udager AM, Ahearn TU, et al. Overexpression of the long non-coding RNA SChLAP1 independently predicts lethal prostate cancer. Eur Urol. 2016;70(4):549–52.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Bottcher R, Hoogland AM, Dits N, et al. Novel long non-coding RNAs are specific diagnostic and prognostic markers for prostate cancer. Oncotarget. 2015;6(6):4036–50.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Prensner JR, Iyer MK, Sahu A, et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013;45(11):1392–8.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Prensner JR, Zhao S, Erho N, et al. RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1. Lancet Oncol. 2014;15(13):1469–80.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Prensner JR, Iyer MK, Balbin OA, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol. 2011;29(8):742–9.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Nelson PS. Targeting the androgen receptor in prostate cancer–a resilient foe. N Engl J Med. 2014;371(11):1067–9.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Abida W, Armenia J, Gopalan A, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precision Oncology. 2017;1:1–16.CrossRefGoogle Scholar
  79. 79.
    Robinson DR, Wu YM, Lonigro RJ, et al. Integrative clinical genomics of metastatic cancer. Nature. 2017;548(7667):297–303.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697–708.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023–31.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Ito K, Miyakubo M, Sekine Y, et al. Diagnostic significance of [−2]pro-PSA and prostate dimension-adjusted PSA-related indices in men with total PSA in the 2.0–10.0 ng/mL range. World J Urol. 2013;31(2):305–11.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Chan TY, Mikolajczyk SD, Lecksell K, et al. Immunohistochemical staining of prostate cancer with monoclonal antibodies to the precursor of prostate-specific antigen. Urology. 2003;62(1):177–81.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Vickers A, Cronin A, Roobol M, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol. 2010;28(15):2493–8.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Salagierski M, Schalken JA. Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2:ERG gene fusion. J Urol. 2012;187(3):795–801.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Hessels D, Klein Gunnewiek JM, van Oort I, et al. DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol. 2003;44(1):8–15; discussion 15–16.CrossRefGoogle Scholar
  87. 87.
    Ankerst DP, Groskopf J, Day JR, et al. Predicting prostate cancer risk through incorporation of prostate cancer gene 3. J Urol. 2008;180(4):1303–8; discussion 1308.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Sanda MG, Feng Z, Howard DH, et al. Association between combined TMPRSS2:ERG and PCA3 RNA urinary testing and detection of aggressive prostate cancer. JAMA Oncol. 2017;3(8):1085–93.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Tomlins SA, Day JR, Lonigro RJ, et al. Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol. 2016;70(1):45–53.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Wei JT, Feng Z, Partin AW, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol. 2014;32(36):4066–72.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Cornu JN, Cancel-Tassin G, Egrot C, Gaffory C, Haab F, Cussenot O. Urine TMPRSS2:ERG fusion transcript integrated with PCA3 score, genotyping, and biological features are correlated to the results of prostatic biopsies in men at risk of prostate cancer. Prostate. 2012;73(3):242–9.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Leyten GH, Hessels D, Jannink SA, et al. Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. Eur Urol. 2014;65(3):534–42.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Stephan C, Jung K, Semjonow A, et al. Comparative assessment of urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion with the serum [−2]proprostate-specific antigen-based prostate health index for detection of prostate cancer. Clin Chem. 2013;59(1):280–8.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Van Neste L, Hendriks RJ, Dijkstra S, et al. Detection of high-grade prostate cancer using a urinary molecular biomarker-based risk score. Eur Urol. 2016;70(5):740–8.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Leyten GH, Hessels D, Smit FP, et al. Identification of a candidate gene panel for the early diagnosis of prostate cancer. Clin Cancer Res. 2015;21(13):3061–70.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    McKiernan J, Donovan MJ, O’Neill V, et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol. 2016;2(7):882–9.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Scher HI, Jia X, de Bono JS, et al. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol. 2009;10(3):233–9.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Danila DC. Circulating tumors cells as biomarkers: progress toward biomarker qualification. Cancer J (Sudbury, Mass). 2011;17(6):438–50.CrossRefGoogle Scholar
  99. 99.
    Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Heller G, Fizazi K, McCormack R, et al. The added value of circulating tumor cell enumeration to standard markers in assessing prognosis in a metastatic castration-resistant prostate cancer population. Clin Cancer Res. 2017;23(8):1967–73.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Scher HI, Lu D, Schreiber NA, et al. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol. 2016;2(11):1441–9.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Wyatt AW, Azad AA, Volik SV, et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2016;2(12):1598–606.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Salvi S, Casadio V, Conteduca V, et al. Circulating AR copy number and outcome to enzalutamide in docetaxel-treated metastatic castration-resistant prostate cancer. Oncotarget. 2016;7(25):37839–45.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Lallous N, Volik SV, Awrey S, et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. Genome Biol. 2016;17:10.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Carreira S, Romanel A, Goodall J, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6(254):254ra125.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Romanel A, Gasi Tandefelt D, Conteduca V, et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015;7(312):312re310.CrossRefGoogle Scholar
  107. 107.
    Wyatt AW, Annala M, Aggarwal R, et al. Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J Natl Cancer Inst (JNCI). 2017;109(12):djx118-djx118.Google Scholar
  108. 108.
    Quigley D, Alumkal JJ, Wyatt AW, et al. Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer Discov. 2017;7:999.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Goodall J, Mateo J, Yuan W, et al. Circulating free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discov. 2017;7(9):1006–17.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Castillo-Martin M, Domingo-Domenech J, Karni-Schmidt O, Matos T, Cordon-Cardo C. Molecular pathways of urothelial development and bladder tumorigenesis. Urol Oncol. 2010;28(4):401–8.CrossRefGoogle Scholar
  111. 111.
    Netto GJ. Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? Nat Rev Urol. 2012;9(1):41–51.CrossRefGoogle Scholar
  112. 112.
    Burger M, van der Aa MN, van Oers JM, et al. Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol. 2008;54(4):835–43.CrossRefGoogle Scholar
  113. 113.
    Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet. 2013;22(4):795–803.CrossRefGoogle Scholar
  114. 114.
    Guo G, Sun X, Chen C, et al. Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet. 2013;45(12):1459–63.CrossRefGoogle Scholar
  115. 115.
    Ross JS, Wang K, Khaira D, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer. 2016;122(5):702–11.CrossRefGoogle Scholar
  116. 116.
    Goebell PJ, Groshen SG, Schmitz-Drager BJ. International study-initiative on bladder C. p53 immunohistochemistry in bladder cancer–a new approach to an old question. Urol Oncol. 2010;28(4):377–88.CrossRefGoogle Scholar
  117. 117.
    van Rhijn BW, Zuiverloon TC, Vis AN, et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. Eur Urol. 2010;58(3):433–41.CrossRefGoogle Scholar
  118. 118.
    George B, Datar RH, Wu L, et al. p53 gene and protein status: the role of p53 alterations in predicting outcome in patients with bladder cancer. J Clin Oncol. 2007;25(34):5352–8.CrossRefGoogle Scholar
  119. 119.
    Margulis V, Lotan Y, Karakiewicz PI, et al. Multi-institutional validation of the predictive value of Ki-67 labeling index in patients with urinary bladder cancer. J Natl Cancer Inst. 2009;101(2):114–9.CrossRefGoogle Scholar
  120. 120.
    Lindgren D, Liedberg F, Andersson A, et al. Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q. Oncogene. 2006;25(18):2685–96.CrossRefGoogle Scholar
  121. 121.
    Lindgren D, Frigyesi A, Gudjonsson S, et al. Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res. 2010;70(9):3463–72.CrossRefGoogle Scholar
  122. 122.
    Cancer Genome Atlas Research N. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–22.CrossRefGoogle Scholar
  123. 123.
    Robertson AG, Kim J, Al-Ahmadie H, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–556.e25.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Hedegaard J, Lamy P, Nordentoft I, et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell. 2016;30(1):27–42.CrossRefGoogle Scholar
  125. 125.
    Choi W, Porten S, Kim S, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25(2):152–65.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    McConkey DJ, Choi W, Shen Y, et al. A prognostic gene expression signature in the molecular classification of chemotherapy-naive urothelial Cancer is predictive of clinical outcomes from neoadjuvant chemotherapy: a phase 2 trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with bevacizumab in urothelial Cancer. Eur Urol. 2016;69(5):855–62.CrossRefGoogle Scholar
  127. 127.
    Mitra AP, Lam LL, Ghadessi M, et al. Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer. J Natl Cancer Inst. 2014;106(11).Google Scholar
  128. 128.
    Damrauer JS, Hoadley KA, Chism DD, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A. 2014;111(8):3110–5.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Seiler R, Ashab HA, Erho N, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol. 2017;72(4):544–54.CrossRefGoogle Scholar
  130. 130.
    Lee JK, Havaleshko DM, Cho H, et al. A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. Proc Natl Acad Sci U S A. 2007;104(32):13086–91.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Smith SC, Baras AS, Lee JK, Theodorescu D. The COXEN principle: translating signatures of in vitro chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer. Cancer Res. 2010;70(5):1753–8.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Gui Y, Guo G, Huang Y, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet. 2011;43(9):875–8.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science (New York, NY). 2012;338(6104):221.CrossRefGoogle Scholar
  134. 134.
    Rebouissou S, Bernard-Pierrot I, de Reynies A, et al. EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype. Sci Transl Med. 2014;6(244):244ra291.CrossRefGoogle Scholar
  135. 135.
    Hussain M, Daignault S, Agarwal N, et al. A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma. Cancer. 2014;120(17):2684–93.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Hussain MH, MacVicar GR, Petrylak DP, et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol. 2007;25(16):2218–24.CrossRefGoogle Scholar
  137. 137.
    Powles T, Huddart RA, Elliott T, et al. Phase III, double-blind, randomized trial that compared maintenance Lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J Clin Oncol. 2017;35(1):48–55.CrossRefGoogle Scholar
  138. 138.
    Sokolova IA, Halling KC, Jenkins RB, et al. The development of a multitarget, multicolor fluorescence in situ hybridization assay for the detection of urothelial carcinoma in urine. J Mol Diagn. 2000;2(3):116–23.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Halling KC, King W, Sokolova IA, et al. A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J Urol. 2000;164(5):1768–75.CrossRefGoogle Scholar
  140. 140.
    Li HX, Wang MR, Zhao H, Cao J, Li CL, Pan QJ. Comparison of fluorescence in situ hybridization, NMP22 bladderchek, and urinary liquid-based cytology in the detection of bladder urothelial carcinoma. Diagn Cytopathol. 2013;41(10):852–7.PubMedGoogle Scholar
  141. 141.
    Bubendorf L, Grilli B, Sauter G, Mihatsch MJ, Gasser TC, Dalquen P. Multiprobe FISH for enhanced detection of bladder cancer in voided urine specimens and bladder washings. Am J Clin Pathol. 2001;116(1):79–86.CrossRefGoogle Scholar
  142. 142.
    Sarosdy MF, Kahn PR, Ziffer MD, et al. Use of a multitarget fluorescence in situ hybridization assay to diagnose bladder cancer in patients with hematuria. J Urol. 2006;176(1):44–7.CrossRefGoogle Scholar
  143. 143.
    Ward DG, Bryan RT. Liquid biopsies for bladder cancer. Transl Androl Urol. 2017;6(2):331–5.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Scott SN, Ostrovnaya I, Lin CM, et al. Next-generation sequencing of urine specimens: a novel platform for genomic analysis in patients with non-muscle-invasive urothelial carcinoma treated with bacille Calmette-Guerin. Cancer. 2017;125(6):416–26.PubMedCentralPubMedGoogle Scholar
  145. 145.
    Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Gupta S, Gill D, Poole A, Agarwal N. Systemic immunotherapy for urothelial cancer: current trends and future directions. Cancers (Basel). 2017;9(2):15.Google Scholar
  147. 147.
    Cancer Genome Atlas Research N, Linehan WM, Spellman PT, et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374(2):135–45.CrossRefGoogle Scholar
  148. 148.
    Davis CF, Ricketts CJ, Wang M, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell. 2014;26(3):319–30.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Cancer Genome Atlas Research N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–9.CrossRefGoogle Scholar
  150. 150.
    Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008;14(15):4726–34.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Zbar B, Brauch H, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature. 1987;327(6124):721–4.CrossRefGoogle Scholar
  152. 152.
    Stillebroer AB, Mulders PF, Boerman OC, Oyen WJ, Oosterwijk E. Carbonic anhydrase IX in renal cell carcinoma: implications for prognosis, diagnosis, and therapy. Eur Urol. 2010;58(1):75–83.CrossRefGoogle Scholar
  153. 153.
    Barocas DA, Mathew S, DelPizzo JJ, et al. Renal cell carcinoma sub-typing by histopathology and fluorescence in situ hybridization on a needle-biopsy specimen. BJU Int. 2007;99(2):290–5.CrossRefGoogle Scholar
  154. 154.
    Hakimi AA, Tickoo SK, Jacobsen A, et al. TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype. Mod Pathol. 2015;28(6):845–53.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Varela I, Tarpey P, Raine K, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011;469(7331):539–42.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Nguyen KA, Syed JS, Espenschied CR, et al. Advances in the diagnosis of hereditary kidney cancer: initial results of a multigene panel test. Cancer. 2017;123:4363.CrossRefGoogle Scholar
  157. 157.
    Schmidt LS, Linehan WM. Genetic predisposition to kidney cancer. Semin Oncol. 2016;43(5):566–74.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007;31(10):1578–85.CrossRefGoogle Scholar
  159. 159.
    Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16(1):68–73.CrossRefGoogle Scholar
  160. 160.
    Shuch B, Hahn AW, Agarwal N. Current treatment landscape of advanced papillary renal cancer. J Clin Oncol. 2017;35(26):2981–3. JCO2017743328.CrossRefGoogle Scholar
  161. 161.
    Argani P, Hawkins A, Griffin CA, et al. A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21.1;q12) chromosome translocation. Am J Pathol. 2001;158(6):2089–96.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001;159(1):179–92.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Green WM, Yonescu R, Morsberger L, et al. Utilization of a TFE3 break-apart FISH assay in a renal tumor consultation service. Am J Surg Pathol. 2013;37(8):1150–63.CrossRefGoogle Scholar
  164. 164.
    Rao Q, Williamson SR, Zhang S, et al. TFE3 break-apart FISH has a higher sensitivity for Xp11.2 translocation-associated renal cell carcinoma compared with TFE3 or cathepsin K immunohistochemical staining alone: expanding the morphologic spectrum. Am J Surg Pathol. 2013;37(6):804–15.CrossRefGoogle Scholar
  165. 165.
    Mosquera JM, Dal Cin P, Mertz KD, et al. Validation of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinomas. Diagn Mol Pathol. 2011;20(3):129–37.CrossRefGoogle Scholar
  166. 166.
    Skala SL, Xiao H, Udager AM, et al. Detection of 6 TFEB-amplified renal cell carcinomas and 25 renal cell carcinomas with MITF translocations: systematic morphologic analysis of 85 cases evaluated by clinical TFE3 and TFEB FISH assays. Mod Pathol. 2017;31(1):179–97.CrossRefGoogle Scholar
  167. 167.
    Zhong M, De Angelo P, Osborne L, et al. Dual-color, break-apart FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of Xp11 translocation renal cell carcinoma and alveolar soft part sarcoma. Am J Surg Pathol. 2010;34(6):757–66.CrossRefGoogle Scholar
  168. 168.
    Williamson SR, Grignon DJ, Cheng L, et al. Renal cell carcinoma with chromosome 6p amplification including the TFEB gene: a novel mechanism of tumor pathogenesis? Am J Surg Pathol. 2017;41(3):287–98.CrossRefGoogle Scholar
  169. 169.
    Argani P, Reuter VE, Zhang L, et al. TFEB-amplified renal cell carcinomas: an aggressive molecular subset demonstrating variable melanocytic marker expression and morphologic heterogeneity. Am J Surg Pathol. 2016;40(11):1484–95.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Sato Y, Yoshizato T, Shiraishi Y, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013;45(8):860–7.CrossRefGoogle Scholar
  171. 171.
    Dalgliesh GL, Furge K, Greenman C, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010;463(7279):360–3.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    van Haaften G, Dalgliesh GL, Davies H, et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet. 2009;41(5):521–3.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Chen YB, Xu J, Skanderup AJ, et al. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nat Commun. 2016;7:13131.CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Guo G, Gui Y, Gao S, et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet. 2011;44(1):17–9.CrossRefGoogle Scholar
  175. 175.
    Posadas EM, Limvorasak S, Figlin RA. Targeted therapies for renal cell carcinoma. Nat Rev Nephrol. 2017;13(8):496–511.CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Winer AG, Motzer RJ, Hakimi AA. Prognostic biomarkers for response to vascular endothelial growth factor-targeted therapy for renal cell carcinoma. Urol Clin North Am. 2016;43(1):95–104.CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008;26(1):127–31.CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–56.CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917–27.CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814–23.CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13.CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Wiecek W, Karcher H. Nivolumab versus Cabozantinib: comparing overall survival in metastatic renal cell carcinoma. PLoS One. 2016;11(6):e0155389.CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus Sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591–7.CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Turajlic S, Litchfield K, Xu H, et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 2017;18(8):1009–21.CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Looijenga LH, Stoop H, de Leeuw HP, et al. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 2003;63(9):2244–50.PubMedPubMedCentralGoogle Scholar
  186. 186.
    Ulbright TM, Tickoo SK, Berney DM, Srigley JR. Members of the IIiDUPG. Best practices recommendations in the application of immunohistochemistry in testicular tumors: report from the International Society of Urological Pathology consensus conference. Am J Surg Pathol. 2014;38(8):e50–9.CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Bosl GJ, Dmitrovsky E, Reuter VE, et al. Isochromosome of the short arm of chromosome 12: clinically useful markers for male germ cell tumors. J Natl Cancer Inst. 1989;81(24):1874–8.CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    di Pietro A, Vries EG, Gietema JA, Spierings DC, de Jong S. Testicular germ cell tumours: the paradigm of chemo-sensitive solid tumours. Int J Biochem Cell Biol. 2005;37(12):2437–56.CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Lutzker SG, Mathew R, Taller DR. A p53 dose-response relationship for sensitivity to DNA damage in isogenic teratocarcinoma cells. Oncogene. 2001;20(23):2982–6.CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Taylor-Weiner A, Zack T, O’Donnell E, et al. Genomic evolution and chemoresistance in germ-cell tumours. Nature. 2016;540(7631):114–8.CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Honecker F, Wermann H, Mayer F, et al. Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors. J Clin Oncol. 2009;27(13):2129–36.CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Bethune G, Campbell J, Rocker A, Bell D, Rendon R, Merrimen J. Clinical and pathologic factors of prognostic significance in penile squamous cell carcinoma in a North American population. Urology. 2012;79(5):1092–7.CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    McDaniel AS, Hovelson DH, Cani AK, et al. Genomic profiling of penile squamous cell carcinoma reveals new opportunities for targeted therapy. Cancer Res. 2015;75(24):5219–27.CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Chaux A, Reuter V, Lezcano C, Velazquez EF, Torres J, Cubilla AL. Comparison of morphologic features and outcome of resected recurrent and nonrecurrent squamous cell carcinoma of the penis: a study of 81 cases. Am J Surg Pathol. 2009;33(9):1299–306.CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Ali SM, Pal SK, Wang K, et al. Comprehensive genomic profiling of advanced penile carcinoma suggests a high frequency of clinically relevant genomic alterations. Oncologist. 2016;21(1):33–9.CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Hoadley KA, Yau C, Wolf DM, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014;158(4):929–44.CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Udager AM, Liu TY, Skala SL, et al. Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. Ann Oncol. 2016;27(9):1706–12.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Martin J. Magers
    • 1
    • 2
  • Joshua I. Warrick
    • 3
  • Scott A. Tomlins
    • 4
    • 5
    • 6
    Email author
  1. 1.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of PathologyIndiana University School of MedicineIndianapolisUSA
  3. 3.Departments of Pathology and SurgeryPenn State College of MedicineHersheyUSA
  4. 4.Departments of Pathology and UrologyUniversity of Michigan Medical SchoolAnn ArborUSA
  5. 5.Michigan Center for Translational PathologyUniversity of Michigan Medical SchoolAnn ArborUSA
  6. 6.Rogel Comprehensive Cancer CenterUniversity of Michigan Medical SchoolAnn ArborUSA

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