Der Urologe

, Volume 53, Issue 4, pp 491–500

Prognostische und prädiktive molekulare Marker urologischer Tumoren

  • A. Hartmann
  • T. Schlomm
  • S. Bertz
  • J. Heinzelmann
  • S. Hölters
  • R. Simon
  • R. Stoehr
  • K. Junker
Leitthema

Zusammenfassung

Molekulare Prognosefaktoren und genetische Veränderungen als prädiktive Marker für die Wirksamkeit spezifischer Target-Therapien sind bei vielen malignen Tumoren in den klinischen Alltag eingezogen. Bei urologischen Tumoren wurden zwar in den letzten Jahren zahlreiche molekulare Marker identifiziert. Diese werden heute jedoch noch nicht in der Klinik genutzt. Beim Prostatakarzinom haben moderne Sequenzierverfahren ein immer differenzierteres Bild der molekularen Grundlagen geliefert. Es zeichnet sich ab, dass durch die Kombination klassischer histologischer und validierter molekularer Marker Verbesserungen in der Prognoseabschätzung zu erwarten sind, die zukünftig für mehr Patienten eine „Active Surveillance“ als realistische Therapieoption erscheinen lassen. Beim Urothelkarzinom sind neben klassischen histopathologischen Faktoren v. a. die Proliferation des Tumors, der Mutationsstatus für proliferationsfördernde Onkogene und Veränderungen in Genen, die zur Invasion und Metastasierung führen, von wesentlicher Bedeutung. Zusätzlich konnten Genexpressionsprofile identifiziert werden, die aggressive, metastasierende von nicht-metastasierenden Tumoren unterscheidet und somit in Zukunft Patienten selektieren könnten, die eine systemische perioperative Therapie benötigen. Für die Nierenzellkarzinome wurden eine ganze Reihe molekularer Marker identifiziert, die eine Korrelation mit der Prognose im Sinne der Metastasierung und dem Überleben der Patienten zeigen. Ein Teil dieser Marker konnte auch als unabhängige Prognoseparameter bestätigt werden. In Zukunft scheint damit eine Selektion von Patienten, die ein erhöhtes Metastasierungsrisiko bei primär organbegrenzten Tumoren haben und einer adjuvanten systemischen Therapie zugeführt werden sollten, möglich.

Schlüsselwörter

Prostatakarzinom Harnblasenkarzinom Nierenzellkarzinom Molekulare Prognosefaktoren Molekulare prädiktive Faktoren 

Prognostic and predictive molecular markers for urologic cancers

Abstract

Molecular prognostic factors and genetic alterations as predictive markers for cancer-specific targeted therapies are used today in the clinic for many malignancies. In recent years, many molecular markers for urogenital cancers have also been identified. However, these markers are not clinically used yet. In prostate cancer, novel next-generation sequencing methods revealed a detailed picture of the molecular changes. There is growing evidence that a combination of classical histopathological and validated molecular markers could lead to a more precise estimation of prognosis, thus, resulting in an increasing number of patients with active surveillance as a possible treatment option. In patients with urothelial carcinoma, histopathological factors but also the proliferation of the tumor, mutations in oncogenes leading to an increasing proliferation rate and changes in genes responsible for invasion and metastasis are important. In addition, gene expression profiles which could distinguish aggressive tumors with high risk of metastasis from nonmetastasizing tumors have been recently identified. In the future, this could potentially allow better selection of patients needing systemic perioperative treatment. In renal cell carcinoma, many molecular markers that are associated with metastasis and survival have been identified. Some of these markers were also validated as independent prognostic markers. Selection of patients with primarily organ-confined tumors and increased risk of metastasis for adjuvant systemic therapy could be clinically relevant in the future.

Keywords

Prostate cancer Bladder cancer Renal cell carcinoma Biological markers Prognosis 

Literatur

  1. 1.
    Alqurashi N, Hashimi SM, Wei MQ (2013) Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) pathway: potential for novel anticancer therapeutics. Int J Mol Sci 14:3874–3900PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Als AB, Dyrskjot L, Maase H von der et al (2007) Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer. Clin Cancer Res 13:4407–4414PubMedCrossRefGoogle Scholar
  3. 3.
    Balbas-Martinez C, Sagrera A, Carrillo-de-Santa-Pau E et al (2013) Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nat Genet 45:1464–1469PubMedCrossRefGoogle Scholar
  4. 4.
    Barbieri CE, Baca SC, Lawrence MS et al (2012) Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 44:685–689PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Berger MF, Lawrence MS, Demichelis F et al (2010) The genomic complexity of primary human prostate cancer. Nature 470:214–220CrossRefGoogle Scholar
  6. 6.
    Burger M, Aa MN van der, Oers JM van et al (2008) 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 54:835–843PubMedCrossRefGoogle Scholar
  7. 7.
    Burkhardt L, Fuchs S, Krohn A et al (2013) CHD1 Is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res 73:2795–2805PubMedCrossRefGoogle Scholar
  8. 8.
    Cancer Genome Atlas Research N (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:43–49CrossRefGoogle Scholar
  9. 9.
    Cho D, Signoretti S, Dabora S et al (2007) Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 5:379–385PubMedCrossRefGoogle Scholar
  10. 10.
    Choi W, Porten S, Kim S et al (2014) Identification of distinct Basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165PubMedCrossRefGoogle Scholar
  11. 11.
    Choudhury A, Nelson LD, Teo MT et al (2010) MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res 70:7017–7026PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Cuzick J, Berney DM, Fisher G et al (2012) Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer 106:1095–1099PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Damrauer JS, Hoadley KA, Chism DD et al (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A 111:3110–3115PubMedCrossRefGoogle Scholar
  14. 14.
    Martino E di, Tomlinson DC, Knowles MA (2012) A decade of FGF receptor research in bladder cancer: past, present, and future challenges. Adv Urol 2012:429213PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Dyrskjot L, Thykjaer T, Kruhoffer M et al (2003) Identifying distinct classes of bladder carcinoma using microarrays. Nat Genet 33:90–96PubMedCrossRefGoogle Scholar
  16. 16.
    Dyrskjot L, Zieger K, Real FX et al (2007) Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study. Clin Cancer Res 13:3545–3551PubMedCrossRefGoogle Scholar
  17. 17.
    Eichelberg C, Chun FK, Bedke J et al (2013) Epithelial cell adhesion molecule is an independent prognostic marker in clear cell renal carcinoma. Int J Cancer 132:2948–2955PubMedCrossRefGoogle Scholar
  18. 18.
    El Gammal AT, Bruchmann M, Zustin J et al (2010) Chromosome 8p deletions and 8q gains are associated with tumor progression and poor prognosis in prostate cancer. Clin Cancer Res 16:56–64CrossRefGoogle Scholar
  19. 19.
    Erbersdobler A, Isbarn H, Dix K et al (2009) Prognostic value of microvessel density in prostate cancer: a tissue microarray study. World J Urol 28: 687–692PubMedCrossRefGoogle Scholar
  20. 20.
    Fleischmann A, Schlomm T, Huland H et al (2008) Distinct subcellular expression patterns of neutral endopeptidase (CD10) in prostate cancer predict diverging clinical courses in surgically treated patients. Clin Cancer Res 14:7838–7842PubMedCrossRefGoogle Scholar
  21. 21.
    Fleischmann A, Schlomm T, Kollermann J et al (2009) Immunological microenvironment in prostate cancer: high mast cell densities are associated with favorable tumor characteristics and good prognosis. Prostate 69:976–981PubMedCrossRefGoogle Scholar
  22. 22.
    Garcia-Donas J, Esteban E, Leandro-Garcia LJ et al (2011) Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol 12:1143–1150PubMedCrossRefGoogle Scholar
  23. 23.
    Graefen M, Ahyai S, Heuer R et al (2008) Active surveillance for prostate cancer. Urologe A 47:261–269PubMedCrossRefGoogle Scholar
  24. 24.
    Grasso CS, Wu YM, Robinson DR et al (2012) The mutational landscape of lethal castration-resistant prostate cancer. Nature 487:239–243PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Guo G, Sun X, Chen C et al (2013) Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet 45:1459–1463PubMedCrossRefGoogle Scholar
  26. 26.
    Hakimi AA, Ostrovnaya I, Reva B et al (2013) Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res 19:3259–3267PubMedCrossRefGoogle Scholar
  27. 27.
    Hauser S, Wulfken LM, Holdenrieder S et al (2012) Analysis of serum microRNAs (miR-26a-2*, miR-191, miR-337-3p and miR-378) as potential biomarkers in renal cell carcinoma. Cancer Epidemiol 36:391–394PubMedCrossRefGoogle Scholar
  28. 28.
    Heinzelmann J, Henning B, Sanjmyatav J et al (2011) Specific miRNA signatures are associated with metastasis and poor prognosis in clear cell renal cell carcinoma. World J Urol 29:367–373PubMedCrossRefGoogle Scholar
  29. 29.
    Hildebrandt MA, Gu J, Lin J et al (2010) Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma. Oncogene 29:5724–5728PubMedCrossRefGoogle Scholar
  30. 30.
    Hoffmann AC, Wild P, Leicht C et al (2010) MDR1 and ERCC1 expression predict outcome of patients with locally advanced bladder cancer receiving adjuvant chemotherapy. Neoplasia 12:628–636PubMedCentralPubMedGoogle Scholar
  31. 31.
    Kapur P, Pena-Llopis S, Christie A et al (2013) Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 14:159–167PubMedCrossRefGoogle Scholar
  32. 32.
    Klatte T, Rao PN, Martino M de et al (2009) Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J Clin Oncol 27:746–753PubMedCrossRefGoogle Scholar
  33. 33.
    Klatte T, Seligson DB, LaRochelle J et al (2009) Molecular signatures of localized clear cell renal cell carcinoma to predict disease-free survival after nephrectomy. Cancer Epidemiol Biomarkers Prev 18:894–900PubMedCrossRefGoogle Scholar
  34. 34.
    Klein EA (2013) A genomic approach to active surveillance: a step toward precision medicine. Asian J Androl 15:340–341PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Kluth M, Harasimowicz S, Burkhardt L et al (2014) Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer. Int J Cancer (Epub ahead of print). doi: 10.1002/ijc.28784Google Scholar
  36. 36.
    Kluth M, Hesse J, Heinl A et al (2013) Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions. Mod Pathol 26:975–983PubMedCrossRefGoogle Scholar
  37. 37.
    Krohn A, Diedler T, Burkhardt L et al (2012) 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 181:401–412PubMedCrossRefGoogle Scholar
  38. 38.
    Laurberg JR, Brems-Eskildsen AS, Nordentoft I et al (2012) Expression of TIP60 (tat-interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment-specific outcome of localised invasive bladder cancer. BJU Int 110:1228–1236CrossRefGoogle Scholar
  39. 39.
    Lindgren D, Frigyesi A, Gudjonsson S et al (2010) Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res 70:3463–3472PubMedCrossRefGoogle Scholar
  40. 40.
    Minner S, De Silva C, Rink M et al (2012) Reduced CD151 expression is related to advanced tumour stage in urothelial bladder cancer. Pathology 44:448–452PubMedCrossRefGoogle Scholar
  41. 41.
    Minner S, Enodien M, Sirma H et al (2011) ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin Cancer Res 17:5878–5888PubMedCrossRefGoogle Scholar
  42. 42.
    Minner S, Jessen B, Stiedenroth L et al (2010) Low level HER2 overexpression is associated with rapid tumor cell proliferation and poor prognosis in prostate cancer. Clin Cancer Res 16:1553–1560PubMedCrossRefGoogle Scholar
  43. 43.
    Minner S, Wittmer C, Graefen M et al (2011) High level PSMA expression is associated with early PSA recurrence in surgically treated prostate cancer. Prostate 71:281–288PubMedCrossRefGoogle Scholar
  44. 44.
    Monzon FA, Alvarez K, Peterson L et al (2011) Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis. Mod Pathol 24:1470–1479PubMedCrossRefGoogle Scholar
  45. 45.
    Muller J, Ehlers A, Burkhardt L et al (2012) Loss of p(Ser2448) -mTOR expression is linked to adverse prognosis and tumor progression in ERG-fusion-positive cancers. Int J Cancer 132:1333–1340PubMedCrossRefGoogle Scholar
  46. 46.
    Nishikawa M, Miyake H, Harada K et al (2014) Expression level of phosphorylated-4E-binding protein 1 in radical nephrectomy specimens as a prognostic predictor in patients with metastatic renal cell carcinoma treated with mammalian target of rapamycin inhibitors. Med Oncol 31:792PubMedCrossRefGoogle Scholar
  47. 47.
    Nordentoft I, Dyrskjot L, Bodker JS et al (2011) Increased expression of transcription factor TFAP2alpha correlates with chemosensitivity in advanced bladder cancer. BMC Cancer 11:135PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Parker AS, Leibovich BC, Lohse CM et al (2009) Development and evaluation of BioScore: a biomarker panel to enhance prognostic algorithms for clear cell renal cell carcinoma. Cancer 115:2092–2103PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Prior C, Perez-Gracia JL, Garcia-Donas J et al (2014) Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma. PloS One 9:86263CrossRefGoogle Scholar
  50. 50.
    Redova M, Poprach A, Nekvindova J et al (2012) Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J Transl Med 10:55PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Sakr WA, Grignon DJ, Crissman JD et al (1994) High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20–69: an autopsy study of 249 cases. In Vivo 8:439–443PubMedGoogle Scholar
  52. 52.
    Sanjmyatav J, Junker K, Matthes S et al (2011) Identification of genomic alterations associated with metastasis and cancer specific survival in clear cell renal cell carcinoma. J Urol 186:2078–2083PubMedCrossRefGoogle Scholar
  53. 53.
    Sato Y, Yoshizato T, Shiraishi Y et al (2013) Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 45:860–867PubMedCrossRefGoogle Scholar
  54. 54.
    Schlomm T, Erbersdobler A, Mirlacher M et al (2007) Molecular staging of prostate cancer in the year 2007. World J Urol 25:19–30PubMedCrossRefGoogle Scholar
  55. 55.
    Schlomm T, Iwers L, Kirstein P et al (2008) Clinical significance of p53 alterations in surgically treated prostate cancers. Mod Pathol 21:1371–1379PubMedCrossRefGoogle Scholar
  56. 56.
    Schlomm T, Kirstein P, Iwers L et al (2007) Clinical significance of epidermal growth factor receptor protein overexpression and gene copy number gains in prostate cancer. Clin Cancer Res 13:6579–6584PubMedCrossRefGoogle Scholar
  57. 57.
    Sjodahl G, Lovgren K, Lauss M et al (2013) Toward a molecular pathologic classification of urothelial carcinoma. Am J Pathol 183:681–691PubMedCrossRefGoogle Scholar
  58. 58.
    Slaby O, Redova M, Poprach A et al (2012) Identification of MicroRNAs associated with early relapse after nephrectomy in renal cell carcinoma patients. Genes Chromosomes Cancer 51:707–716PubMedCrossRefGoogle Scholar
  59. 59.
    Smith SC, Baras AS, Dancik G et al (2011) A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol 12:137–143PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Teixeira AL, Ferreira M, Silva J et al (2013) Higher circulating expression levels of miR-221 associated with poor overall survival in renal cell carcinoma patients. Tumour Biol 8(8):72419Google Scholar
  61. 61.
    The Cancer Genome Atlas Research N (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 505:495–501CrossRefGoogle Scholar
  62. 62.
    Veldt AA van der, Eechoute K, Gelderblom H et al (2011) Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 17:620–629PubMedCrossRefGoogle Scholar
  63. 63.
    Kessel KE van, Kompier LC, Bekker-Grob EW de et al (2013) FGFR3 mutation analysis in voided urine samples to decrease cystoscopies and cost in nonmuscle invasive bladder cancer surveillance: a comparison of 3 strategies. J Urol 189:1676–1681PubMedCrossRefGoogle Scholar
  64. 64.
    Rhijn BW van, Kwast TH van der, Liu L et al (2012) The FGFR3 mutation is related to favorable pT1 bladder cancer. J Urol 187:310–314PubMedGoogle Scholar
  65. 65.
    Rhijn BW van, Vis AN, Kwast TH van der et al (2003) Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol 21:1912–1921PubMedCrossRefGoogle Scholar
  66. 66.
    Weischenfeldt J, Simon R, Feuerbach L et al (2013) Integrative genomic analyses reveal androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell 23:159–170PubMedCrossRefGoogle Scholar
  67. 67.
    Williams SV, Hurst CD, Knowles MA (2013) Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet 22:795–803PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Wu X, Weng L, Li X et al (2012) Identification of a 4-microRNA signature for clear cell renal cell carcinoma metastasis and prognosis. PloS One 7:35661CrossRefGoogle Scholar
  69. 69.
    Xu CF, Bing NX, Ball HA et al (2011) Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes. J Clin Oncol 29:2557–2564PubMedCrossRefGoogle Scholar
  70. 70.
    Xu C, Johnson T, Choueiri T et al (2013) Association of IL8 polymorphisms with overall survival in patients with renal cell carcinoma in COMPARZ (pazopanib versus sunitinib phase III study). J Clin Oncol 31(Suppl):4519Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • A. Hartmann
    • 1
  • T. Schlomm
    • 2
  • S. Bertz
    • 1
  • J. Heinzelmann
    • 3
  • S. Hölters
    • 3
  • R. Simon
    • 2
  • R. Stoehr
    • 1
  • K. Junker
    • 3
  1. 1.Institut für PathologieUniversität ErlangenErlangenDeutschland
  2. 2.Martini-Klinik, Prostatakarzinomzentrum und Institut für PathologieUniversitätsklinikum Hamburg-EppendorfHamburgDeutschland
  3. 3.Klinik für Urologie und KinderurologieUniversitätsklinikum des SaarlandesHomburgDeutschland

Personalised recommendations