Molecular pathology of urothelial carcinoma: prognostic and predictive biomarkers

Authors

  • O.N. Sulaieva Laboratory of Pathology “CSD Health Care”, Kyiv, Ukraine,
  • О.E. Stakhovskyi National Cancer Institute, Kyiv, Ukraine,
  • D.O. Shapochka Laboratory of Pathology “CSD Health Care”, Kyiv, Ukraine,
  • A.A. Seleznev Laboratory of Pathology “CSD Health Care”, Kyiv, Ukraine,

DOI:

https://doi.org/10.22141/2663-3272.2.4.2019.195181

Keywords:

urothelial carcinomas, biomarkers, treatment

Abstract

Urothelial carcinomas (UC) accounts for about 90 % of all bladder cancers. Nowadays, the prognosis and treatment of patients with UC is based on clinical, instrumental and histopathological features. However, widely recognized clinical and pathological characteristics are often insufficient for precise prognosis and prediction of therapy efficacy. In this review, we analyzed the molecular mechanisms of UC development and discussed current approaches to UC prognostication and individualized therapy selection using molecular biomarkers. UCs have an extremely complex genetic profile. To date, more than 300 mutations, above 200 copy number variations, and more than 20 rearrangements have been identified in UC. Study of UC biology showed the multifactorial nature of genetic and genomic disorders, both in the tumor cells and in tumor microenvironment. The most challenging task while interpreting molecular alterations is to define the clinical significance of each molecular biomarker in UC. In this review, the authors discuss the role of chromosomal and genetic alterations, including chromosome 9 aberrations, FGFR3, RAS, PI3KCA, TP53 and RB1 mutations, in the pathogenesis of UC development and progression. In addition, the manuscript presents data on prognostic and predictive markers of muscle-invasive UCs, including regulators of proliferation and apoptosis, hypoxia, DNA repair enzymes, as well as immunological biomarkers. A comprehensive study of chromosomal and genetic alterations, the signatures of gene expression and immune checkpoints in combination with clinical, laboratory, instrumental and histopathological data made it possible not only to understand better the nature and significance of various molecular disorders, but also contributed to further development of advanced UC classification based on molecular subtypes with specific treatment recommendations in line with molecular profiling of the tumor.

References

Antoni S., Ferlay J., Soerjomataram I., Znaor A., Jemal A., Bray F. Bladder Cancer incidence and mortality: a global overview and recent trends. Eur. Urology. 2017. 71(1). 96-108. doi: 10.1016/j.eururo.2016.06.010.

Boström P.J., Thoms J., Sykes J., Ahmed O. Hypoxia Marker GLUT-1 (Glucose Transporter 1) is an Independent Prognostic Factor for Survival in Bladder Cancer Patients Treated with Radical Cystectomy. Bladder Cancer. 2016. 2(1). 101-109. doi: 10.3233/BLC-150033.

Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018. 68(6). 394-424. doi: 10.3322/caac.21492.

Breyer J., Shalekenov S., Aziz A., van Rhijn B.W.G., Bründl J. Increased Proliferation as Independent Predictor of Disease Recurrence in Initial Stage pTa Urothelial Bladder Cancer. Bladder Cancer. 2017. 3(3). 173-180. doi: 10.3233/BLC-170103.

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014. 507. 315-22. doi: 10.1038/nature12965.

Chai C.Y., Chen W.T., Hung W.C., Kang W.Y., Huang Y.C., Su Y.C. Hypoxia-inducible factor-1α expression correlates with focal macrophage infiltration, angiogenesis and unfavorable prognosis in urothelial carcinoma. J. Clin. Pathol. 2008. 61(5). 658-664. doi: 10.1136/jcp.2007.050666

Chakravarti A., Winter K., Wu C.L., Kaufman D., Hammond E., Parliament M. Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: A report from the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 2005. 62. 309-317. doi: 10.1016/j.ijrobp.2004.09.047.

Choudhury A., West C.M., Porta N., Hall E., Denley H., Hendron C., Lewis R., Hussain S.A. The predictive and prognostic value of tumour necrosis in muscle invasive bladder cancer patients receiving radiotherapy with or without chemotherapy in the BC2001 trial (CRUK/01/004). Br. J. Cancer. 2017. 116(5). 649-657. doi: 10.1038/bjc.2017.2.

Choudhury A., Nelson L.D., Teo M.T., Chilka S., Bhattarai S., Johnston C.F. MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res. 2010. 70. 7017-7026. doi: 10.1158/0008-5472.CAN-10-1202.

Compérat E.M., Burger M., Gontero P., Mostafid A.H., Palou J., Rouprêt M. Grading of Urothelial Carcinoma and The New “World Health Organisation Classification of Tumours of the Urinary System and Male Genital Organs 2016”. Eur. Urol. Focus. 2019. 5(3). 457-466. doi: 10.1016/j.euf.2018.01.003.

Desai N.B., Scott S.N., Zabor E.C., Cha E.K., Hreiki J., Sfakianos J.P. Genomic characterization of response to chemoradiation in urothelial bladder cancer. Cancer. 2016. 122. 3715-3723. doi: 10.1002/cncr.30219.

Dhani N., Fyles A., Hedley D., Milosevic M. The clinical significance of hypoxia in human cancers. Semin. Nucl. Med. 2015. 45(2). 110-121. doi: 10.1053/j.semnuclmed.2014.11.002.

Ding W., Gou Y., Sun C., Xia G., Wang H., Chen Z. Ki-67 is an independent indicator in non-muscle invasive bladder cancer (NMIBC); combination of EORTC risk scores and Ki-67 expression could improve the risk stratification of NMIBC. Urol. Oncol. 2014. 32(1). e13-9. doi: 10.1016/j.urolonc.2013.05.004.

Dueñas M., Pérez-Figueroa A., Oliveira C., Suárez-Cabrera C., Sousa A., Oliveira P. Gene Expression Analyses in Non Muscle Invasive Bladder Cancer Reveals a Role for Alternative Splicing and Tp53 Status. Sci. Rep. 2019. 9(1). 10362. doi: 10.1038/s41598-019-46652-4.

He Y., Wang N., Zhou X., Wang J., Ding Z., Chen X. Prognostic value of ki67 in BCG-treated non-muscle invasive bladder cancer: a meta-analysis and systematic review. BMJ Open. 2018. 8(4). e019635. doi: 10.1136/bmjopen-2017-019635.

Hedegaard J., Lamy P., Nordentoft I., Algaba F., Høyer S. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer cell. 2016. 30(1). 27-42. doi: 10.1016/j.ccell.2016.05.004.

Humphrey P.A., Moch H., Cubilla A.L., Ulbright T.M., Reuter V.E. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur. Urol. 2016. 70(1). 106-119. doi: 10.1016/j.eururo.2016.02.028.

Hunter B.A., Eustace A., Irlam J.J., Valentine H.R., Denley H., Oguejiofor K.K. Expression of hypoxia-inducible factor-1alpha predicts benefit from hypoxia modification in invasive bladder cancer. BJC. 2014. 111. 437-443. doi: 10.1038/bjc.2014.315.

Inoue M., Koga F., Yoshida S., Tamura T., Fujii Y., Ito E. Significance of ERBB2 overexpression in therapeutic resistance and cancer-specific survival in muscle-invasive bladder cancer patients treated with chemoradiation-based selective bladder-sparing approach. Int. J. Radiat. Oncol. Biol. Phys. 2014. 90. 303-311. doi: 10.1016/j.ijrobp.2014.05.043.

Kaufman D.S., Shipley W.U., Feldman A.S. Bladder cancer. Lancet. 2009. 374(9685). 239-249. doi: 10.1016/S0140-6736(16)30512-8.

Kawashima A., Nakayama M., Kakuta Y., Abe T., Hatano K., Mukai M. Excision repair cross-complementing group 1 may predict the efficacy of chemoradiation therapy for muscle-invasive bladder cancer. Clin. Cancer Res. 2011. 17. 2561-2569. doi: 10.1158/1078-0432.CCR-10-1963.

Kawauchi S., Sakai H., Ikemoto K. 9p21 index as estimated by dual-color fluorescence in situ hybridization is useful to predict urothelial carcinoma recurrence in bladder washing cytology. Hum. Pathol. 2009. 40. 1783-9. doi: 10.1016/j.hum­path.2009.06.011.

Knowles M.A., Hurst C.D. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat. Rev. Cancer. 2015. 15. 25-41. doi: 10.1038/nrc3817.

Koga F., Takemura K., Fukushima H. Biomarkers for Predicting Clinical Outcomes of Chemoradiation-Based Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer. Int. J. Mol. Sci. 2018. 19(9). E2777. doi: 10.3390/ijms19092777.

Kompier L.C., Lurkin I., van der Aa M.N. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS One. 2010. 5. e13821. doi: 10.1371/journal.pone.0013821.

Ku J.H., Yuk H.D., Godoy G., Amiel G.E., Lerner S.P. Prognostication in Patients Treated with Radical Cystectomy for Urothelial Bladder Carcinoma: A New Simplified Model Incorporating Histological Variants. Bladder Cancer. 2018. 4(2). 195-203. doi: 10.3233/BLC-170156.

Lautenschlaeger T., George A., Klimowicz A.C., Efstathiou J.A., Wu C.L., Sandler H. Bladder preservation therapy for muscle-invading bladder cancers on Radiation Therapy Oncology Group trials 8802, 8903, 9506, and 9706: Vascular endothelial growth factor B overexpression predicts for increased distant metastasis and shorter survival. Oncologist. 2013. 18. 685-686. doi: 10.1634/theoncologist.2012-0461.

Luo Y., Zhang X., Mo M., Tan Z., Huang L., Zhou H. High Ki-67 Immunohistochemical Reactivity Correlates With Poor Prognosis in Bladder Carcinoma: A Comprehensive Meta-Analysis with 13,053 Patients Involved. Medicine (Baltimore). 2016. 95(15). e3337. doi: 10.1097/MD.0000000000003337.

Masoud G.N., Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B. 2015. 5(5). 378-389. doi: 10.1016/j.apsb.2015.05.007.

Matsuyama H., Ikemoto K., Eguchi S. Copy number aberrations using multicolour fluorescence in situ hybridization for prognostication in non-muscle-invasive bladder cancer (NIMBC). BJU Int. 2014. 113. 662-667. doi: 10.1111/bju.12232.

Matulay J.T., Kamat A.M. Advances in risk stratification of bladder cancer to guide personalized medicine. F1000Res. 2018. 7. F1000 Faculty Rev-1137. doi: 10.12688/f1000research.14903.1.

Millis S.Z., Bryant D., Basu G. Molecular profiling of infiltrating urothelial carcinoma of bladder and nonbladder origin. Clin. Genitourin. Cancer. 2015. 13. e37-4914. doi: 10.1016/j.clgc.2014.07.010.

Mitra A.P., Cote R.J. Molecular pathogenesis and diagnostics of bladder cancer. Annu. Rev. Pathol. 2009. 4. 251-85. doi: 10.1146/annurev.pathol.4.110807.092230.

Mitra A.P., Lam L.L., Ghadessi M., Erho N., Vergara I.A., Alshalalfa M. Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer. J. Natl. Cancer Inst. 2014. 106(11). pii: dju290. doi: 10.1093/jnci/dju290.

Moch H., Humphrey P.A., Ulbright T.M., Reuter V.E. WHO classification of tumours of the urinary system and male genital organs. Geneva, Switserland: WHO Press, 2016.

Netto G.J., Cheng L. Emerging critical role of molecular tes­ting in diagnostic genitourinary pathology. Arch. Pathol. Lab. Med. 2012. 36. 372-390. doi: 10.5858/arpa.2011-0471-RA.

Oszczudlowski M., Dobruch J. Prediction of progression to muscle-invasive disease in patients with high-risk bladder cancer. Transl. Androl. Urol. 2018. 7(4). 749-751. doi: 10.21037/tau.2018.06.14.

Palit V., Phillips R.M., Puri R., Shah T., Bibby M.C. Expression of HIF-1alpha and Glut-1 in human bladder cancer. Oncol. Rep. 2005. 14(4). 909-913. doi: 10.3892/or.14.4.909.

Pandith A.A., Shah Z.A., Siddiqi M.A. Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer. Urol. Oncol. 2013. 31. 398-406. doi: 10.1016/j.urolonc.2010.07.014.

Rademakers S.E., Lok J., van der Kogel A.J., Bussink J., Kaanders J.H. Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1α, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer. 2011. 12(11). 167. doi: 10.1186/1471-2407-11-167.

Rentsch C.A., Müller D.C., Ruiz C., Bubendorf L. Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma: A Step Closer to Clinical Translation? Eur. Urol. 2017. 72(6). 960-961. doi: 10.1016/j.eururo.2017.06.022.

Rodel C., Grabenbauer G.G., Rodel F., Birkenhake S., Kuhn R., Martus P. Apoptosis, p53, bcl-2, and Ki-67 in invasive bladder carcinoma: Possible predictors for response to radiochemotherapy and successful bladder preservation. Int. J. Radiat. Oncol. Biol. Phys. 2000. 46. 1213-1221. doi: 10.1016/S0360-3016(99)00544.

Sakano S., Ogawa S., Yamamoto Y., Nishijima J., Miyachika Y., Matsumoto H. ERCC1 and XRCC1 expression predicts survival in bladder cancer patients receiving combined trimoda­lity therapy. Mol. Clin. Oncol. 2013. 1. 403-410. doi: 10.3892/mco.2013.85.

Shariat S.F., Chade D.C., Karakiewicz P.I. Combination of multiple molecular markers can improve prognostication in patients with locally advanced and lymph node positive bladder cancer. J. Urol. 2010. 183. 68-75. doi: 10.1016/j.juro.2009.08.115.

Spiess P.E., Czerniak B. Dual-Track Pathway of Bladder Carcinogenesis: Practical Implications. Archives of Pathology & Laboratory Medicine. 2006. 130(6). 844-852. doi: 10.1043/1543-2165(2006)130[844:DPOBCP]2.0.CO;2.

Tanabe K., Yoshida S., Koga F., Inoue M., Kobayashi S., Ishioka J. High Ki-67 Expression Predicts Favorable Survival in Muscle-Invasive Bladder Cancer Patients Treated With Chemoradiation-Based Bladder-Sping Protocol. Clin. Genitourin. Cancer. 2015. 13(4). e243-e251. doi: 10.1016/j.clgc.2015.03.002.

Tanaka H., Yoshida S., Koga F. Impact of Immunohistochemistry-Based Subtypes in Muscle-Invasive Bladder Cancer on Response to Chemoradiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2018. 102(5). 1408-1416. doi: 10.1016/j.ijrobp.2018.06.030.

Wu X.R. Urothelial tumorigenesis: a tale of divergent pathways. Nat. Rev. Cancer. 2005. 5. 713-25. doi: 10.1038/nrc1697.

Issue

Section

Original Researches