Altered p53/p16 expression is linked to urothelial carcinoma progression but largely unrelated to prognosis in muscle-invasive tumors

References

• Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660.
   PubMed Web of Science ®Google Scholar
• Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234–241. doi: 10.1016/j.eururo.2012.07.033.
   PubMed Web of Science ®Google Scholar
• Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15(1):25–41. doi: 10.1038/nrc3817.
   PubMed Web of Science ®Google Scholar
• Marei HE, Althani A, Afifi N, et al. p53 signaling in cancer progression and therapy. Cancer Cell Int. 2021;21(1):703. doi: 10.1186/s12935-021-02396-8.
   PubMed Web of Science ®Google Scholar
• Hussain SP, Harris CC. p53 mutation spectrum and load: the generation of hypotheses linking the exposure of endogenous or exogenous carcinogens to human cancer. Mutat Res. 1999;428(1–2):23–32. doi: 10.1016/s1383-5742(99)00028-9.
   PubMed Web of Science ®Google Scholar
• Bellini MF, Cadamuro AC, Succi M, et al. Alterations of the TP53 gene in gastric and esophageal carcinogenesis. J Biomed Biotechnol. 2012;2012:891961. doi: 10.1155/2012/891961.
   PubMedGoogle Scholar
• Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res. 2000;60(24):6788–6793.
   PubMed Web of Science ®Google Scholar
• Schmitz-Dräger BJ, Goebell PJ, Ebert T, et al. p53 immunohistochemistry as a prognostic marker in bladder cancer. Playground for urology scientists? Eur Urol. 2000;38(6):691–699; discussion 700. doi: 10.1159/000020364.
   PubMed Web of Science ®Google Scholar
• Malats N, Bustos A, Nascimento CM, et al. P53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol. 2005;6(9):678–686. doi: 10.1016/S1470-2045(05)70315-6.
   PubMed Web of Science ®Google Scholar
• Liao Y, Tang H, Wang M, et al. The potential diagnosis role of TP53 mutation in advanced bladder cancer: a meta-analysis. J Clin Lab Anal. 2021;35(5):e23765. doi: 10.1002/jcla.23765.
   PubMed Web of Science ®Google Scholar
• Nenutil R, Smardova J, Pavlova S, et al. Discriminating functional and non-functional p53 in human tumours by p53 and MDM2 immunohistochemistry. J Pathol. 2005;207(3):251–259. doi: 10.1002/path.1838.
   PubMed Web of Science ®Google Scholar
• Hodgson A, van Rhijn BWG, Kim SS, et al. Reassessment of p53 immunohistochemistry thresholds in invasive high grade bladder cancer shows a better correlation with TP53 and FGFR3 mutations. Pathol Res Pract. 2020;216(11):153186. doi: 10.1016/j.prp.2020.153186.
   PubMed Web of Science ®Google Scholar
• Hodgson A, Xu B, Downes MR. p53 immunohistochemistry in high-grade urothelial carcinoma of the bladder is prognostically significant. Histopathology. 2017;71(2):296–304. doi: 10.1111/his.13225.
   PubMed Web of Science ®Google Scholar
• Sangoi AR, Chan E, Abdulfatah E, et al. p53 null phenotype is a "positive result" in urothelial carcinoma in situ. Mod Pathol. 2022;35(9):1287–1292. doi: 10.1038/s41379-022-01062-2.
   PubMed Web of Science ®Google Scholar
• Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366(6456):704–707. doi: 10.1038/366704a0.
   PubMed Web of Science ®Google Scholar
• Witkiewicz AK, Knudsen KE, Dicker AP, et al. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle. 2011;10(15):2497–2503. doi: 10.4161/cc.10.15.16776.
   PubMed Web of Science ®Google Scholar
• Eble JN, World Health Organization, International Agency for Research on Cancer. Pathology and genetics of tumours of the urinary system and male genital organs. IARC Press; 2004.
   Google Scholar
• Mostofi FK. International histological classification of tumours – histological typing of urinary bladder tumours. Geneva: World Health Organization; 1973.
   Google Scholar
• Bubendorf L, Nocito A, Moch H, et al. Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies. J Pathol. 2001;195(1):72–79. doi: 10.1002/path.893.
   PubMed Web of Science ®Google Scholar
• Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4(7):844–847. doi: 10.1038/nm0798-844.
   PubMed Web of Science ®Google Scholar
• De Wispelaere N, Rico SD, Bauer M, et al. High prevalence of p16 staining in malignant tumors. PLOS One. 2022;17(7):e0262877. doi: 10.1371/journal.pone.0262877.
   PubMed Web of Science ®Google Scholar
• Simon R, Mirlacher M, Sauter G. Immunohistochemical analysis of tissue microarrays. Methods Mol Biol. 2010;664:113–126. doi: 10.1007/978-1-60761-806-5_12.
   PubMedGoogle Scholar
• Torhorst J, Bucher C, Kononen J, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol. 2001;159(6):2249–2256. doi: 10.1016/S0002-9440(10)63075-1.
   PubMed Web of Science ®Google Scholar
• Sauter G. Representativity of TMA studies. Methods Mol Biol. 2010;664:27–35. doi: 10.1007/978-1-60761-806-5_3.
   PubMedGoogle Scholar
• Mhawech P, Greloz V, Oppikofer C, et al. Expression of cell cycle proteins in T1a and T1b urothelial bladder carcinoma and their value in predicting tumor progression. Cancer. 2004;100(11):2367–2375. doi: 10.1002/cncr.20306.
   PubMed Web of Science ®Google Scholar
• Bartoletti R, Cai T, Nesi G, et al. Loss of P16 expression and chromosome 9p21 LOH in predicting outcome of patients affected by superficial bladder cancer. J Surg Res. 2007;143(2):422–427. doi: 10.1016/j.jss.2007.01.012.
   PubMed Web of Science ®Google Scholar
• Krüger S, Mahnken A, Kausch I, et al. P16 immunoreactivity is an independent predictor of tumor progression in minimally invasive urothelial bladder carcinoma. Eur Urol. 2005;47(4):463–467. doi: 10.1016/j.eururo.2004.12.018.
   PubMed Web of Science ®Google Scholar
• Santos LL, Amaro T, Pereira SA, et al. Expression of cell-cycle regulatory proteins and their prognostic value in superficial low-grade urothelial cell carcinoma of the bladder. Eur J Surg Oncol. 2003;29(1):74–80. doi: 10.1053/ejso.2002.1371.
   PubMed Web of Science ®Google Scholar
• Hitchings AW, Kumar M, Jordan S, et al. Prediction of progression in pTa and pT1 bladder carcinomas with p53, p16 and pRb. Br J Cancer. 2004;91(3):552–557. doi: 10.1038/sj.bjc.6601954.
   PubMed Web of Science ®Google Scholar
• Chiang Y, Wang CC, Tsai YC, et al. Nuclear factor-κB overexpression is correlated with poor outcomes after multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer. J Clin Med. 2019;8(11):1954.
   PubMed Web of Science ®Google Scholar
• Rajcani J, Kajo K, Adamkov M, et al. Immunohistochemical characterization of urothelial carcinoma. Bratisl Lek Listy. 2013;114(8):431–438. doi: 10.4149/bll_2013_091.
   PubMed Web of Science ®Google Scholar
• Yin M, Bastacky S, Parwani AV, et al. p16ink4 immunoreactivity is a reliable marker for urothelial carcinoma in situ. Hum Pathol. 2008;39(4):527–535. doi: 10.1016/j.humpath.2007.08.005.
   PubMed Web of Science ®Google Scholar
• Røtterud R, Pettersen EO, Berner A, et al. Cell cycle inhibitors and outcome after radiotherapy in bladder cancer patients. Acta Oncol. 2002;41(5):463–470. doi: 10.1080/028418602320405069.
   PubMed Web of Science ®Google Scholar
• Niehans GA, Kratzke RA, Froberg MK, et al. G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder. Br J Cancer. 1999;80(8):1175–1184. doi: 10.1038/sj.bjc.6690483.
   PubMed Web of Science ®Google Scholar
• Zhao R, Choi BY, Lee MH, et al. Implications of genetic and epigenetic alterations of CDKN2A (p16(INK4a)) in cancer. EBioMedicine. 2016;8:30–39. doi: 10.1016/j.ebiom.2016.04.017.
   PubMed Web of Science ®Google Scholar
• Yamakoshi K, Takahashi A, Hirota F, et al. Real-time in vivo imaging of p16Ink4a reveals cross talk with p53. J Cell Biol. 2009;186(3):393–407. doi: 10.1083/jcb.200904105.
   PubMed Web of Science ®Google Scholar
• Inoue K, Fry EA. Aberrant expression of p16. Cancer Rep Rev. 2018;2(2). doi: 10.15761/CRR.1000145.
   Google Scholar
• Grignon DJ. The current classification of urothelial neoplasms. Mod Pathol. 2009;22(Suppl. 2):S60–S69. doi: 10.1038/modpathol.2008.235.
   PubMedGoogle Scholar
• Tosoni I, Wagner U, Sauter G, et al. Clinical significance of interobserver differences in the staging and grading of superficial bladder cancer. BJU Int. 2000;85(1):48–53. doi: 10.1046/j.1464-410x.2000.00356.x.
   PubMed Web of Science ®Google Scholar
• Lawless ME, Tretiakova MS, True LD, et al. Flat urothelial lesions with atypia: interobserver concordance and added value of immunohistochemical profiling. Appl Immunohistochem Mol Morphol. 2018;26(3):180–185. doi: 10.1097/PAI.0000000000000401.
   PubMedGoogle Scholar
• Koyuncuer A. Immunohistochemical expression of p63, p53 in urinary bladder carcinoma. Indian J Pathol Microbiol. 2013;56(1):10–15. doi: 10.4103/0377-4929.116141.
   PubMed Web of Science ®Google Scholar
• Compérat E, Camparo P, Haus R, et al. Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases. Virchows Arch. 2006;448(3):319–324. doi: 10.1007/s00428-005-0092-2.
   PubMed Web of Science ®Google Scholar
• van Rhijn BW, Vis AN, van der Kwast TH, et al. 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. 2003;21(10):1912–1921. doi: 10.1200/JCO.2003.05.073.
   PubMed Web of Science ®Google Scholar
• Gonzalez-Campora R, Davalos-Casanova G, Beato-Moreno A, et al. BCL-2, TP53 and BAX protein expression in superficial urothelial bladder carcinoma. Cancer Lett. 2007;250(2):292–299. doi: 10.1016/j.canlet.2006.10.011.
   PubMed Web of Science ®Google Scholar
• Maeng YH, Eun SY, Huh JS. Expression of fibroblast growth factor receptor 3 in the recurrence of non-muscle-invasive urothelial carcinoma of the bladder. Korean J Urol. 2010;51(2):94–100. doi: 10.4111/kju.2010.51.2.94.
   PubMedGoogle Scholar
• Hegazy R, Kamel M, Salem EA, et al. The prognostic significance of p53, p63 and her2 expression in non-muscle-invasive bladder cancer in relation to treatment with bacille Calmette-Guerin. Arab J Urol. 2015;13(3):225–230. doi: 10.1016/j.aju.2015.05.001.
   PubMed Web of Science ®Google Scholar
• van Oers JM, Wild PJ, Burger M, et al. FGFR3 mutations and a normal CK20 staining pattern define low-grade noninvasive urothelial bladder tumours. Eur Urol. 2007;52(3):760–768. doi: 10.1016/j.eururo.2007.01.009.
   PubMed Web of Science ®Google Scholar
• Esrig D, Elmajian D, Groshen S, et al. Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med. 1994;331(19):1259–1264. doi: 10.1056/NEJM199411103311903.
   PubMed Web of Science ®Google Scholar
• Nakopoulou L, Constantinides C, Papandropoulos J, et al. Evaluation of overexpression of p53 tumor suppressor protein in superficial and invasive transitional cell bladder cancer: comparison with DNA ploidy. Urology. 1995;46(3):334–340. doi: 10.1016/S0090-4295(99)80216-7.
   PubMed Web of Science ®Google Scholar
• Gupta G, Gupta R, Pasricha S, et al. Molecular stratification of high-grade urothelial carcinoma by immunohistochemistry with its histomorphological and clinical correlation. Indian J Pathol Microbiol. 2022;65(4):832–838.
   PubMed Web of Science ®Google Scholar
• Korkolopoulou P, Givalos N, Saetta A, et al. Minichromosome maintenance proteins 2 and 5 expression in muscle-invasive urothelial cancer: a multivariate survival study including proliferation markers and cell cycle regulators. Hum Pathol. 2005;36(8):899–907. doi: 10.1016/j.humpath.2005.06.008.
   PubMed Web of Science ®Google Scholar
• Tsai YS, Tzai TS, Chow NH, et al. Prognostic values of p53 and HER-2/neu coexpression in invasive bladder cancer in Taiwan. Urol Int. 2003;71(3):262–270. doi: 10.1159/000072676.
   PubMed Web of Science ®Google Scholar
• Ong F, Moonen LM, Gallee MP, et al. Prognostic factors in transitional cell cancer of the bladder: an emerging role for bcl-2 and p53. Radiother Oncol. 2001;61(2):169–175. doi: 10.1016/s0167-8140(01)00421-2.
   PubMed Web of Science ®Google Scholar
• Kong G, Shin KY, Oh YH, et al. Bcl-2 and p53 expressions in invasive bladder cancers. Acta Oncol. 1998;37(7–8):715–720. doi: 10.1080/028418698430098.
   PubMed Web of Science ®Google Scholar
• Garcia del Muro X, Condom E, Vigués F, et al. p53 and p21 expression levels predict organ preservation and survival in invasive bladder carcinoma treated with a combined-modality approach. Cancer. 2004;100(9):1859–1867. doi: 10.1002/cncr.20200.
   PubMed Web of Science ®Google Scholar
• Kuczyk MA, Bokemeyer C, Serth J, et al. p53 overexpression as a prognostic factor for advanced stage bladder cancer. Eur J Cancer. 1995;31A(13–14):2243–2247. doi: 10.1016/0959-8049(95)00443-2.
   PubMed Web of Science ®Google Scholar
• Koskinen I, Boström PJ, Taimen P, et al. Prediction of neo-adjuvant chemotherapy response in bladder cancer: the impact of clinical parameters and routine biomarkers. Scand J Urol. 2021;55(6):448–454. doi: 10.1080/21681805.2021.1962403.
   PubMed Web of Science ®Google Scholar
• Jangir H, Nambirajan A, Seth A, et al. Prognostic stratification of muscle invasive urothelial carcinomas using limited immunohistochemical panel of Gata3 and cytokeratins 5/6, 14 and 20. Ann Diagn Pathol. 2019;43:151397. doi: 10.1016/j.anndiagpath.2019.08.001.
   PubMed Web of Science ®Google Scholar
• Shigeta K, Matsumoto K, Tanaka N, et al. Profiling the biological characteristics and transitions through upper tract tumor origin, bladder recurrence, and muscle-invasive bladder progression in upper tract urothelial carcinoma. Int J Mol Sci. 2022;23(9):5154.
   PubMed Web of Science ®Google Scholar
• Wang CC, Tsai YC, Jeng YM. Biological significance of GATA3, cytokeratin 20, cytokeratin 5/6 and p53 expression in muscle-invasive bladder cancer. PLOS One. 2019;14(8):e0221785. doi: 10.1371/journal.pone.0221785.
   PubMed Web of Science ®Google Scholar
• Ogura K, Habuchi T, Yamada H, et al. Immunohistochemical analysis of p53 and proliferating cell nuclear antigen (PCNA) in bladder cancer: positive immunostaining and radiosensitivity. Int J Urol. 1995;2(5):302–308. doi: 10.1111/j.1442-2042.1995.tb00004.x.
   PubMedGoogle Scholar
• Hemal AK, Khaitan A, Dinda AK, et al. Prognostic significance of p53 nuclear overexpression in patients of muscle invasive urinary bladder carcinoma treated with cystectomy. Urol Int. 2003;70(1):42–46. doi: 10.1159/000067703.
   PubMed Web of Science ®Google Scholar
• Ashcroft M, Vousden KH. Regulation of p53 stability. Oncogene. 1999;18(53):7637–7643. doi: 10.1038/sj.onc.1203012.
   PubMed Web of Science ®Google Scholar
• Upadhyay PR, Starner RJ, Swope VB, et al. Differential induction of reactive oxygen species and expression of antioxidant enzymes in human melanocytes correlate with melanin content: implications on the response to solar UV and melanoma susceptibility. Antioxidants. 2022;11(6):1204. doi: 10.3390/antiox11061204.
   Web of Science ®Google Scholar
• Boyd MT, Vlatkovic N. p53: a molecular marker for the detection of cancer. Expert Opin Med Diagn. 2008;2(9):1013–1024. doi: 10.1517/17530059.2.9.1013.
   PubMedGoogle Scholar
• Chemotherapy efficacy is dependent upon p53 dynamics. Cancer Discov. 2016;6(6):OF12.
   Google Scholar
• Lee CL, Blum JM, Kirsch DG. Role of p53 in regulating tissue response to radiation by mechanisms independent of apoptosis. Transl Cancer Res. 2013;2(5):412–421.
   PubMed Web of Science ®Google Scholar
• Nguyen JK, Przybycin CG, McKenney JK, et al. Immunohistochemical staining patterns of ki-67 and p53 in florid reactive urothelial atypia and urothelial carcinoma in situ demonstrate significant overlap. Hum Pathol. 2020;98:81–88. doi: 10.1016/j.humpath.2020.02.008.
   PubMed Web of Science ®Google Scholar
• Fraune C, Simon R, Höflmayer D, et al. High homogeneity of mismatch repair deficiency in advanced prostate cancer. Virchows Arch. 2020;476(5):745–752. doi: 10.1007/s00428-019-02701-x.
   PubMed Web of Science ®Google Scholar
• Wang L, Yu X, Li J, et al. Prognostic significance of p53 expression in patients with esophageal cancer: a meta-analysis. BMC Cancer. 2016;16(1):373. doi: 10.1186/s12885-016-2427-6.
   PubMedGoogle Scholar
• Zhou R, Wei C, Liu J, et al. The prognostic value of p53 expression for patients with cervical cancer: a meta analysis. Eur J Obstet Gynecol Reprod Biol. 2015;195:210–213. doi: 10.1016/j.ejogrb.2015.10.006.
   PubMed Web of Science ®Google Scholar
• Wei K, Jiang L, Wei Y, et al. The prognostic significance of p53 expression in gastric cancer: a meta-analysis. J Cancer Res Clin Oncol. 2015;141(4):735–748. doi: 10.1007/s00432-014-1844-7.
   PubMed Web of Science ®Google Scholar
• Mitsudomi T, Hamajima N, Ogawa M, et al. Prognostic significance of p53 alterations in patients with non-small cell lung cancer: a meta-analysis. Clin Cancer Res. 2000;6(10):4055–4063.
   PubMed Web of Science ®Google Scholar
• Beltran AL, Cheng L, Montironi R, et al. Clinicopathological characteristics and outcome of nested carcinoma of the urinary bladder. Virchows Arch. 2014;465(2):199–205. doi: 10.1007/s00428-014-1601-y.
   PubMed Web of Science ®Google Scholar
• Humphrey PA, Moch H, Cubilla AL, et al. 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.
   PubMed Web of Science ®Google Scholar