Expression of MDM2 mRNA, MDM2, P53 and P16 Proteins in Urothelial Lesions in the View of the WHO 4th Edition Guidelines as A Molecular Insight towards Personalized Medicine

Authors

  • Olfat Hammam Department of Pathology, Theodor Bilharz Research Institute (TBRI), Imbaba, Giza
  • Mona Magdy Department of Pathology, Theodor Bilharz Research Institute (TBRI), Imbaba, Giza
  • Mohamed Badawy Department of Urology, Theodor Bilharz Research Institute (TBRI), Imbaba, Giza
  • Khalid Al Osili Department of Urology, Theodor Bilharz Research Institute (TBRI), Imbaba, Giza
  • Amr El Kholy Department of Urology, Theodor Bilharz Research Institute (TBRI), Imbaba, Giza
  • Tarek El LeitHy Department of Urology, Theodor Bilharz Research Institute (TBRI), Imbaba, Giza

DOI:

https://doi.org/10.3889/oamjms.2017.100

Keywords:

P53, MDM2mRNA, P16, urothelial, grade, bilharzia

Abstract

AIM: Here we imposed a multimarker molecular panel composed of P53, MDM2 protein & mRNA & P16 with the identification of sensitive and specific cut offs among the Egyptian urothelial carcinomas bilharzial or not emphasize the pathological and molecular classifications, pathways and prognosis as a privilege for adjuvant therapy.

METHODS: Three hundred and ten urothelial lesions were pathologically evaluated and grouped as follows: 50 chronic cystitis as benign, 240 urothelial carcinomas and 20 normal bladder tissue as a control. Immunohistochemistry for MDM Protein, P16 & p53 and In Situ Hybridization for MDM2mRNA were done.

RESULTS: MDM2mRNA overexpression correlated with low grade low stage non invasive tumors, while P53 > 40% & p16 < 10% cut offs correlated with high grade high stage invasive carcinomas & bilharzial tumors (P=0.000).

CONCLUSION: MDM2mRNA overexpression vs. P53 > 40% & P16 < 10% constitutes a multimarker molecular panel with significant cut offs, proved to distinguish low grade, low stage non invasive urothelial carcinomas (MDM2mRNA overexpression, P53 < 40%, P16 > 10%) from high grade, high stage invasive urothelial carcinomas (with p53 > 40, p16 < 10% & absent MDM2mRNA overexpression). Combined P53 > 40 & p16 < 10%, together with the histopathological features can distinguish in situ urothelial lesions from dysplastic and atypical lesions.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

El-Bolkainy MN. Topographic pathology of cancer 2nd. Edition, chapter 7, AL Ahram Press, Cairo, 2000: 57-63.

Ferlay J, Bray F, Pisani P, Parkin DM. International Agency for Research on Cancer (IARC). Cancer Incidence, Mortality and Prevalence Worldwide. GLOBOCAN . 2002: Cancer Base No. 5, version 2.0. Lyon, France: IARC Press, 2004.

Humphrey AP, Moch H, Cubilla LA, Ulbright MT, Reuter EV. 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs Part B: Prostate and Bladder Tumours. European Urology. 2016: 70 (1):106-119. https://doi.org/10.1016/j.eururo.2016.02.028 PMid:26996659

Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998; 22:1435–48. https://doi.org/10.1097/00000478-199812000-00001 PMid:9850170

Netto GJ. Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? Nat Rev Urol. 2011; 9: 41–51. https://doi.org/10.1038/nrurol.2011.193 PMid:22158597

Hsu I, Vitkus S, Da J & Yeh S. Role of oestrogen receptors in bladder cancer development. Nature Reviews Urology. 2013; 10: 317-326. https://doi.org/10.1038/nrurol.2013.53 PMid:23588401

Damrauer SJ, Hoadley AK, Chism DD, Fan C, Tiganelli JC, Wobker ES, Yeh JJ, Milowsky IM, Iyer G, Parker SJ, and Kim WY. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA. 2014;111(8): 3110–3115. https://doi.org/10.1073/pnas.1318376111 PMid:24520177 PMCid:PMC3939870

Choi W, Porten S, Kim S, Willis D, Plimack E, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014: 25: 152–165. https://doi.org/10.1016/j.ccr.2014.01.009 PMid:24525232 PMCid:PMC4011497

Mitra PA. Molecular sub stratification of bladder cancer: moving towards individualized patient management. Ther Adv Urol. 2016; 8(3): 215–233. https://doi.org/10.1177/1756287216638981 PMid:27247631 PMCid:PMC4872193

Mitra A, Cote R. Searching for novel therapeutics and targets: insights from clinical trials. Urol Oncol. 2007; 25: 341–343. https://doi.org/10.1016/j.urolonc.2007.05.004 PMid:17628305

Mitra A, Datar R, Cote R. Molecular pathways in invasive bladder cancer: new insights into mechanisms, progression, and target identification Clin Oncol . 2006; 24: 5552–5564. https://doi.org/10.1200/JCO.2006.08.2073 PMid:17158541

Malats N, Bustos A, Nascimento C, Fernandez F, Rivas M, Puente D, et al. p53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol. 2005; 6: 678–686. https://doi.org/10.1016/S1470-2045(05)70315-6

Shariat SF, Chromecki TF, Cha EK, Karakiewicz PI, Sun M, Fradet Y, Isbarn H, Scherr DS, Bastian PJ, Pummer K, Fajkovic H, Sagalowsky AI, Ashfaq R, Doblinger M, Cote RJ, Lotan Y. Risk stratification of organ confined bladder cancer after radical cystectomy using cell cycle related biomarkers. J Urol. 2012;187(2):457-62. https://doi.org/10.1016/j.juro.2011.10.031 PMid:22177145

Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993;362(6423):857-60. https://doi.org/10.1038/362857a0 PMid:8479525

Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature. 1997;387(6630):299-303. https://doi.org/10.1038/387299a0 PMid:9153396

Stephen G. Williams, Maurizio Buscarini, and John P. Stein. Molecular Markers for Diagnosis, Staging, and Prognosis of Bladder Cancer. Oncology. 2001. http://www.cancernetwork.com/review-article/molecular-markers-diagnosis-staging-and-prognosis-bladder-cancer-2/page/0/5

Tuna B, YorukoÄŸlu K, Tuzel E, et al. Expression of p53 and mdm2 and their significance in recurrence of superficial bladder cancer. Pathol Res Pract. 2003;199:323-8. https://doi.org/10.1078/0344-0338-00424 PMid:12908522

El-Abd E, Hassan A, El-Ashry O, Al-Ipshiti M, El-Swedy S. P27 And Mdm2 As Molecular Grading Biomarkers In Transitional Cell Carcinoma. Turkish Journal Of Cancer. 2008;38 (2).

Ross SJ, Wang K, Al-Rohil NR, Nazeer T, Sheehan EC, Otto AG, He J, Palmer G, Yelensky R, Lipson D, Ali S, Balasubramanian S, Curran AJ, Garcia L, Mahoney K, Downing RS, Hawryluk M, Miller AV and Stephens JP. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Modern Pathology. 2014; 27: 271–280. https://doi.org/10.1038/modpathol.2013.135 PMid:23887298

Shigemasa K, Hu C, West CM, Clarke J, Parham GP, Parmley TH, et al. p16 overexpression: a potential early indicator of transformation in ovarian carcinoma. J Soc Gynecol Investig. 1997;4:95e102.

Yang HC, Wu CC, Chen ZW, Chai YC, Yang FC. Expressions of p16 and p27 in urothelial carcinoma and their prognostic value. Kaohsiung Journal of Medical Sciences. 2014; 30: 453e458.

Cheng L, Davison DD, Adams J, Lopez-Beltran A, Wang L, Montironi R, Zhang S. Biomarkers in bladder cancer: Translational and clinical implications. Critical Reviews in Oncology/Hematology. 2014; 89(1): 73-111. https://doi.org/10.1016/j.critrevonc.2013.08.008 PMid:24029603

Gan X, Lin X, He R, Lin X, Wang H, Yan L, Zhou H, Qin H, and Chen G. Prognostic and Clinicopathological Significance of Downregulated p16 Expression in Patients with Bladder Cancer: A Systematic Review and Meta-Analysis. Disease Markers. 2016; 5259602:13. https://doi.org/10.1155/2016/5259602

Mostafa MH, Sheweita S, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999; 12:97-11. PMid:9880476 PMCid:PMC88908

Osman H, Abadeer N, Mohamed S, Fahmy A. Expression of p16, p15 and Cyclin D1 in bladder cancer and correlates with cancer progression and clinical outcome. The Internet Journal of Urology. 2006; 4(2).

Rosin MP, Anwar WA and Ward AJ. Inflammation, chromosomal instability, and cancer: the schistosomiasis model. Cancer Res. 1994; 54(suppl.): 1929-193.

Alameda F, Juanpere N, Pijuan L , Lloveras B, Gimeno J, Baró T, Salido M, Serrano S and Lloreta J. Value of p16INK4a in the diagnosis of low-grade urothelial carcinoma of the urinary bladder in urinary cytology. Cancer cytopathology. 2012; 120 (4): 276–282. https://doi.org/10.1002/cncy.21193 PMid:22419364

Larue, H, Allard P, Simoneau M, Normand C, Pfister C, Moore L, Meyer F, Têtu, B, Fradet Y. p53 point mutations in initial superficial bladder cancer occur only in tumors from current or recent cigarette smokers. Carcinogenesis. 1999.

Lianes P, Orlow, I, Zhang ZF, Oliva MR, Sarkis AS, Reuter VE and Cordon-Cardo, C, Altered patterns of MDM2 and p53 expression in human bladder cancer. J Nat Cancer Inst. 1994; 86:1325-1330. https://doi.org/10.1093/jnci/86.17.1325 PMid:8064890

Schmitz-Dräger BJ, Kushima M, Goebell P, Jax TW, Gerharz CD, Bültel, H, Schulz W, Ebert T. and Ackermann R. p53 and MDM2 in the development and progression of bladder cancer. Europ Urol. 1997; 32: 487-493. PMid:9412812

Zhao M, He LH, Teng DX. Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview. Chinese journal of cancer research. 2016; 28(1).

Mohammed AA, EL-Tanni H, EL-Khatib MH, Mirza AA, and Alturaifi HT . Urinary Bladder Cancer: Biomarkers and Target Therapy, New Era for More Attention. Onchology reviews. 2016; 10(2).

Stephen G. Williams, Maurizio Buscarini, and John P. Stein. Molecular Markers for Diagnosis, Staging, and Prognosis of Bladder Cancer. Oncology. 2001.

Schlott T, Quentin T, Korabiowska M, Budd B, Kunze E. Alteration of the MDM2-p73-P14ARF pathway related to tumour progression during urinary bladder carcinogenesis. Int J Mol Med. 2004;14(5):825-36. https://doi.org/10.3892/ijmm.14.5.825

Pfister C, Larue LH, Moore L, Lacombe L, Veilleux C, Tetu B, Meyer F and Fradet Y. Tumorigenic Pathways In Low-Stage Bladder Cancer Based On P53, Mdm2 And P21 Phenotypes. Int J Cancer (Pred Oncol). 2000; 89: 100–104. https://doi.org/10.1002/(SICI)1097-0215(20000120)89:1<100::AID-IJC16>3.0.CO;2-Q

Uchida T, Minei S, Gao JP, Wang C, Satoh T, Baba S. Clinical significance of p53, MDM2 and bcl-2 expression in transitional cell carcinoma of the bladder. Oncol Rep. 2002; 9(2):253-9. https://doi.org/10.3892/or.9.2.253

Olsson H , Hultman P, Rosell J, Söderkvist P, Jahnson S. MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T1. BMC Urol. 2013;28:13-5. https://doi.org/10.1186/1471-2490-13-5

Peter J. Goebell, Susan G. Groshen, Bernd J. Schmitz-Dräger. p53 immunohistochemistry in bladder cancer—a new approach to an old question. Urologic oncology. 2010; 28(4): 377–388. https://doi.org/10.1016/j.urolonc.2010.03.021 PMid:20610276

Xu X, Stower, MJ, Reid IN, Garner RC, Burns PA. A hot spot for p53 mutation in transitional cell carcinoma of the bladder: Clues to the etiology of bladder cancer. Cancer Epidemiology Biomarkers and Prevention. 1997; 6 (8): 611-616. PMid:9264274

Dalbagni G, Cordon-Cardo C, Reuter V, Fair WR. Tumor suppressor gene alterations in bladder carcinoma. Translational correlates to clinical practice. Surgical oncology clinics of North America . 1995;4(2): 231-240. PMid:7796283

Petitjean A, Achatz MI, Borresen-Dale AL, et al. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26:2157-65. https://doi.org/10.1038/sj.onc.1210302 PMid:17401424

Yurakh AO, Ramos D, Calabuig-Fari-as S, et al., Molecular and immunohistochemical analysis of the prognostic value of cell-cycle regulators in urothelial neoplasms of the bladder. European Urology. 2006; 50(3): 506–515. https://doi.org/10.1016/j.eururo.2006.03.027 PMid:16624482

Mitra AP, Hansel DE, Cote RJ. Prognostic value of cell-cycle regulation biomarkers in bladder cancer. Seminars in Oncology. 2012; 39(5): 524–533. https://doi.org/10.1053/j.seminoncol.2012.08.008 PMid:23040249 PMCid:PMC3478886

Krüger S, Mahnken A, Kausch I, Feller AC. P16 immunoreactivity is an independent predictor of tumor progression in minimally invasive urothelial bladder carcinoma. European Urology. 1995;47(4): 463–467. https://doi.org/10.1016/j.eururo.2004.12.018 PMid:15774242

Yang C, Chu KC, Chen HY, Chen W. Expression of p16 and Cyclin D1 in Bladder Cancer and Correlation in Cancer Progression. Urol Int. 2002;69:190–194. https://doi.org/10.1159/000063945 PMid:12372886

Published

2017-08-05

How to Cite

1.
Hammam O, Magdy M, Badawy M, Al Osili K, El Kholy A, El LeitHy T. Expression of MDM2 mRNA, MDM2, P53 and P16 Proteins in Urothelial Lesions in the View of the WHO 4th Edition Guidelines as A Molecular Insight towards Personalized Medicine. Open Access Maced J Med Sci [Internet]. 2017 Aug. 5 [cited 2021 Jul. 31];5(5):578-86. Available from: https://oamjms.eu/index.php/mjms/article/view/oamjms.2017.100

Issue

Section

A - Basic Science

Most read articles by the same author(s)