Overview of MDM2 and B-RAF Expression in Gastric Lesions

Authors

  • Tarek Aboushousha Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza
  • Noha Helal Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza
  • Olfat Hammam Faculty of Biotechnology, October University of Modern Sciences and Arts, Giza
  • Manar Ibrahim Faculty of Biotechnology, October University of Modern Sciences and Arts, Giza
  • Samar Khaled Faculty of Biotechnology, October University of Modern Sciences and Arts, Giza
  • Amr Mostafa Department of Surgery, Theodor Bilharz Research Institute, Imbaba, Giza
  • Amgad Anas Department of Hepato-Gastroenterology, Theodor Bilharz Research Institute, Giza

DOI:

https://doi.org/10.3889/oamjms.2018.338

Keywords:

MDM2, B-RAF, Gastritis, Gastric cancer, H. pylori

Abstract

BACKGROUND: Globally, gastric cancer (GC) it is the fourth most common cancer and the third cause of cancer-related deaths. Overexpression of MDM2 and B-RAF appeared to be increased in malignancy and associated with poor prognosis in several human tumours, but their role in gastric cancer remains controversial.

AIM: We had investigated the immunohistochemical expression of MDM2 and B-RAF in 136 gastric lesions with/without H. pylori association.

MATERIAL AND METHODS: Studied specimens include chronic gastritis (32), intestinal type GC (70), diffuse GC (22) and gastrointestinal stromal tumours (GIST) (12).

RESULTS: MDM2 expression increased significantly in intestinal GC compared to other groups (p < 0.001), while B-RAF expression increased significantly in GIST compared to other groups (p < 0.001). H. pylori increased expression of MDM2 in intestinal GC cases but did not affect B-RAF expression. MDM2 expression correlated with high grade of tumor differentiation (p < 0.001), deep invasion (p < 0.05), nodal metastases (p < 0.05) and distant metastases (p < 0.1) in intestinal GC, while B-RAF expression did not correlate with TNM stage (p < 0.1).

CONCLUSION: MDM2 up-regulation was more frequent in intestinal GC, while B-RAF up-regulation was more frequent in GIST compared to other groups; MDM2 expression in intestinal GC was correlated with H. pylori association, high grade of differentiation, deep invasion, nodal and distant metastases, meanwhile, B-RAF expression was correlated with high-grade intestinal GC but did not correlate with H. pylori or TNM stage. The possible role of both MDM2 and B-RAF in predicting progression of gastric tumours and prognosis deserves further investigations.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

References

Ferlay J, SoerjomataramI, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, BrayF. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136(5):E359–E386. https://doi.org/10.1002/ijc.29210 PMid:25220842

Ferro A, Peleteiro B, Malvezzic M, Bosetti C, Bertuccio P, Levi F, Negri E, La Vecchia C, Lunet N. Worldwide trends in gastric cancer mortality (1980–2011), with predictions to 2015, and incidence by subtype. Eur J Cancer. 2014; 50:1330–44. https://doi.org/10.1016/j.ejca.2014.01.029 PMid:24650579

Monograph of the incidence of Gastric carcinoma in Middle East: Middle East Cancer Consortium (MECC). Available at: http://www.cancer.gov/cancertopics/pdq/treatment/gastric/HealthProfessional/page4#Reference4.1. [accessed on 2014 Jan 10]

Parkin DM. The global health burden of infection-associated cancers in the year 2002. International Journal of Cancer. 2006; 118(12):3030–3044. https://doi.org/10.1002/ijc.21731 PMid:16404738

Poteca T, Poteca A, Sajin M, Comanescu M. Biological prognostic parameters in gastric carcinomas. Chirurgia (Bucur). 2014; 109(3):347–54.

Mohammad MA, Hussein L, Coward A, Jackson SJ. Prevalence of Helicobacter pylori infection among Egyptian children: impact of social background and effect on growth. Public Health Nutr. 2008; 11(3):230–236. https://doi.org/10.1017/S1368980007000481 PMid:17666124

GLOBOSCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide 2012, Population fact sheets, Egypt, available at http://globocan.iarc.fr/Pages/fact_sheets_population.aspx

Oliner JD, Kinzler KW, Melzer PS, George D, Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992; 358:80–83. https://doi.org/10.1038/358080a0 PMid:1614537

Moll UM and Petrenko O. The MDM2-p53 interaction. Mol Cancer Res. 2003; 1:1001–1008. PMid:14707283

Li Q, Lozano G. Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin Cancer Res. 2013; 19:34–41. https://doi.org/10.1158/1078-0432.CCR-12-0053 PMid:23262034 PMCid:PMC3537867

Peng Q, Lao X, Chen Z, Lai H, Deng Y, Wang J, Mo C, Sui J, Wu J, Zhai L, Yang S, Qin X, Li S. TP53 and MDM2 gene polymorphisms, gene-gene interaction, and hepatocellular carcinoma risk: evidence from an updated meta-analysis. PLoS One. 2013; 8:e82773. https://doi.org/10.1371/journal.pone.0082773 PMid:24376578 PMCid:PMC3871586

Park HS, Park JM, Park S, Cho J, Kim SI, Park BW. Subcellular localization of Mdm2 expression and prognosis of breast cancer. Int J Clin Oncol. 2014; 19(5):842-51. https://doi.org/10.1007/s10147-013-0639-1 PMid:24292333

Rahman MA, Salajegheh A, Smith RA, Lam AK. B-Raf mutation: a key player in molecular biology of cancer. Exp Mol Pathol. 2013; 95:336-42. https://doi.org/10.1016/j.yexmp.2013.10.005 PMid:24161954

Emuss V, Garnett M, Mason C, Marais R. Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res. 2005; 65:9719-9726. https://doi.org/10.1158/0008-5472.CAN-05-1683 PMid:16266992

Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004; 5:875-885. https://doi.org/10.1038/nrm1498 PMid:15520807

Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr Opin Genet Dev. 2007; 17:31-9. https://doi.org/10.1016/j.gde.2006.12.005 PMid:17208430

Davies H, Bignell GR, Cox C. Mutations of the BRAF gene in human cancer. Nature. 2002; 417:949-954 https://doi.org/10.1038/nature00766 PMid:12068308

Turbin DA, Cheang MC, Bajdik CD, Gelmon KA, Yorida E, De Luca A, Nielsen TO, Huntsman DG, Gilks CB. MDM2 protein expression is a negative prognostic marker in breast carcinoma. Mod Pathol. 2006; 19(1):69-74. https://doi.org/10.1038/modpathol.3800484 PMid:16258514

Bosmuller H, Fischer A, Pham DL, Fehm T, Capper D, von Deimling A, Bonzheim I, Staebler A, Fend F. Detection of the B-RAF V600E mutation in serous ovarian tumors: a comparative analysis of immunohistochemistry with a mutation-specific monoclonal antibody and allele specific PCR. Hum Pathol. 2013; 44:329-35. https://doi.org/10.1016/j.humpath.2012.07.010 PMid:23089489

Huss S, Pasternack H, Ihle MA, Merkelbach-Bruse S, Heitkötter B, Hartmann W, Trautmann M, Gevensleben H, Büttner R, Schildhaus HU, Wardelmann E. Clinicopathological and molecular features of a large cohort of gastrointestinal stromal tumors (GISTs) and review of the literature: BRAF mutations in KIT/PDGFRA wild-type GISTs are rare events. Hum Pathol. 2017; 62:206-214. https://doi.org/10.1016/j.humpath.2017.01.005 PMid:28159677

Busuttil RA, Zapparoli GV, Haupt S, Fennell C, Wong SQ, Pang JM, Takeno EA, Mitchell C, Di Costanzo N, Fox S, Haupt Y, Dobrovic A, Boussioutas A. Role of p53 in the progression of gastric cancer. Oncotarget. 2014; 5(23):12016-12026. https://doi.org/10.18632/oncotarget.2434 PMid:25427447 PMCid:PMC4322971

Northern Ireland Cancer Registry. Cancer incidence and mortality cancer research united kingdom (online) Avail-able:http://info.cancerresearchuk.org/. (Accessed January, 2012).

Gaballah A, Moawad M, Yassin M, El-Wasly N, El-Mahdy M. Clinicopathological, epidemiological and outcome of treatment of advanced gastric cancer in Egypt: single institution experience. Annals of Oncology. 2016: 27(2):86–101.

Darwish H, Sakr A, Basaam W, Ghorab A. 10 years' Experience in the Treatment of Gastric Cancer: A Single Egyptian Cancer Center (NEMROCK). PAJO. 2016; 9(3):35-41

Amieva M and Peek RM Jr. Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology. 2015; 150:64-78. https://doi.org/10.1053/j.gastro.2015.09.004 PMid:26385073 PMCid:PMC4691563

Hegazi A, Hassan E, El-Atrebi KA, El-Bassyouni HT. P53 protein and Ki-67 expression in chronic gastritis patients with positive Helicobacter pylori infection. J Genetic Engin Biotechnol. 2011; 9(1):73–6. https://doi.org/10.1016/j.jgeb.2011.05.008

Sabry D, Ahmed R, Abdalla S, Fathy W, Eldemery A, Elamir A. Braf, Kras and Helicobacter pylori epigenetic changes-associated chronic gastritis in Egyptian patients with and without gastric cancer. World Journal of Microbiology and Biotechnology. 2016; 32(6):92. https://doi.org/10.1007/s11274-016-2048-x PMid:27116958

Ramírez-Lázaro MJ, Lario S, Casalots A, Sanfeliu E, Boix L, García-Iglesias P, Sánchez-Delgado J, Montserrat A, Bella-Cueto MR, Gallach M, Sanfeliu I, Segura F, Calvet X. Real-time PCR improves Helicobacter pylori detection in patients with peptic ulcer bleeding. PLoS One. 2011; 6(5):e20009. https://doi.org/10.1371/journal.pone.0020009 PMid:21625499 PMCid:PMC3098855

Wu WK, Cho CH, Lee CW, Fan D, WuK, Yu J, Sung JJ. Dysregulation of cellular signaling in gastric cancer. Cancer Lett. 2010; 295:144–53. https://doi.org/10.1016/j.canlet.2010.04.025 PMid:20488613

Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013; 13:83–96. https://doi.org/10.1038/nrc3430 PMid:23303139 PMCid:PMC4161369

Gunther T, Schneider-Stock R, Hackel C, Kasper HU, Pross M, Hackelsberger A, Lippert H, Roessner A. Mdm2 gene amplification in gastric cancer correlation with expression of Mdm2 protein and p53 alterations. Mod Pathol. 2000; 13:621–626. https://doi.org/10.1038/modpathol.3880107 PMid:10874665

Ye Y, Li X, Yang J, Miao S, Wang S, Chen Y, Xia X, Wu X, Zhang J, Zhou Y, He S, Tan Y, Qiang F, Li G, Røe OD, Zhou J. MDM2 is a useful prognostic biomarker for resectable gastric cancer. Cancer Sci. 2013; 104:590–598. https://doi.org/10.1111/cas.12111 PMid:23347235

Nakajima N, Ito Y, Yokoyama K, Uno A, Kinukawa N, Nemoto N and Moriyama M. The Expression of Murine Double Minute 2 (MDM2) on Helicobacter pylori-Infected Intestinal Metaplasia and Gastric Cancer. Journal of clinical biochemistry and nutrition. 2009; 44:196-202. https://doi.org/10.3164/jcbn.08-254 PMid:19308274 PMCid:PMC2654476

Shen J, Niu W, Zhou M, Zhang H, Ma J, Wang L, Zhang H. MicroRNA-410 suppresses migration and invasion by targeting MDM2 in gastric cancer. PLoS One. 2014; 19:9(8):e104510.

Hostein I, Faur N, Primois C, Boury F, Denard J, Emile F, Bringuier PP, Scoazec JY, Coindre JM. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol. 2010; 133(1):141-148. https://doi.org/10.1309/AJCPPCKGA2QGBJ1R PMid:20023270

Agaimy A, Terracciano LM, Dirnhofer S, Tornillo L, Foerster A, Hartmann A, Bihl MP. V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours. J Clin Pathol. 2009; 62(7): 613-6. https://doi.org/10.1136/jcp.2009.064550 PMid:19561230

Martinho O, Gouveia A, Viana-Pereira M, Silva P, Pimenta A, Reis RM, Lopes JM. Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs. Histopathology. 2009; 55(1):53-62. https://doi.org/10.1111/j.1365-2559.2009.03323.x PMid:19614767

Daniels M, Lurkin I, Pauli R, Erbstößer E, Hildebrandt U, Hellwig K, Zschille U, Lüders P, Krüger G, Knolle J, Stengel B. Spectrum of KIT/PDGFRA/BRAF mutations and Phosphatidylinositol-3-Kinase pathway gene alterations in gastrointestinal stromal tumors (GIST). Cancer letters. 2011; 312(1):43-54. https://doi.org/10.1016/j.canlet.2011.07.029 PMid:21906875

Lee SH, Lee JW, Soung YH, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Nam SW, Kim SH, Lee JY, Yoo NJ. BRAF and KRAS mutations in stomach cancer. Oncogene. 2003; 22(44):6942–6945. https://doi.org/10.1038/sj.onc.1206749 PMid:14534542

Kim TM, Jung SH, Kim MS, Baek IP, Park SW, Lee SH, Lee HH, Kim SS, Chung YJ, Lee SH. The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers. J Pathol. 2014; 234:365-74. https://doi.org/10.1002/path.4401 PMid:25042771

Moradi MT, Salehi Z, Asl SF, Aminian K, Hashtchin AR. Helicobacter pylori infection and MDM2 SNP309 association with gastric cancer susceptibility. Genetic testing and molecular biomarkers. 2013; 17(11):794-8. https://doi.org/10.1089/gtmb.2013.0173 PMid:24010568

Fenouille N, Puissant A, Tichet M, Zimniak G, Abbe P, Mallavialle A, Rocchi S, Ortonne JP, Deckert M, Ballotti R, Tartare-Deckert S. SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival. Oncogene. 2011; 30:4887-4900. https://doi.org/10.1038/onc.2011.198 PMid:21685937

Kodama, M, Fujioka T, Murakami K, Okimoto T, Sato R, Watanabe K, Nasu M.. Eradication of Helicobacter pylori reduced the immunohistochemical detection of p53 and MDM2 in gastric mucosa. J Gastroenterol Hepatol. 2005; 20:941–946. https://doi.org/10.1111/j.1440-1746.2005.03880.x PMid:15946145

Sepideh S, Mohammadreza JN, Ali D, holamreza TP, Samira G. Study of the Murine Double Minute 2 status in patients with gastric and colorectal carcinomas and its correlation with prognostic factors. Indian J Pathol Microbiol. 2012; 55:192-5. https://doi.org/10.4103/0377-4929.97866 PMid:22771642

Corso G, Velho S, Paredes J, Pedrazzani C, Martins D, Milanezi F, Pascale V, Vindigni C, Pinheiro H, Leite M, Marrelli D, Sousa S, Carneiro F, Oliveira C, Roviello F, Seruca R. Oncogenic mutations in gastric cancer with microsatellite instability. Eur J Cancer. 2011; 47:443–451. https://doi.org/10.1016/j.ejca.2010.09.008 PMid:20937558

Stella G, Rojas Llimpe F, Barone C, Falcone A, Di Fabio F, Martoni A, Lamba S, Ceccarelli C, Siena S, Bardelli A, Pinto C. KRAS and BRAF mutational status as response biomarkers to cetuximab combination therapy in advanced gastric cancer patients. Journal of Clinical Oncology. 2009; 27(Suppl. 15):e15503.

Sasao S, Hiyama T, Tanaka S, Yoshihara M, Yasui W, Chayama K. Clinicopathologic and genetic characteristics of gastric cancer in young male and female patients. Oncol Rep. 2006; 16:11–15. https://doi.org/10.3892/or.16.1.11

Published

2018-10-10

How to Cite

1.
Aboushousha T, Helal N, Hammam O, Ibrahim M, Khaled S, Mostafa A, Anas A. Overview of MDM2 and B-RAF Expression in Gastric Lesions. Open Access Maced J Med Sci [Internet]. 2018 Oct. 10 [cited 2021 May 15];6(10):1795-802. Available from: https://oamjms.eu/index.php/mjms/article/view/oamjms.2018.338

Issue

Section

A - Basic Science

Most read articles by the same author(s)