Turkiye Klinikleri Journal of Pediatrics

.: ORIGINAL RESEARCH
Atipik Teratoid Rabdoid Tümörlü Olgularda Demografik, Klinik, Patolojik Özelliklerin ve HSNF5 (SMARCB1)/INI1 Gen Mutasyonlarının Araştırılması
Investigation of Demographic, Clinical, Pathological Features and HSNF5 (SMARCB1)/INI1 Gene Mutations in Patients Diagnosed as Atypical Teratoid Rhabdoid Tumors
Elif KIYMETa, Tahir ATİKb, Esra IŞIKb, Bilçağ AKGÜNb , Nazan ÇETİNGÜLc, Taner AKALINd, Ferda ÖZKINAYb
aEge Üniversitesi Tıp Fakültesi, Çocuk Sağlığı ve Hastalıkları ABD, İzmir, TÜRKİYE
bEge Üniversitesi Tıp Fakültesi, Çocuk Genetik Hastalıkları BD, İzmir, TÜRKİYE
cEge Üniversitesi Tıp Fakültesi, Çocuk Onkoloji BD, İzmir, TÜRKİYE
dEge Üniversitesi Tıp Fakültesi, Patoloji ABD, İzmir, TÜRKİYE
Turkiye Klinikleri J Pediatr. 2020;29(3):139-47
doi: 10.5336/pediatr.2019-72772
Article Language: TR
Full Text
ÖZET
 Amaç: Atipik teratoid/rabdoid tümör (AT/RT), çocukluk çağı santral sinir sistemi (SSS) tümörlerinden olan embriyonel tümörlerin nadir bir alt grubunu oluşturmaktadır. 22q11.2'de lokalize SMARCB1/INI1 geninde somatik dokularda oluşan değişikliklerin (delesyon, nokta mutasyonu, heterozigosite kaybı), AT/RT'lerin yaklaşık %75-98'inde bulunduğu gösterilmiştir. Ayrıca AT/RT'li hastaların 1/3'ünde SMARCB1/INI1 geninde germline mutasyonlar bildirilmiştir. Bu çalışmada, AT/RT tanısı alan hastalarda bu tümör ile ilişkili bir tümör supresör gen olan SMARCB1/INI1 mutasyonlarının araştırılması amaçlanmıştır. Gereç ve Yöntemler: Bu çalışmada, 2010-2015 yılları arasında Ege Üniversitesi Tıp Fakültesinde, AT/RT tanısı almış olguların demografik, klinik, patolojik özellikleri ve SMARCB1/INI1 mutasyonları değerlendirildi. Olguların hepsinin tümör dokusuna ait patoloji preparatlarından ve ulaşılabilen olguların periferik kanlarından DNA izole edilerek, SMARCB1/INI1 geni için tüm ekzonik bölgeler polimeraz zincir reaksiyonu ile çoğaltıldı, jel elektroforezi ile kontrol edildikten sonra DNA dizi analizi gerçekleştirildi. Tespit edilen varyasyonların patojenitesi, Amerikan Tıbbi Genetik Koleji 2015 kriterlerine göre değerlendirildi. Bulgular: Çalışmaya alınan 10 hastanın 7'si SSS'nin AT/RT'si, 2'si yumuşak dokuda RT, biri renal RT tanılıydı. Hastaların %77'sinde tümör dokusunda immünohistokimyasal yöntemler ile SMARCB1/INI1 protein ekspresyonu kaybı saptandı ve bu hastaların ortanca sağkalım süresinin 5 ay (1-69 ay, SE: 9,29 ay) olduğu görüldü. Dört hastanın tümör dokusunda SMARCB1/INI1 geninde, mutasyon saptandı ve bu hastaların ortanca sağkalım süresi 5,5 ay (1-15 ay, SE: 2,95 ay) olarak saptandı. SMARCB1/INI1 geninde mutasyon saptanmayan hastaların ortanca sağkalım süresi 10,5 ay (1-81 ay, SE: 14,6 ay) olarak saptandı. Sonuç: Tümör dokusunda SMARCB1/INI1 geninde mutasyon saptanan hastaların ortanca sağkalım sürelerinin, mutasyon saptanmayanlara göre daha kısa olduğu gözlenmiştir. Önceki yayınlardan farklı olarak AT/RT tanılı hasta grubumuzda, hiçbir hastada SMARCB1/INI1 geninde germline mutasyon saptanmamıştır.

Anahtar Kelimeler: Santral sinir sistemi neoplazileri; tümör baskılayıcı genler; SMARCB1 protein; rabdoid tümör
ABSTRACT
 Objective: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare subgroup of embryonal tumors of childhood central nervous system (CNS) tumors. It has been reported that approximately 75-98% of patients with AT/RT have somatic changes (deletion, point mutation, loss of heterozygosity) in the SMARCB1/INI1 gene localized in 22q11.2 and also one-third of the patients have germline mutations. This study aimed to investigate the SMARCB1/INI1 mutations, a tumor suppressor gene associated with this tumor, in patients with AT/RT. Material and Methods: The demographic, clinical, pathological features and SMARCB1/INI1 mutations of patients diagnosed at Ege University between 2010-2015 were evaluated. DNA was isolated from pathological preparations of tumor tissue of all cases and peripheral blood of accessible patients, and all exonic regions for the SMARCB1/INI1 gene were reproduced by polymerase chain reaction, and DNA sequence analysis was performed after control by gel electrophoresis. Pathogenicity of the variations found was evaluated according to American College of Medical Genetics 2015 criteria. Results: 7/10 patients were diagnosed as AT/RT of CNS, 2/10 as soft tissue RT, and 1/10 as the renal RT. In 77% of the patients, loss of SMARCB1/INI1 protein expression was detected by immunohistochemical methods in tumor tissue and mean survival was 5 months (1-69 months, SE: 9.29 months). The mutation was detected in SMARCB1/INI1 in tumor tissue of four patients and median survival was 5.5 months (1-15 months, SE: 2.95 months). The median survival of patients without a mutation in the SMARCB1/INI1 gene was found to be 10.5 months (1-81 months, SE: 14.6 months). Conclusion: The median survival time of the patients with SMARCB1/INI1 mutation seems to be shorter than the ones without the mutation. Unlike previous publications, in our patient group diagnosed as AT/RT, no germline mutation was detected in the SMARCB1/INI1 gene.

Keywords: Central nervous system neoplasms; tumor suppressor genes; SMARCB1 protein; rhabdoid tumor
REFERENCES:
  1. Kutluk T. Çocukluk çağı kanserlerinin epidemiyolojisi. Klin Gelişim. 2007;20(2):6-12.
  2. Biegel JA, Kalpana G, Knudsen ES, Packer RJ, Roberts CWM, Thiele CJ, et al. The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res. 2002;62(1):323-8.
  3. Rorke LB, Packer R, Biegel J. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood. J Neurooncol. 1995;24(1):21-8. [Crossref]  [PubMed] 
  4. Woehrer A, Slavc I, Waldhoer T, Heinzl H, Zielonke N, Czech T, et al. Incidence of atypical teratoid/rhabdoid tumors in children: a population-based study by the Austrian Brain Tumor Registry, 1996-2006. Cancer. 2010;116(24):5725-32. [Crossref]  [PubMed] 
  5. Haberler C, Laggner U, Slavc I, Czech T, Ambros IM, Ambros PF, et al. Immunohistochemical analysis of INI1 protein in malignant pediatric CNS tumors: lack of INI1 in atypical teratoid/rhabdoid tumors and in a fraction of primitive neuroectodermal tumors without rhabdoid phenotype. Am J Surg Pathol. 2006;30(11):1462-8. [Crossref]  [PubMed] 
  6. Kalpana GV, Marmon S, Wang W, Crabtree GR, Goff SP. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science. 1994;266(5193):2002-6. [Crossref]  [PubMed] 
  7. Ho DMT, Shih CC, Liang ML, Tsai CY, Hsieh TH, Tsai CH, et al. Integrated genomics has identified a new AT/RT-like yet INI1-positive brain tumor subtype among primary pediatric embryonal tumors. BMC Med Genomics. 2015;8:32. [Crossref]  [PubMed]  [PMC] 
  8. Biegel JA, Tan L, Zhang F, Wainwright L, Russo P, Rorke LB. Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res. 2002;8(11):3461-7.
  9. Biegel JA. Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus. 2006;20(1):E11. [Crossref]  [PubMed] 
  10. Jackson EM, Sievert AJ, Gai X, Hakonarson H, Judkins AR, Tooke L, et al. Genomic analysis using high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin Cancer Res. 2009;15(6):1923-30. [Crossref]  [PubMed]  [PMC] 
  11. Tsai CY, Wong T, Lee YH, Chao ME, Lin SC, Liu DJ, et al. Intact INI1 gene region with paradoxical loss of protein expression in AT/RT: implications for a possible novel mechanism associated with absence of INI1 protein immunoreactivity. Am J Surg Pathol. 2012;36(1):128-33. [Crossref]  [PubMed] 
  12. Judkins AR. Immunohistochemistry of INI1 expression: a new tool for old challenges in CNS and soft tissue pathology. Adv Anat Pathol. 2007;14(5):335-9. [Crossref]  [PubMed] 
  13. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-20. [Crossref]  [PubMed] 
  14. Lafay-Cousin L, Hawkins C, Carret AS, Johnston D, Zelcer S, Wilson B, et al. Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience. Eur J Cancer. 2012;48(3):353-9. [Crossref]  [PubMed] 
  15. Chi SN, Zimmerman MA, Yao X, Cohen KJ, Burger P, Biegel JA, et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol. 2009;27(3):385-9. [Crossref]  [PubMed]  [PMC] 
  16. Benesch M, Bartelheim K, Fleischhack G, Gruhn B, Schlegel PG, Witt O, et al. High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB). Bone Marrow Transplant. 2014;49(3):370-5. [Crossref]  [PubMed] 
  17. Tekautz TM, Fuller CE, Blaney S, Fouladi M, Broniscer A, Merchant TE, et al. Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol. 2005;23(7):1491 -9. [Crossref]  [PubMed] 
  18. Panandiker ASP, Merchant TE, Beltran C, Wu S, Sharma S, Boop FE, et al. Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system. Int J Radiat Oncol Biol Phys. 2012;82(5):1756-63. [Crossref]  [PubMed]  [PMC] 
  19. Mohapatra I, Santosh V, Chickabasaviah YT, Mahadevan A, Tandon A, Ghosh A, et al. Histological and immunohistochemical characterization of AT/RT: a report of 15 cases from India. Neuropathology. 2010;30(3):251-9. [Crossref]  [PubMed] 
  20. Hilden JM, Watterson J, Longee DC, Moertel CL, Dunn ME, Kurtzberg J, et al. Central nervous system atypical teratoid tumor/rhabdoid tumor: response to intensive therapy and review of the literature. J Neurooncol. 1998;40(3):265-75. [Crossref]  [PubMed] 
  21. Lafay-Cousin L, Hawkins C, Carret AS, Johnston D, Zelcer S, Wilson B, et al. Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience. Eur J Cancer. 2012;48(3):353-9. [Crossref]  [PubMed] 
  22. Packer RJ, Biegel JA, Blaney S, Finlay J, Geyer JR, Heideman R, et al. Atypical teratoid/rhabdoid tumor of the central nervous system : report on workshop. J Pediatr Hematol Oncol. 2002;24(5):337-42. [Crossref]  [PubMed] 
  23. Sévenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet. 1999;65(5):1342-8. [Crossref]  [PubMed]  [PMC] 
  24. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 1999;59(1):74-9.
  25. Hilden JM, Meerbaum S, Burger P, Finlay J, Janss A, Scheithauer BW, et al. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol. 2004;22(14):2877-84. [Crossref]  [PubMed] 
  26. Judkins AR, Mauger J, Ht A, Rorke LB, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol. 2004;28(5):644-50. [Crossref]  [PubMed] 
  27. Sigauke E, Rakheja D, Maddox DL, Hladik CL, White CL, Timmons CF, et al. Absence of expression of SMARCB1/INI1 in malignant rhabdoid tumors of the central nervous system, kidneys and soft tissue: an immunohistochemical study with implications for diagnosis. Mod Pathol. 2006;19(5):717-25. [Crossref]  [PubMed] 
  28. Lever E, Sheer D. The role of nuclear organization in cancer. J Pathol. 2010;220(2):114-25. [Crossref]  [PubMed] 
  29. Hasselblatt M, Gesk S, Oyen F, Rossi S, Viscardi E, Giangaspero F, et al. Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol. 2011;35(6):933-5. [Crossref]  [PubMed] 
  30. Schneppenheim R, Frühwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes U, et al. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet. 2010;86(2):279-84. [Crossref]  [PubMed]  [PMC] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com