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] 

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