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Lösemi ve Hodgkin Lenfomalı Pediatrik Hastalarda Epstein-Barr Virüsü Genomunun Tespiti: Türkiye'de Pediatrik Kanserlerde Viral Etiyoloji

Yıl 2023, , 438 - 447, 26.12.2023
https://doi.org/10.24938/kutfd.1345541

Öz

Amaç: Kanser, yaygın görülmesi ve zorlu tedavi süreci ile karakterize yaygın bir hastalıktır. Virüsler de dahil olmak üzere birçok etken hem yetişkinlerde hem de çocuklarda kanserin potansiyel nedenleri olarak tanımlanmış olsa da kanserlerin patogenezi tam olarak aydınlatılamamıştır. Bu çalışma, B hücreli akut lenfoblastik lösemi (ALL), T hücreli ALL, Hodgkin lenfoma tanısı almış ve lösemi ile lenfoma nükseden pediatrik hastalardan elde edilen kan örneklerinde (n=64), insan T-hücreli lenfotropik virüs tip 1 (HTLV-1), Epstein-Barr virüsü (EBV), Kaposi sarkom ilişkili herpesvirüs (KSHV) ve insan parvovirus B19'un (HPV B19) varlığını incelemeyi amaçlamıştır.
Gereç ve Yöntemler: Hastalardan hem tedavi öncesi hem tedavi sonrası dönemlerinde tam kan örnekleri alınmış ve bu örneklerde HTLV-1, EBV, KSHV ve HPV B19 viral genom varlığını tespit etmek için polimeraz zincir reaksiyonu (PCR) ve gerçek zamanlı PCR yapılmıştır. Pozitif örneklerden Sanger sekanslama ile sekans analizi yapılmış ve filogenetik analizler gerçekleştirilmiştir.
Bulgular: Toplam 64 örnek analiz edildiğinde, HTLV-1, KSHV ve HPV B19'un negatif olduğu belirlenmiştir. Ancak, EBV genomu ALL ve Hodgkin lenfoma hastalarından altı örnekte (%9.37) tespit edilmiştir; bu örnekler hem tedavi öncesi (n=3) hem de tedavi sonrası (n=3) vakalarda saptanmıştır. Pozitif EBV örneklerinin sekanslama sonrasında ve GenBank'ta bulunan diğer EBV dizileri ile hizalanması, birbirleri ile yüksek derecede benzerlik gösterdiğini ortaya koymuştur.
Sonuç: Bulgularımız, EBV'nin, lösemi ve Hodgkin lenfomalı pediatrik kanser vakalarında etkili olan viral ajanlardan biri olabileceğini düşündürmektedir. Bu nedenle, Türkiye'deki bu hasta popülasyonunda EBV genomunun varlığını test edilmesi önemli olabilecektir. Bu veri, pediatrik kanserlerin temelindeki viral etiyolojiyi daha iyi anlamamıza ve gelecekte hedefe yönelik tanı ve tedavi stratejilerinin geliştirilmesine yardımcı olacaktır.

Destekleyen Kurum

Kırıkkale Üniversitesi Bilimsel Araştırma Projeleri Birimi

Proje Numarası

2016/116

Kaynakça

  • Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F et al. International incidence of childhood cancer, 2001-10: A population-based registry study. Lancet Oncol. 2017;18(6):719-31.
  • National Vital Statistics Reports. Accessed date: 3 September 2023 / Erişim tarihi: 3 Eylül 2023: https://www.cdc.gov/nchs/data/nvsr/nvsr62/nvsr62_ 06.pdf
  • Ameya G, Birri DJ. The molecular mechanisms of virus-induced human cancers. Microb Pathog. 2023;183:106292.
  • Kerr JR, Mattey DL. The role of parvovirus B19 and the immune response in the pathogenesis of acute leukemia. Rev Med Virol. 2015;25(3):133-55.
  • Eusebio-Ponce E, Anguita E, Paulino-Ramirez R, Candel FJ. HTLV-1 infection: An emerging risk. Pathogenesis, epidemiology, diagnosis and associated diseases. Revista Española de Quimioterapia. 2019;32(6):485-496.
  • Ratner L. Molecular biology of human T cell leukemia virus. Semin Diagn Pathol. 2020;37(2):104-9.
  • Grywalska E, Rolinski J. Epstein-Barr virus- associated lymphomas. Semin Oncol. 2015;42(2):291-303.
  • Calabrò ML, Sarid R. Human Herpesvirus 8 and lymphoproliferative disorders. Mediterr J Hematol Infect Dis. 2018;10(1):e2018061.
  • Heegaard ED, Brown KE. Human parvovirus B19. Clin Microbiol Rev. 2002;15(3):485-505.
  • Weir EG, Borowitz MJ. Flow cytometry in the diagnosis of acute leukemia. Semin Hematol. 2001;38(2):124-38.
  • Li W. Flow Cytometry in the Diagnosis of Leukemias. In: Leukemia. Exon Publications. 2022: 53-77.
  • Klinisyen-Patolog Ortak Lenfoma Kursu- Hodgkin Lenfoma: Histopatoloji ve Ayırıcı Tanı. Accessed date: 1 September 2023 / Erişim tarihi: 1 Eylül 2023: https://www.thd.org.tr/etkinlikler/3/kongre-ve- kurslar/328/klinisyen-patolog-ortak-lenfoma-kursu.
  • A Randomized Trial of the I-BFM-SG for the Management of Childhood non-B Acute Lymphoblastic Leukemia. Accessed date: 1 September 2023 / Erişim tarihi: 1 Eylül 2023: https://www.bialaczka.org/wp- content/uploads/2016/10/ALLIC_BFM_2009.pdf.
  • Schwartz CL, Constine LS, Villaluna D, London WB, Hutchison RE, Sposto R et al. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: The results of P9425. Blood. 2009;114(10):2051-59.
  • Azkur AK, van der Poel WHM, Aksoy E, Hakze-van der Honing R, Yildirim M, Yıldız K. Development and validation of SYBR Green- and probe-based reverse-transcription real-time PCR assays for detection of the S and M segments of Schmallenberg virus. J Vet Diagn Invest. 2020;32(5):710-17.
  • Azkur AK, Bolat Y, Doymaz MZ. Amplification of the matrix gene of RBOK vaccine strain of rinderpest virus (RPV) by polymerase chanin reaction and cloning into TOPOR XL cloning vector. Turk J Vet Anim Sci. 2003;27(1):229-33.
  • International Agency For Research On Cancer (IARC). Accessed date: 1 September 2023 / Erişim tarihi: 1 Eylül 2023:https://monographs.iarc.who.int/agents-classified- by-the-iarc/.
  • Yazan Sertoz R, Kalfaoglu H, Dundar IH, Birinci I, Bakir Saygan M, Baskir MB et al. Anti-HTLV I/II seroprevalence in healthy blood donors the first diagnosed two cases in Turkey. Journal of Clinical Virology. 2015;70:S119.
  • Yuksekkaya HA, Arikan C, Yazici A, Baran M, Aydogdu S, Kilic M. Successful treatment of a child having generalized Kaposi’s sarcoma after living donor liver transplantation with conversion to sirolimus. Pediatr Transplant. 2009;13(3):375-78.
  • Karakoyun M, Onen S, Baran M, Cakir M, Ecevit CO, Kilic M et al. Post-transplant malignancies in pediatric liver transplant recipients: Experience of two centers in Turkey. Turk J Gastroenterol. 2018;29(1):89-93.
  • Türk Daği H, Özdemı̇r M, Baykan M, Baysal B, Üniversitesi Meram Tıp Fakültesi S, ve Klinik Mikrobiyoloji Anabilim Dalı M et al. Investigation of parvovirus B19 seroprevalence in various age groups in Central Anatolia Region, Turkey. Mikrobiyol Bul. 2010;44(3):467-72.
  • Tüfekçi Ö, Bengoa ŞY, Erdem M, Ören H. Induction failure in acute leukemia or parvovirus B19 infection? J Pediatr Hematol Oncol. 2017;39(7):565.
  • Yetgin S, Çetin M, Aslan D, Özyürek E, Anlar B, Uçkan D. Parvovirus B19 infection presenting as pre-B-cell acute lymphoblastic leukemia: A transient and progressive course in two children. J Pediatr Hematol Oncol. 2004;26(10):689-92.
  • Tacyildiz N, Cavdar AO, Ertem U, Oksal A, Kutluay L, Uluoglu O et al. Unusually high frequency of a 69-bp deletion within the carboxy terminus of the LMP-1 oncogene of Epstein-Barr virus detected in Burkitt’s lymphoma of Turkish children. Leukemia. 1998;12(11):1796-805.
  • Tinguely M, Bründler MA, Gogos S, Kerl K, Borisch B. Epstein-Barr virus association in pediatric abdominal non-Hodgkin-lymphomas from Turkey. Arch Immunol Ther Exp (Warsz). 2000;48(4):317-22.
  • Cekic S, Metin A, Aytekin C, Edeer Karaca N, Baris S, Karali Y et al. The evaluation of malignancies in Turkish primary immunodeficiency patients; a multicenter study. Pediatr Allergy Immunol. 2020;31(5):528-36.
  • Chen WJ, Xu WN, Wang HY, Chen XX, Li XQ, Xie SH et al. Plasma Epstein-Barr virus DNA and risk of nasopharyngeal carcinoma in a prospective seropositive population. BMC Cancer. 2021;21(1):651.
  • Jo SA, Hwang S-H, Kim SY, Shin H-J, Chung JS, Sol MY et al. Quantitation of whole blood Epstein- Barr virus DNA is useful for assessing treatment response in patients with non-Hodgkin’s lymphoma. Int J Lab Hematol. 2010;32(1 Pt 1):e106-13.
  • Li X, Yang SE, Guo YQ, Shen MX, Gulikezi LG, Zhao B et al. Clinical significance of quantitative analysis of plasma epstein-barr virus DNA in patients of Xinjiang Uygur nationality with Hodgkin’s Lymphoma. Asian Pac J Cancer Prev. 2012;13(12):6379-84.
  • Hohaus S, Santangelo R, Giachelia M, Vannata B, Massini G, Cuccaro A et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17(9):2885-92.
  • Zeng M, Jia Q, Chen J, Xu L, Xie L, Cheng Q et al. High plasma EBV-DNA load and positive EBER status associated with viral recurrence and persistent infection in early treatment of lymphoma. Clin Exp Med. 2023;23(4):1307-16.
  • Van Esser JWJ, Niesters HGM, Thijsen SFT, Meijer E, Osterhaus ADME, Wolthers KC et al. Molecular quantification of viral load in plasma allows for fast and accurate prediction of response to therapy of Epstein-Barr virus-associated lymphoproliferative disease after allogeneic stem cell transplantation. Br J Haematol. 2001;113(3):814-21.
  • Liu J, Gao H, Xu LP, Mo XD, Liu R, Liang S et al. Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2+ T cells activities after hematopoietic transplantation for blood malignancies. J Immunother Cancer. 2020;8(1):e000208.
  • Lallemand F, Desire N, Rozenbaum W, Nicolas JC, Marechal V. Quantitative analysis of human herpesvirus 8 viral load using a real-time PCR assay. J Clin Microbiol. 2000;38(4):1404-8.
  • Telenti A, Marshall WF, Smith TF. Detection of Epstein-Barr virus by polymerase chain reaction. J Clin Microbiol. 1990;28(10):2187-90.
  • Toppinen M, Norja P, Aaltonen LM, Wessberg S, Hedman L, Söderlund-Venermo M et al. A new quantitative PCR for human parvovirus B19 genotypes. J Virol Methods. 2015;218:40-5.
  • Mahzounieh M, Ghorani M, Karimi A, Pourgheysari B, Nikoozad R. Prevalence of Human t- lymphotropic virus types I and II in patients with hematological Disorders in Isfahan, Iran. Jundishapur J Microbiol. 2015; 8(6):e17201.
  • Ito TK, Ishii G, Chiba H, Ochiai A. The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene. 2007; 26(51):7194-203.

DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE

Yıl 2023, , 438 - 447, 26.12.2023
https://doi.org/10.24938/kutfd.1345541

Öz

Objective: Cancer is a pervasive disease characterized by its widespread occurrence and challenging treatment process. While numerous agents, including viruses, have been identified as potential causes of cancer in both adults and children, the complete pathogenesis of cancers remains incompletely elucidated. This study aimed to examine the presence of four viral agents, namely Human T-cell Lymphotropic Virus Type 1 (HTLV-1), Epstein-Barr Virus (EBV), Kaposi's Sarcoma- Associated Herpesvirus (KSHV), and Human Parvovirus B19 (HPV B19), in blood samples obtained from pediatric patients (n=64) diagnosed with B cell acute lymphoblastic leukemia (ALL), T cell ALL, Hodgkin lymphoma, and patients with relapsed leukemia and lymphoma.
Material and Methods: The whole blood samples collected from the patients during the pre-treatment and post-treatment periods underwent polymerase chain reaction (PCR) and real- time PCR to identify the presence of the viral genomes of HTLV-1, EBV, KSHV, and HPV B19. The samples that tested positive were subsequently subjected to Sanger sequencing, followed by phylogenetic analysis.
Results: Among a total of 64 samples analyzed, HTLV-1, KSHV, and HPV B19 were found to be negative. However, EBV genome was detected in six samples (9.37%) from patients with ALL and Hodgkin lymphoma, comprising both pre- treatment (n=3) and post-treatment (n=3) cases. Subsequent sequencing and alignment of the positive EBV samples with other EBV sequences deposited in GenBank revealed a high degree of similarity.
Conclusion: Our findings suggest that EBV may be one of the viral agents implicated in pediatric cancer cases involving leukemia and Hodgkin lymphoma. Therefore, it is recommended to consider testing for the presence of EBV genome in these patient populations within the context of Türkiye. This information contributes to a better understanding of the viral etiology underlying pediatric cancers, enabling the development of targeted diagnostic and therapeutic strategies in the future.

Destekleyen Kurum

Scientific Research Projects Coordination Unit of Kırıkkale University

Proje Numarası

2016/116

Kaynakça

  • Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F et al. International incidence of childhood cancer, 2001-10: A population-based registry study. Lancet Oncol. 2017;18(6):719-31.
  • National Vital Statistics Reports. Accessed date: 3 September 2023 / Erişim tarihi: 3 Eylül 2023: https://www.cdc.gov/nchs/data/nvsr/nvsr62/nvsr62_ 06.pdf
  • Ameya G, Birri DJ. The molecular mechanisms of virus-induced human cancers. Microb Pathog. 2023;183:106292.
  • Kerr JR, Mattey DL. The role of parvovirus B19 and the immune response in the pathogenesis of acute leukemia. Rev Med Virol. 2015;25(3):133-55.
  • Eusebio-Ponce E, Anguita E, Paulino-Ramirez R, Candel FJ. HTLV-1 infection: An emerging risk. Pathogenesis, epidemiology, diagnosis and associated diseases. Revista Española de Quimioterapia. 2019;32(6):485-496.
  • Ratner L. Molecular biology of human T cell leukemia virus. Semin Diagn Pathol. 2020;37(2):104-9.
  • Grywalska E, Rolinski J. Epstein-Barr virus- associated lymphomas. Semin Oncol. 2015;42(2):291-303.
  • Calabrò ML, Sarid R. Human Herpesvirus 8 and lymphoproliferative disorders. Mediterr J Hematol Infect Dis. 2018;10(1):e2018061.
  • Heegaard ED, Brown KE. Human parvovirus B19. Clin Microbiol Rev. 2002;15(3):485-505.
  • Weir EG, Borowitz MJ. Flow cytometry in the diagnosis of acute leukemia. Semin Hematol. 2001;38(2):124-38.
  • Li W. Flow Cytometry in the Diagnosis of Leukemias. In: Leukemia. Exon Publications. 2022: 53-77.
  • Klinisyen-Patolog Ortak Lenfoma Kursu- Hodgkin Lenfoma: Histopatoloji ve Ayırıcı Tanı. Accessed date: 1 September 2023 / Erişim tarihi: 1 Eylül 2023: https://www.thd.org.tr/etkinlikler/3/kongre-ve- kurslar/328/klinisyen-patolog-ortak-lenfoma-kursu.
  • A Randomized Trial of the I-BFM-SG for the Management of Childhood non-B Acute Lymphoblastic Leukemia. Accessed date: 1 September 2023 / Erişim tarihi: 1 Eylül 2023: https://www.bialaczka.org/wp- content/uploads/2016/10/ALLIC_BFM_2009.pdf.
  • Schwartz CL, Constine LS, Villaluna D, London WB, Hutchison RE, Sposto R et al. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: The results of P9425. Blood. 2009;114(10):2051-59.
  • Azkur AK, van der Poel WHM, Aksoy E, Hakze-van der Honing R, Yildirim M, Yıldız K. Development and validation of SYBR Green- and probe-based reverse-transcription real-time PCR assays for detection of the S and M segments of Schmallenberg virus. J Vet Diagn Invest. 2020;32(5):710-17.
  • Azkur AK, Bolat Y, Doymaz MZ. Amplification of the matrix gene of RBOK vaccine strain of rinderpest virus (RPV) by polymerase chanin reaction and cloning into TOPOR XL cloning vector. Turk J Vet Anim Sci. 2003;27(1):229-33.
  • International Agency For Research On Cancer (IARC). Accessed date: 1 September 2023 / Erişim tarihi: 1 Eylül 2023:https://monographs.iarc.who.int/agents-classified- by-the-iarc/.
  • Yazan Sertoz R, Kalfaoglu H, Dundar IH, Birinci I, Bakir Saygan M, Baskir MB et al. Anti-HTLV I/II seroprevalence in healthy blood donors the first diagnosed two cases in Turkey. Journal of Clinical Virology. 2015;70:S119.
  • Yuksekkaya HA, Arikan C, Yazici A, Baran M, Aydogdu S, Kilic M. Successful treatment of a child having generalized Kaposi’s sarcoma after living donor liver transplantation with conversion to sirolimus. Pediatr Transplant. 2009;13(3):375-78.
  • Karakoyun M, Onen S, Baran M, Cakir M, Ecevit CO, Kilic M et al. Post-transplant malignancies in pediatric liver transplant recipients: Experience of two centers in Turkey. Turk J Gastroenterol. 2018;29(1):89-93.
  • Türk Daği H, Özdemı̇r M, Baykan M, Baysal B, Üniversitesi Meram Tıp Fakültesi S, ve Klinik Mikrobiyoloji Anabilim Dalı M et al. Investigation of parvovirus B19 seroprevalence in various age groups in Central Anatolia Region, Turkey. Mikrobiyol Bul. 2010;44(3):467-72.
  • Tüfekçi Ö, Bengoa ŞY, Erdem M, Ören H. Induction failure in acute leukemia or parvovirus B19 infection? J Pediatr Hematol Oncol. 2017;39(7):565.
  • Yetgin S, Çetin M, Aslan D, Özyürek E, Anlar B, Uçkan D. Parvovirus B19 infection presenting as pre-B-cell acute lymphoblastic leukemia: A transient and progressive course in two children. J Pediatr Hematol Oncol. 2004;26(10):689-92.
  • Tacyildiz N, Cavdar AO, Ertem U, Oksal A, Kutluay L, Uluoglu O et al. Unusually high frequency of a 69-bp deletion within the carboxy terminus of the LMP-1 oncogene of Epstein-Barr virus detected in Burkitt’s lymphoma of Turkish children. Leukemia. 1998;12(11):1796-805.
  • Tinguely M, Bründler MA, Gogos S, Kerl K, Borisch B. Epstein-Barr virus association in pediatric abdominal non-Hodgkin-lymphomas from Turkey. Arch Immunol Ther Exp (Warsz). 2000;48(4):317-22.
  • Cekic S, Metin A, Aytekin C, Edeer Karaca N, Baris S, Karali Y et al. The evaluation of malignancies in Turkish primary immunodeficiency patients; a multicenter study. Pediatr Allergy Immunol. 2020;31(5):528-36.
  • Chen WJ, Xu WN, Wang HY, Chen XX, Li XQ, Xie SH et al. Plasma Epstein-Barr virus DNA and risk of nasopharyngeal carcinoma in a prospective seropositive population. BMC Cancer. 2021;21(1):651.
  • Jo SA, Hwang S-H, Kim SY, Shin H-J, Chung JS, Sol MY et al. Quantitation of whole blood Epstein- Barr virus DNA is useful for assessing treatment response in patients with non-Hodgkin’s lymphoma. Int J Lab Hematol. 2010;32(1 Pt 1):e106-13.
  • Li X, Yang SE, Guo YQ, Shen MX, Gulikezi LG, Zhao B et al. Clinical significance of quantitative analysis of plasma epstein-barr virus DNA in patients of Xinjiang Uygur nationality with Hodgkin’s Lymphoma. Asian Pac J Cancer Prev. 2012;13(12):6379-84.
  • Hohaus S, Santangelo R, Giachelia M, Vannata B, Massini G, Cuccaro A et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17(9):2885-92.
  • Zeng M, Jia Q, Chen J, Xu L, Xie L, Cheng Q et al. High plasma EBV-DNA load and positive EBER status associated with viral recurrence and persistent infection in early treatment of lymphoma. Clin Exp Med. 2023;23(4):1307-16.
  • Van Esser JWJ, Niesters HGM, Thijsen SFT, Meijer E, Osterhaus ADME, Wolthers KC et al. Molecular quantification of viral load in plasma allows for fast and accurate prediction of response to therapy of Epstein-Barr virus-associated lymphoproliferative disease after allogeneic stem cell transplantation. Br J Haematol. 2001;113(3):814-21.
  • Liu J, Gao H, Xu LP, Mo XD, Liu R, Liang S et al. Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2+ T cells activities after hematopoietic transplantation for blood malignancies. J Immunother Cancer. 2020;8(1):e000208.
  • Lallemand F, Desire N, Rozenbaum W, Nicolas JC, Marechal V. Quantitative analysis of human herpesvirus 8 viral load using a real-time PCR assay. J Clin Microbiol. 2000;38(4):1404-8.
  • Telenti A, Marshall WF, Smith TF. Detection of Epstein-Barr virus by polymerase chain reaction. J Clin Microbiol. 1990;28(10):2187-90.
  • Toppinen M, Norja P, Aaltonen LM, Wessberg S, Hedman L, Söderlund-Venermo M et al. A new quantitative PCR for human parvovirus B19 genotypes. J Virol Methods. 2015;218:40-5.
  • Mahzounieh M, Ghorani M, Karimi A, Pourgheysari B, Nikoozad R. Prevalence of Human t- lymphotropic virus types I and II in patients with hematological Disorders in Isfahan, Iran. Jundishapur J Microbiol. 2015; 8(6):e17201.
  • Ito TK, Ishii G, Chiba H, Ochiai A. The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene. 2007; 26(51):7194-203.
Toplam 38 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Hizmetleri ve Sistemleri (Diğer)
Bölüm Özgün Araştırma
Yazarlar

Yasin Köksal 0000-0003-0797-9568

Ahmet Kürşat Azkur 0000-0002-5597-8917

Emel Aksoy 0000-0001-9536-4322

Habibe Meltem Özgüner 0000-0003-0364-5907

Proje Numarası 2016/116
Yayımlanma Tarihi 26 Aralık 2023
Gönderilme Tarihi 29 Ağustos 2023
Yayımlandığı Sayı Yıl 2023

Kaynak Göster

APA Köksal, Y., Azkur, A. K., Aksoy, E., Özgüner, H. M. (2023). DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE. The Journal of Kırıkkale University Faculty of Medicine, 25(3), 438-447. https://doi.org/10.24938/kutfd.1345541
AMA Köksal Y, Azkur AK, Aksoy E, Özgüner HM. DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE. Kırıkkale Üni Tıp Derg. Aralık 2023;25(3):438-447. doi:10.24938/kutfd.1345541
Chicago Köksal, Yasin, Ahmet Kürşat Azkur, Emel Aksoy, ve Habibe Meltem Özgüner. “DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE”. The Journal of Kırıkkale University Faculty of Medicine 25, sy. 3 (Aralık 2023): 438-47. https://doi.org/10.24938/kutfd.1345541.
EndNote Köksal Y, Azkur AK, Aksoy E, Özgüner HM (01 Aralık 2023) DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE. The Journal of Kırıkkale University Faculty of Medicine 25 3 438–447.
IEEE Y. Köksal, A. K. Azkur, E. Aksoy, ve H. M. Özgüner, “DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE”, Kırıkkale Üni Tıp Derg, c. 25, sy. 3, ss. 438–447, 2023, doi: 10.24938/kutfd.1345541.
ISNAD Köksal, Yasin vd. “DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE”. The Journal of Kırıkkale University Faculty of Medicine 25/3 (Aralık 2023), 438-447. https://doi.org/10.24938/kutfd.1345541.
JAMA Köksal Y, Azkur AK, Aksoy E, Özgüner HM. DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE. Kırıkkale Üni Tıp Derg. 2023;25:438–447.
MLA Köksal, Yasin vd. “DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE”. The Journal of Kırıkkale University Faculty of Medicine, c. 25, sy. 3, 2023, ss. 438-47, doi:10.24938/kutfd.1345541.
Vancouver Köksal Y, Azkur AK, Aksoy E, Özgüner HM. DETECTION OF EPSTEIN-BARR VIRUS GENOME IN PEDIATRIC PATIENTS WITH LEUKEMIA AND HODGKIN LYMPHOMA: VIRAL ETIOLOGY IN PEDIATRIC CANCERS IN TÜRKİYE. Kırıkkale Üni Tıp Derg. 2023;25(3):438-47.

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