Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients
Yıl: 2022 Cilt: 18 Sayı: 4 Sayfa Aralığı: 463 - 470 Metin Dili: İngilizce DOI: 10.4274/BMJ.galenos.2022.2021.11-14 İndeks Tarihi: 06-05-2023
Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients
Öz: Objective: The genetic factors responsible for the etiopathogenesis of childhood acute leukemia have been extensively investigated. High- resolution expression analysis of the whole genome, and results of gene studies including whole genome sequencing, copy number changes of DNA, loss of heterozygosity and epigenetic changes revealed the classification of acute lymphoblastic leukemia (ALL). A variable number of tandem repeats (VNTRs) can regulate many biological processes, including gene transcription, protein function, morphological development, and cancer formation. They may also play a role in many disorders in humans such as labile repeat expansions. In this paper, our aim was to compare the genotype and allele frequencies in VNTR variants of XRCC4, eNOS, and PER3 between pediatric ALL patients and healthy controls. Methods: Seventy-four high-risk pediatric ALL patients (82.4% B-ALL, 17.6% T-ALL) who were consecutively admitted to the Pediatric Hematology Units of İstanbul Medical Faculty and Yeni Yuzyıl Medical Faculty and 100 healthy volunteers were included in this case-control study. VNTRs of three genes were analyzed using the polymerase chain reaction method. Results: The frequency of the eNOS VNTR 4a/4a genotype was found to be higher in the pediatric patients with ALL compared to the healthy controls (p=0.044) and the risk factor for childhood ALL was found to be 8.382 (95% confidence interval =0.985-71.262). The frequency of eNOS 4/a allele was found to be higher in the childhood ALL group compared to the controls (p=0.013). The frequencies of the 5R/5R genotype and 5R allele of the PER3 VNTR were found to be significantly lower in the childhood ALL patients (p=0.039 and p=0.015, respectively). Conclusion: Our results show that functional variants of the eNOS and PER3 genes may have an important relationship with the etiopathogenesis of childhood ALL. Further studies including larger groups and different ethnic populations are needed to determine the effect of VNTR variants on the risk of developing childhood ALL.
Anahtar Kelime: Türk Hastalarında XRCC4, eNOS ve PER3 VNTR Varyantlarının Çocukluk Çağı Akut Lenfoblastik Lösemi ile İlişkisi
Öz: Amaç: Çocukluk çağı akut lösemi etiyopatogenezinden sorumlu olan genetik faktörler kapsamlı bir şekilde araştırılmıştır. Tüm genomun yüksek çözünürlüklü ekspresyon analizi, ve tüm genom dizilimi, DNA’nın kopya sayısı değişiklikleri, heterozigotluk kaybı, epigenetik değişiklikler gibi gen çalışmalarının sonuçları, tüm akut lenfoblastik lösemi (ALL) hastalarının sınıflandırılabilmesini sağladı. Değişken sayıda tandem tekrarları (VNTR) gen transkripsiyonu, protein fonksiyonu, morfolojik gelişim, kanser davranışı ve fizyoloji gibi birçok biyolojik süreci modüle edebilirler. İnsanlarda, kararsız tekrar açılımlarını da içeren birçok bozukluktan da sorumlu olabilirler. Bu çalışmada çocukluk çağı ALL’li hastalarda XRCC4, eNOS ve PER3’ün VNTR varyantlarındaki genotip ve alel frekanslarını sağlıklı kontrollerle karşılaştırmayı amaçladık. Gereç ve Yöntem: İstanbul Tıp Fakültesi Pediatrik Hematoloji Ünitelerine ve Yeni Yüzyıl Tıp Fakültesi’ne ardışık olarak başvuran toplam 74 yüksek riskli çocukluk çağı ALL hastası (%82,4 B-ALL, %17,6 T-ALL) ve 100 sağlıklı gönüllü bu olgu-kontrol çalışmasına dahil edildi. Polimeraz zincir reaksiyonu yöntemi kullanılarak üç gen VNTR bölgesi analiz edildi. Bulgular: Çocukluk çağı ALL’li olgular sağlıklı kontrollere göre daha yüksek eNOS VNTR 4a/4a genotipine sahipti (p=0,044) ve çocukluk çağı ALL’si için (Olasılık oranı: 8.382 %95 güven aralığı =0.985-71.262) risk faktörü olarak gösterildi. eNOS 4a alelinin sıklığı, çocukluk çağı ALL grubunda kontrollere göre daha yüksekti (p=0,013). Çocukluk çağı ALL hastalarında sırasıyla PER3 VNTR’nin 5R/5R genotipi ve 5R alelinin frekansları önemli ölçüde daha düşük saptandı (p=0,039, p=0,015). Sonuç: Sonuçlarımız, eNOS ve PER3 genlerinin fonksiyonel varyantlarının çocukluk çağı ALL etiyopatogenezi ile önemli bir ilişkisi olabileceğini düşündürmektedir. VNTR varyantlarının çocukluk çağı ALL gelişme riski üzerindeki etkisini belirlemek için daha büyük gruplar ve farklı etnik kökenler ile daha ileri çalışmalara ihtiyaç vardır.
Anahtar Kelime: Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
- 1. Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR. DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci U S A 1992;89:3030-4.
- 2. Somasundaram V, Basudhar D, Bharadwaj G, No JH, Ridnour LA, Cheng RYS, et al. Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism. Antioxid Redox Signal 2019;30:1124-43.
- 3. Thomas DD, Wink DA. NOS2 as an Emergent Player in Progression of Cancer. Antioxid Redox Signal 2017;26:963-5.
- 4. Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, et al. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 1991;254:1001-3.
- 5. Baak JP, Path FR, Hermsen MA, Meijer G, Schmidt J, Janssen EA. Genomics and proteomics in cancer. Eur J Cancer 2003;39:1199- 215.
- 6. Jiang J, Zhang X, Yang H, Wang W. Polymorphism of DNA repair genes: ADPRT, XRCC1 AND XPD and cancer risk in genetics epidemiology. Methods Mol Biol 2009;471:305-33.
- 7. Öztürk E, Pehlivan S, Balat O, Ugur MG, Ozcan HC, Erkılıç S. DNA Repair Gene (XPD, XRCC4, and XRCC1) Polymorphisms in Patients with Endometrial Hyperplasia: A Pilot Study. Med Sci Monit Basic Res 2018;24:146-50.
- 8. Dattolo T, Coomans CP, van Diepen HC, Patton DF, Power S, Antle MC, et al. Neural activity in the suprachiasmatic circadian clock of nocturnal mice anticipating a daytime meal. Neuroscience 2016;315:91-103.
- 9. Forni D, Pozzoli U, Cagliani R, Tresoldi C, Menozzi G, Riva S, et al. Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders. Genome Biol 2014;15:499.
- 10. Imaizumi T, Kay SA. Photoperiodic control of flowering: not only by coincidence. Trends Plant Sci 2006;11:550-8.
- 11. Qiu C, Gelaye B, Denis M, Tadesse MG, Luque Fernandez MA, Enquobahrie DA, et al. Circadian clock-related genetic risk scores and risk of placental abruption. Placenta 2015;36:1480-6.
- 12. Moore RY. Circadian rhythms: basic neurobiology and clinical applications. Annu Rev Med 1997;48:253-66.
- 13. Lee J, Lee S, Chung S, Park N, Son GH, An H, et al. Identification of a novel circadian clock modulator controlling BMAL1 expression through a ROR/REV-ERB-response element-dependent mechanism. Biochem Biophys Res Commun 2016;469:580-6.
- 14. Chen CY, Logan RW, Ma T, Lewis DA, Tseng GC, Sibille E, et al. Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc Natl Acad Sci U S A 2016;113:206-11.
- 15. Leu HB, Chung CM, Lin SJ, Chiang KM, Yang HC, Ho HY, et al. Association of circadian genes with diurnal blood pressure changes and non-dipper essential hypertension: a genetic association with young-onset hypertension. Hypertens Res 2015;38:155-62.
- 16. Yeim S, Boudebesse C, Etain B, Belliviera F. Biomarqueurs et gènes circadiens dans le trouble bipolaire [Circadian markers and genes in bipolar disorder]. Encephale 2015;41(4 Suppl 1):S38-44.
- 17. Cifci S, Yilmaz M, Pehlivan M, Sever T, Okan V, Pehlivan S. DNA repair genes polymorphisms in multiple myeloma: no association with XRCC1 (Arg399Gln) polymorphism, but the XRCC4 (VNTR in intron 3 and G-1394T) and XPD (Lys751Gln) polymorphisms is associated with the disease in Turkish patients. Hematology 2011;16:361-7.
- 18. Ramírez-Patiño R, Figuera LE, Puebla-Pérez AM, Delgado-Saucedo JI, Legazpí-Macias MM, Mariaud-Schmidt RP, et al. Intron 4 VNTR (4a/b) polymorphism of the endothelial nitric oxide synthase gene is associated with breast cancer in Mexican women. J Korean Med Sci 2013;28:1587-94.
- 19. Benedetti F, Dallaspezia S, Colombo C, Pirovano A, Marino E, Smeraldi E. A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci Lett 2008;445:184-7.
- 20. Vivarelli S, Falzone L, Basile MS, Candido S, Libra M. Nitric Oxide in Hematological Cancers: Partner or Rival? Antioxid Redox Signal 2021;34:383-401.
- 21. Armenis I, Kalotychou V, Tzanetea R, Kollia P, Kontogeorgiou Z, Anastasopoulou D, et al. Prognostic value of T786C and G894T eNOS polymorphisms in sickle cell disease. Nitric Oxide 2017;62:17-23.
- 22. Wu PY, Frit P, Meesala S, Dauvillier S, Modesti M, Andres SN, et al. Structural and functional interaction between the human DNA repair proteins DNA ligase IV and XRCC4. Mol Cell Biol 2009;29:3163-72.
- 23. Gupta MK, Kushwah AS, Singh R, Banerjee M. Genotypic analysis of XRCC4 and susceptibility to cervical cancer. Br J Biomed Sci 2020;77:7-12.
- 24. Wu KH, Wang CH, Yang YL, Peng CT, Lin WD, Tsai FJ, et al. Significant association of XRCC4 single nucleotide polymorphisms with childhood leukemia in Taiwan. Anticancer Res 2010;30:529-33.
- 25. Evans JA, Davidson AJ. Health consequences of circadian disruption in humans and animal models. Prog Mol Biol Transl Sci 2013;119:283-323.
- 26. Taniguchi H, Fernández AF, Setién F, Ropero S, Ballestar E, Villanueva A, et al. Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Res 2009;69:8447-54.
- 27. Gery S, Gombart AF, Yi WS, Koeffler C, Hofmann WK, Koeffler HP. Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. Blood 2005;106:2827-36.
- 28. Yang MY, Chang JG, Lin PM, Tang KP, Chen YH, Lin HY, et al. Downregulation of circadian clock genes in chronic myeloid leukemia: alternative methylation pattern of hPER3. Cancer Sci 2006;97:1298-307.
- 29. Boivin DB, James FO, Wu A, Cho-Park PF, Xiong H, Sun ZS. Circadian clock genes oscillate in human peripheral blood mononuclear cells. Blood 2003;102:4143-5.
- 30. Yang MY, Lin PM, Hsiao HH, Hsu JF, Lin HY, Hsu CM, et al. Up- regulation of PER3 Expression Is Correlated with Better Clinical Outcome in Acute Leukemia. Anticancer Res 2015;35:6615-22.
| APA | Oguz R, Gokce M, pehlivan s, Oyacı Y, Senturk Ciftci H, atay A, KARAKAS Z, Aydin F (2022). Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. , 463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| Chicago | Oguz Rustu,Gokce Muge,pehlivan sacide,Oyacı Yasemin,Senturk Ciftci Hayriye,atay Avni,KARAKAS ZEYNEP,Aydin Filiz Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. (2022): 463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| MLA | Oguz Rustu,Gokce Muge,pehlivan sacide,Oyacı Yasemin,Senturk Ciftci Hayriye,atay Avni,KARAKAS ZEYNEP,Aydin Filiz Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. , 2022, ss.463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| AMA | Oguz R,Gokce M,pehlivan s,Oyacı Y,Senturk Ciftci H,atay A,KARAKAS Z,Aydin F Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. . 2022; 463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| Vancouver | Oguz R,Gokce M,pehlivan s,Oyacı Y,Senturk Ciftci H,atay A,KARAKAS Z,Aydin F Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. . 2022; 463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| IEEE | Oguz R,Gokce M,pehlivan s,Oyacı Y,Senturk Ciftci H,atay A,KARAKAS Z,Aydin F "Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients." , ss.463 - 470, 2022. 10.4274/BMJ.galenos.2022.2021.11-14 |
| ISNAD | Oguz, Rustu vd. "Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients". (2022), 463-470. https://doi.org/10.4274/BMJ.galenos.2022.2021.11-14 |
| APA | Oguz R, Gokce M, pehlivan s, Oyacı Y, Senturk Ciftci H, atay A, KARAKAS Z, Aydin F (2022). Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. Bakırköy Tıp Dergisi, 18(4), 463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| Chicago | Oguz Rustu,Gokce Muge,pehlivan sacide,Oyacı Yasemin,Senturk Ciftci Hayriye,atay Avni,KARAKAS ZEYNEP,Aydin Filiz Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. Bakırköy Tıp Dergisi 18, no.4 (2022): 463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| MLA | Oguz Rustu,Gokce Muge,pehlivan sacide,Oyacı Yasemin,Senturk Ciftci Hayriye,atay Avni,KARAKAS ZEYNEP,Aydin Filiz Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. Bakırköy Tıp Dergisi, vol.18, no.4, 2022, ss.463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| AMA | Oguz R,Gokce M,pehlivan s,Oyacı Y,Senturk Ciftci H,atay A,KARAKAS Z,Aydin F Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. Bakırköy Tıp Dergisi. 2022; 18(4): 463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| Vancouver | Oguz R,Gokce M,pehlivan s,Oyacı Y,Senturk Ciftci H,atay A,KARAKAS Z,Aydin F Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients. Bakırköy Tıp Dergisi. 2022; 18(4): 463 - 470. 10.4274/BMJ.galenos.2022.2021.11-14 |
| IEEE | Oguz R,Gokce M,pehlivan s,Oyacı Y,Senturk Ciftci H,atay A,KARAKAS Z,Aydin F "Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients." Bakırköy Tıp Dergisi, 18, ss.463 - 470, 2022. 10.4274/BMJ.galenos.2022.2021.11-14 |
| ISNAD | Oguz, Rustu vd. "Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients". Bakırköy Tıp Dergisi 18/4 (2022), 463-470. https://doi.org/10.4274/BMJ.galenos.2022.2021.11-14 |
