Pediatrik akut lenfoblastik lösemi hastalarında DNA polimeraz delta (POLD1 ve POLD2) gen ekspresyonu ve prognoz ile ilişkisi

Year 2023, Volume: 48 Issue: 2, 377 - 384, 02.07.2023

Ahmet Yöntem , İbrahim Bayram , Gülay Sezgin , Serhan Küpeli , Ayşe Özkan , Atila Tanyel,i

https://doi.org/10.17826/cumj.1221593

Abstract

Amaç: Bu çalışmada pediatrik akut lenfoblastik lösemi (ALL) hastalarında tanı anında DNA polimeraz delta (POLD1 ve POLD2) gen ekspresyonunun normal popülasyona göre durumu, prognoz ve diğer klinik bulgularla ilişkisinin araştırılması amaçlandı.
Gereç ve Yöntem: Çalışmaya Ocak 2008 ile Kasım 2015 tarihleri arasında ALL tanısı almış 73 hasta ve 29 sağlıklı kontrol olgu dahil edildi. Periferik kan örneklerinde gen ekspresyon profili Real-time PCR yöntemi kullanılarak yapıldı.
Bulgular: POLD1 gen ekspresyonunun ortalama değeri, ALL hastalarında tanı anında kontrol grubuna göre anlamlı olarak yüksek bulundu (sırasıyla 376,5± 685,8 ve 17,9± 19,8), ancak POLD2 gen ekspresyonunda fark yok idi (sırasıyla 511,5± 898,1 ve 125,4± 132,7). POLD1 ve POLD2 gen ekspresyonları, relaps ve exitus olan hastalarda düşük saptandı ancak sonuçlar istatitiksel olarak anlamlı değildi. Düşük POLD1 ekspresyonu olan hastalarda yüksek olanlara göre 5. yılda sağkalım oranları daha düşük saptandı (sırasıyla %54 ve %68), benzer şekilde düşük POLD2 ekspresyonu olan hastalarda yüksek olanlara göre 5. yılda sağkalım oranları daha düşük saptandı (sırasıyla, %58 ve %68).
Sonuç: Akut lenfoblastik lösemi hastalarında tanı anında POLD1 ve POLD2 ekspresyonlarının düşük olması prognozu olumsuz etkileyebilir.

Keywords

akut lenfoblastik lösemi, DNA polimeraz enzimleri, POLD1 ve POLD2, pediatrik, prognoz

Project Number

TTU-2015-5085.

DNA polymerase delta (POLD1 and POLD2) gene expression in pediatric acute lymphoblastic leukemia patients and its relationship with prognosis

Abstract

Purpose: This study aimed to investigate the status of DNA polymerase delta (POLD1 and POLD2) gene expression at the time of diagnosis in pediatric acute lymphoblastic leukemia (ALL) patients, compared with the normal population, and its relationship with prognosis and other clinical findings.
Materials and Methods: Seventy-three patients diagnosed with ALL between January 2008 and November 2015 and 29 healthy control subjects were included in the study. Gene expression profiling of peripheral blood samples was performed using Real-time PCR.
Results: The mean value of POLD1 gene expression was found to be significantly higher in ALL patients at the time of diagnosis than the control group (376.5± 685.8 and 17.9± 19.8, respectively), but there was no difference in POLD2 gene expression (511.5± 898.1 and 125.4± 132.7, respectively). POLD1 and POLD2 gene expressions were found to be low in patients with relapse and exitus, but the results were not statistically significant. Patients with low levels of POLD1 expression had lower survival rates in the 5th year than those with high levels of expression (54% and 68%, respectively), and similarly, patients with low levels of POLD2 expression had lower survival rates in the 5th year compared to those with high levels of expression (58% and 68%, respectively).
Conclusion: Lower POLD1 and POLD2 expressions at the time of diagnosis in ALL patients may adversely affects the prognosis.

Keywords

acute lymphoblactic leukemia, DNA polymerase enzymes, POLD1 and POLD2, pediatric, prognosis

Supporting Institution

Cukurova University Research Projects Funding Unit

Project Number

TTU-2015-5085.

References

• Pillai MP, Carroll WL. Acute lymphoblastic leukemia in Lanzkowsky’s Manual of Peadiatric Hematol and Oncology, 7th ed. (Eds JD Fish, JM Lipton, P Lanzkowsky):413-37. Amsterdam, Elsevier Academic Press. 2022.
• Arceci RJ, Meshinchi S. Acute Myeloid Leukemia AND Myelodysplastic Syndromes. In Pizzo and Poplack’s Pediatric Oncology, 8th ed. (Eds SM Blaney, LJ Helman, PC Adamson):498-544. Philadelphia, Wolters Kluwer. 2021.
• Siegel RL, Miller KD, Funchs, HE; Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7-33.
• Rabin KR, Gramatges MM, Margolin JF, Poplack DG. Acute Lymphoblastic Leukemia. In Pizzo and Poplack’s Pediatric Oncology, 8th ed. (Eds SM Blaney, LJ Helman, PC Adamson):463-97. Philadelphia, Wolters Kluwer, 2021.
• Nelson DL, Cox MM. DNA Metabolism. In Lehninger Principles of Biochemistry, 8th ed. (Eds DL Nelson, MM Cox): 948-94. North Bay, W.H.Freeman & Co Ltd, 2021.
• Goldsby RE, Lawrence NA, Hays LE, Olmsted EA, Chen X, Singh M et al. Defective DNA polymerase-delta proofreading causes cancer susceptibility in mice. Nat Med. 2001;7:638–9.
• Goldsby RE, Hays LE, Chen X, Olmsted EA, Slayton WB, Spangrude GJ et al. High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading. Proc Natl Acad Sci U S A. 2002;99:15560–5.
• Venkatesan RN, Treuting PM, Fuller ED, Goldsby RE, Norwood TH, Gooley TA et al. Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis. Mol Cell Biol. 2007;27:7669–82.
• Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45:136–44.
• Church DN, Briggs SEW, Palles C, Domingo E, Kearsey SJ, Grimes JM et al. DNA polymerase epsilon and delta exonuclease domain mutations in endometrial cancer. Hum Mol Genet. 2013;22:2820–8.
• Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer. 2016;16:71–81.
• Magrath I, Steliarova-Foucher E, Epelman S, Ribeiro RC, Harif M, Li CK et al. Pediatric cancer in low-income and middle-income countries. Lancet Oncol. 2013;14:104-16.
• Larrea AA, Lujan SA, McElhinny SAN, Mieczkowski PA, Resnick MA, Gordenin DA et al. Genome-wide model for the normal eukaryotic DNA replication fork. Proc Natl Acad Sci U S A. 2010;107:17674-9.
• Laningham FH, Kun LE, Reddick WE, Ogg RJ, Morris EB, Pui CH. Childhood central nervous system leukemia: historical perspectives, current therapy, and acute neurological sequelae. Neuroradiology. 2007;49:873–88.
• Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360:2730–41.
• Manley S, Keenan R, Campbell H, Caswell M, Pizer B. No evidence for routine cerebrospinal fluid cytology in detecting asymptomatic central nervous system relapse in children with acute lymphoblastic leukaemia: 20 years' experience of a UK primary treatment center. Br J Haematol. 2014;164:462-4.
• Sunamak EÇ, Özdemir N, Koka A, Yantiri L, Apak H, Celkan T. Comparison of outcomes of children with acute lymphoblastic leukemia treated with BMF protocol across 2 decades. Pediatr Hematol Oncol. 2021;38:134-46.
• Li S, Wang C, Wang W, Liu W, Zhang G. Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia. Medicine. 2018;97: e10734.
• Wang X, Hu Y, Mo J, Zhang J, Wang Z, Wei W et al. Arsenene: A potential therapeutic agent for acute promyelocytic leukaemia cells by acting on nuclear proteins. Angew Chem Int Ed Engl. 2020;59:5151-8.
• Liao X, Zou PL, Shen YL, Guo YX, Song L, Xia JW. Second-generation sequencing analysis of Ph+ and Ph-like childhood T-cell acute lymphoblastic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021;29:1101-8.