Hale GÜLER KARA, Ege SEVİNÇ, Burçin KAYMAZ, Gülay ALP, Fahri ŞAHİN, Güray SAYDAM, Buket KOSOVA, Bahar VATANSEVER, Duygu AYGÜNEŞ JAFARİ

Miyelodisplastik sendrom hastalığında P53 polimorfizmlerinin önemi

Amaç: Miyelodisplastik sendrom (MDS) akut miyeloid lösemiye dönüşüm riski yüksek olan, artmış apoptozis ve azalmış hematopoez oranlarıyla karakterize klonal bir hastalıktır. MDS patogenezi tam olarak açıklanabilmiş değildir. Olguların ~%50' si anormal karyotiptedir ve bu oran ikincil MDS' de %80 civarındadır. P53 proteini kök hücre homeostazının önemli düzenleyicisidir ve hücre döngüsünün düzenlenmesi, apoptotik ile enflamatuar yanıt gibi bir dizi hücresel olayda yer alır. Genomik bütünlüğün korunmasında da önemli görevleri bulunan TP53 geni kanserlerde sıklıkla mutasyona uğramaktadır; ancak, mutasyonlarının yanında bazı gen polimorfizmlerinin de kanserle ilişkili oldukları bilinmektedir. Çalışmadaki amacımız, dört yaygın p53 tek nükleotid polimorfizminin MDS’ deki yaygınlıklarını ve hastalık gelişimi üzerine etkilerini belirlemektir. Bu amaçla, Ege Üniversitesi Tıp Fakültesi Dahiliye Anabilim Dalı Hematoloji Bilim Dalı' nda MDS tanısı ile takip edilen ya da yeni tanı almış 100 olgu çalışmaya dahil edildi. Gereç ve Yöntem: MDS’li olguların periferik kan lökositlerinden izole edilen DNA’lar gerçek-zamanlı PCR yöntemiyle çalışılarak, p53 polimorfizmleri (rs35163653, rs35993958, rs1800371, rs1042522) uygun probların kullanımıyla ve erime eğrisi analizleriyle belirlendi. Bulgular: İncelenen dört yaygın p53 polimorfizmin arasında özellikle rs1042522 polimorfizmindeki atasal olmayan G alelinin MDS’li olgularda artmış olduğu gözlenmiştir (C:%30.3; G:%69.7). Fonksiyonel olduğu, yani sentez edilen proteinin fonksiyonunu etkilediği bilinen bu polimorfizmde 417. pozisyonundaki C nukleotidinin G’ye transisyonu (C>G), proteinin 72. pozisyonundaki prolin amino asidinin arjinine (P72R) kodlanmasına yol açmaktadır. Sonuç: Çalışmamız, MDS hastalık grubunda rs35163653, rs35993958, rs1800371 ve rs1042522 p53 polimorfizmlerinin araştırıldığı ilk çalışmadır. Bunlardan, rs1042522 polimorfizminin kansere yatkınlık ve duyarlılıkla ilişkili olduğu yapılan diğer bazı çalışmalarla gösterilmiş olması nedeniyle, MDS hastalığı için de yüksek risk oluşturabileceği düşünülmektedir. Sonuç olarak, MDS hastalığı için gerçekleştirilen bu çalışmanın daha geniş bir olgu grubuyla tekrarlanmasıyla rs1042522 polimorfizmi ileride MDS teşhisinde belirteç olarak kullanılabilecektir.

Importance of p53 gene polymorphisms in myelodysplastic syndrome disease

Aim: Myelodysplastic syndrome (MDS) is a clonal disease with a high risk of conversion to acute myeloid leukemia, characterized by increased apoptosis and decreased hematopoiesis. The pathogenesis of MDS has not been fully explained. ~50% of cases have abnormal karyotype and this rate is around 80% in secondary MDS. The p53 protein is an important regulator of stem cell homeostasis and is involved in a range of cellular events such as cell cycle regulation, apoptotic and inflammatory response. The TP53 gene, which has important roles in maintaining genomic integrity, is frequently mutated in cancers; however, some gene polymorphisms are known to be associated with cancer, as well as mutations. Our aim in the study is to determine the prevalence of four common p53 single nucleotide polymorphisms in MDS and their effects on disease development. For this reason, 100 cases followed up with the diagnosis of MDS or newly diagnosed in Ege University Faculty of Medicine, Department of Internal Medicine, Department of Hematology were included in the study. Materials and Methods: DNAs isolated from peripheral blood leukocytes of MDS cases were studied by real-time PCR method, p53 polymorphisms (rs35163653, rs35993958, rs1800371, rs1042522) were determined by using appropriate probes and melting curve analysis. Results: Among the four common p53 polymorphisms examined, especially the non-ancestral G allele in the rs1042522 polymorphism was observed to be increased in MDS cases (C: 30.3%; G: 69.7%). In this polymorphism, which is known to be functional, that is, affecting the function of the synthesized protein, the transition of the C nucleotide at position 417 to G (C>G) causes the coding of the amino acid proline at position 72 of the protein to arginine (P72R). Conclusion: Our study is the first to investigate the p53 polymorphisms of rs35163653, rs35993958, rs1800371 and rs1042522 in the MDS disease group. Of these, rs1042522 polymorphism has been shown to be associated with cancer susceptibility and susceptibility, and it is thought that it may pose a high risk for MDS disease as well. In conclusion, rs1042522 polymorphism may be used as a marker in the diagnosis of MDS in the future by repeating this study for MDS disease with a larger case group.

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