Abstract
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.
Keywords
References
- Jabbour E, Short NJ, Montalban-Bravo G, Huang X, Bueso-Ramos C, Qiao W, Yang H, Zhao C, Kadia T, Borthakur G, Pemmaraju N, Sasaki K, Estrov Z, Cortes J, Ravandi F, Alvarado Y, Komrokji R, Sekeres MA, Steensma DP, DeZern A, Roboz G, Kantarjian H, Garcia-Manero G. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood 2017; 130 (13): 1514-22
- Solé F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Luño E, Prieto F, Granada I, Hernández JM, Cigudosa JC, Diez JL, Bureo E, Marqués ML, Arranz E, Ríos R, Martínez Climent JA, Vallespí T, Florensa L, Woessner S. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. British Journal of Haematology, 2000; 108 (2), 346-56.
- Paydaş, S. Young age MDS: differences between Western and Eastern countries. Leukemia Research 2006; 30 (3), 362.
- Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127, 2391-405.
- Greenberg PL, Attar E, Bennett JM, Bloomfield CD, Borate U, De Castro CM, Deeg HJ, Frankfurt O, Gaensler K, Garcia-Manero G, Gore SD, Head D, Komrokji R, Maness LJ, Millenson M, O'Donnell MR, Shami PJ, Stein BL, Stone RM, Thompson JE, Westervelt P, Wheeler B, Shead DA, Naganuma M. Myelodysplastic Syndromes: Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network 2013; JNCCN, 11 (7), 838-74.
- Greenblatt M.S., Bennett W. P., Hollstein M., Harris C.C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Research 1994; 54, 4855-78.
- Soussi, T., p53 alterations in human cancer: more questions than answers. Oncogene 2017 (26(15)), 2145-56.
- Soussi, T. and Wiman, KG. Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell 2007; (12(4)), 303-12.
- Ekmekçi A., Konaç E., Önen H.İ. Gen Polimorfizmi ve Kansere Yatkınlık. Marmara Medical Journal 2018, 21(3), 282-95.
- Kokate P., Dalvi R., Koppaka N. ve Mandava S. Prognostic classification of MDS is improved by the inclusion of FISH panel testing with conventional cytogenetics . Cancer Genetics 2017, 120–7.
- Ma X. Epidemiology of myelodysplastic syndromes. The American Journal of Medicine 2012, 125, 2-5.
- Kanehira K., Ketterling R.P. and Van Dyke D.L. del (5q) in myeloid neoplasms. Atlas of Genetics and Cytogenetics in Oncology and Haematology 2009; 314-6.
- Schanz J., Tüchler H., Sole F., Mallo M., Luno E., Cervera J., Granada I. New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge. American Society of Clinical Oncology (Journal Of Clinical Oncology) 2012, 820-9.
- Zahid M.F., Malik U.A., Sohail M., Hassan I.N., Ali S., Shaukat M.H.S. Cytogenetic Abnormalities in Myelodysplastic Syndromes: An Overview. International Journal of Hematology-Oncology and Stem Cell Research 2016, 231-9.
- Tidow H, Melero R, Mylonas E, Freund SM, Grossmann JG, Carazo JM, Svergun DI, Valle M, Fersht AR. Quaternary structures of tumor suppressor p53 and a specific p53 DNA complex. Proceedings of the National Academy of Sciences of the United States of America 2007; 104 (30), 12324-9.
- Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proceedings of the National Academy of Sciences of the United States of America 2003; (100(14)), 8424-9.
- Felley-Bosco, E., Weston, A., Cawley, H. M., Bennett, W. P. & Harris, C. C.. Functional studies of a germ-line polymorphism at codon 47 within the p53 gene. American Journal of Human Genetics1993; (53), 752-9.
- Hamadou W.S., Besbes S., Bourdon V., Youssef Y.B., Laatiri M.A., Noguchi T., Khelif A., Sobol H. and Soua Z. Mutational analysis of TP53 gene in Tunisian familial hematological malignancies and sporadic acute leukemia cases. Familial Cancer 2017; 153-7.
- McGraw K.L., Zhang L.M., Rollison D.E., Basiorka A.A., Fulp W., Rawal B., Jerez A. The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes . Blood Cancer Journal 2015; 1-7.
- Weich N, Ferri C, Moiraghi B, Bengió R, Giere I, Pavlovsky C, Larripa I, Fundia A. TP53 codon 72 polymorphisim perdicts chronic myeloid leukemia susceptibility and treatment outcome. Blood Cells, Molecules and Diseases 2016; 129-33.
- Üren N., Korak T., Altınok D., Ergül E., Güllüoğlu B., Şimşek T. Canturk N.Z., Utkan N.Z, Sazci A. (2016). TP53 (RS1042522) POLYMORPHISM IN BREAST CANCER. Journal of Health Sciences of Kocaeli University 2016; 2, 28-31.
- Arenillas L, Mallo M, Ramos F, Guinta K, Barragán E, Lumbreras E, Larráyoz MJ, De Paz R, Tormo M, Abáigar M, Pedro C, Cervera J, Such E, José Calasanz M, Díez-Campelo M, Sanz GF, Hernández JM, Luño E, Saumell S, Maciejewski J, Florensa L, Solé F. Single Nucleotide Polymorphism Array Karyotyping: A Diagnostic and Prognostic Tool in Myelodysplastic Syndromes with Unsuccessful Conventional Cytogenetic Testing. Genes, Chromosomes & Cancer 2013, 1167-77.
Abstract
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.
Keywords
References
- Jabbour E, Short NJ, Montalban-Bravo G, Huang X, Bueso-Ramos C, Qiao W, Yang H, Zhao C, Kadia T, Borthakur G, Pemmaraju N, Sasaki K, Estrov Z, Cortes J, Ravandi F, Alvarado Y, Komrokji R, Sekeres MA, Steensma DP, DeZern A, Roboz G, Kantarjian H, Garcia-Manero G. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood 2017; 130 (13): 1514-22
- Solé F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Luño E, Prieto F, Granada I, Hernández JM, Cigudosa JC, Diez JL, Bureo E, Marqués ML, Arranz E, Ríos R, Martínez Climent JA, Vallespí T, Florensa L, Woessner S. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. British Journal of Haematology, 2000; 108 (2), 346-56.
- Paydaş, S. Young age MDS: differences between Western and Eastern countries. Leukemia Research 2006; 30 (3), 362.
- Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127, 2391-405.
- Greenberg PL, Attar E, Bennett JM, Bloomfield CD, Borate U, De Castro CM, Deeg HJ, Frankfurt O, Gaensler K, Garcia-Manero G, Gore SD, Head D, Komrokji R, Maness LJ, Millenson M, O'Donnell MR, Shami PJ, Stein BL, Stone RM, Thompson JE, Westervelt P, Wheeler B, Shead DA, Naganuma M. Myelodysplastic Syndromes: Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network 2013; JNCCN, 11 (7), 838-74.
- Greenblatt M.S., Bennett W. P., Hollstein M., Harris C.C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Research 1994; 54, 4855-78.
- Soussi, T., p53 alterations in human cancer: more questions than answers. Oncogene 2017 (26(15)), 2145-56.
- Soussi, T. and Wiman, KG. Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell 2007; (12(4)), 303-12.
- Ekmekçi A., Konaç E., Önen H.İ. Gen Polimorfizmi ve Kansere Yatkınlık. Marmara Medical Journal 2018, 21(3), 282-95.
- Kokate P., Dalvi R., Koppaka N. ve Mandava S. Prognostic classification of MDS is improved by the inclusion of FISH panel testing with conventional cytogenetics . Cancer Genetics 2017, 120–7.
- Ma X. Epidemiology of myelodysplastic syndromes. The American Journal of Medicine 2012, 125, 2-5.
- Kanehira K., Ketterling R.P. and Van Dyke D.L. del (5q) in myeloid neoplasms. Atlas of Genetics and Cytogenetics in Oncology and Haematology 2009; 314-6.
- Schanz J., Tüchler H., Sole F., Mallo M., Luno E., Cervera J., Granada I. New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge. American Society of Clinical Oncology (Journal Of Clinical Oncology) 2012, 820-9.
- Zahid M.F., Malik U.A., Sohail M., Hassan I.N., Ali S., Shaukat M.H.S. Cytogenetic Abnormalities in Myelodysplastic Syndromes: An Overview. International Journal of Hematology-Oncology and Stem Cell Research 2016, 231-9.
- Tidow H, Melero R, Mylonas E, Freund SM, Grossmann JG, Carazo JM, Svergun DI, Valle M, Fersht AR. Quaternary structures of tumor suppressor p53 and a specific p53 DNA complex. Proceedings of the National Academy of Sciences of the United States of America 2007; 104 (30), 12324-9.
- Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proceedings of the National Academy of Sciences of the United States of America 2003; (100(14)), 8424-9.
- Felley-Bosco, E., Weston, A., Cawley, H. M., Bennett, W. P. & Harris, C. C.. Functional studies of a germ-line polymorphism at codon 47 within the p53 gene. American Journal of Human Genetics1993; (53), 752-9.
- Hamadou W.S., Besbes S., Bourdon V., Youssef Y.B., Laatiri M.A., Noguchi T., Khelif A., Sobol H. and Soua Z. Mutational analysis of TP53 gene in Tunisian familial hematological malignancies and sporadic acute leukemia cases. Familial Cancer 2017; 153-7.
- McGraw K.L., Zhang L.M., Rollison D.E., Basiorka A.A., Fulp W., Rawal B., Jerez A. The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes . Blood Cancer Journal 2015; 1-7.
- Weich N, Ferri C, Moiraghi B, Bengió R, Giere I, Pavlovsky C, Larripa I, Fundia A. TP53 codon 72 polymorphisim perdicts chronic myeloid leukemia susceptibility and treatment outcome. Blood Cells, Molecules and Diseases 2016; 129-33.
- Üren N., Korak T., Altınok D., Ergül E., Güllüoğlu B., Şimşek T. Canturk N.Z., Utkan N.Z, Sazci A. (2016). TP53 (RS1042522) POLYMORPHISM IN BREAST CANCER. Journal of Health Sciences of Kocaeli University 2016; 2, 28-31.
- Arenillas L, Mallo M, Ramos F, Guinta K, Barragán E, Lumbreras E, Larráyoz MJ, De Paz R, Tormo M, Abáigar M, Pedro C, Cervera J, Such E, José Calasanz M, Díez-Campelo M, Sanz GF, Hernández JM, Luño E, Saumell S, Maciejewski J, Florensa L, Solé F. Single Nucleotide Polymorphism Array Karyotyping: A Diagnostic and Prognostic Tool in Myelodysplastic Syndromes with Unsuccessful Conventional Cytogenetic Testing. Genes, Chromosomes & Cancer 2013, 1167-77.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Health Care Administration |
| Journal Section | Research Articles |
| Authors | |
| Publication Date | June 13, 2022 |
| Submission Date | June 23, 2021 |
| Published in Issue | Year 2022 |