Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Characterization of CEBPA Mutations and Polymorphisms and their Prognostic Relevance in De Novo Acute Myeloid Leukemia Patients

  • Sarojam, Santhi (Laboratory of Cytogenetics and Molecular Diagnostics, Division of Cancer Research, Medical College P.O) ;
  • Raveendran, Sureshkumar (Laboratory of Cytogenetics and Molecular Diagnostics, Division of Cancer Research, Medical College P.O) ;
  • Vijay, Sangeetha (Laboratory of Cytogenetics and Molecular Diagnostics, Division of Cancer Research, Medical College P.O) ;
  • Sreedharan, Jayadevan (Research Division, Gulf Medical University) ;
  • Narayanan, Geetha (Division of Medical Oncology, Regional Cancer Centre, Medical College P.O) ;
  • Sreedharan, Hariharan (Laboratory of Cytogenetics and Molecular Diagnostics, Division of Cancer Research, Medical College P.O)
  • Published : 2015.05.18
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Abstract

The CCAAT/enhancer-binding protein-alpha (CEBPA) is a transcriptional factor that plays a crucial role in the control of proliferation and differentiation of myeloid precursors. This gene was recognized as the target of genetic alterations and were associated with clinical complexity among AML. We here analyze the frequency and types of CEBPA mutations and polymorphisms in a de novo AML patients from South India and tried to find out associations of these variations with different clinical parameters and the prognostic significance in AML. Study was carried out in 248 de novo AML patients, cytogenetic analysis was performed from the bone marrow samples and was karyotyped. PCR-SSCP analysis and sequencing was performed for the detection of CEBPA gene variations. All the statistical analysis was performed using SPSS 17 (statistical package for social sciences) software. Pearson Chi-square test, Mann-Whitney U test, Kaplan-Meier survival analysis and log rank tests were performed. CEBPA mutations were detected in 18% and CEBPA polymorphisms were detected in 18.9% of AML cases studied. Most of the mutations occured at the C terminal region. Polymorphisms were detected in both N and C terminal region. with most common being, c.584_589dup ACCCGC and c.690G>T. A significant association was not observed for the mutation and polymorphism with respect to clinical and laboratory parameters. Survival advantage was observed for the mutated cases compared to non mutated cases, especially for the normal karyotype groups. Polymorphisms has no effect on the survival pattern of AML patients. CEBPA mutation and polymorphisms were observed with similar frequency and was identified in all the FAB subtypes as well as in cytogenetic risk groups in our study population, but CEBPA mutations alone confer a prognostic value for NK AML patients.

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References

  1. Ahmad F, Rajput S, Mandava S, Das BR (2012). Molecular evaluation of CEBPA gene mutation in normal karyotype acute myeloid leukemia: a comparison of two methods and report of novel CEBPA mutations from Indian acute myeloid leukemia patients. Genet Test Mol Biomarkers, 16, 707-15. https://doi.org/10.1089/gtmb.2011.0317
  2. Bienz M, Ludwig M, Leibundgut EO, et al (2005). Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res, 11, 1416-24. https://doi.org/10.1158/1078-0432.CCR-04-1552
  3. Cammenga J, Mulloy JC, Berguido FJ, et al (2003). Induction of C/EBPalpha activity alters gene expression and differentiation of human CD34+ cells. Blood, 101, 2206-14. https://doi.org/10.1182/blood-2002-05-1546
  4. Dufour A, Schneider F, Hoster E, et al (2012). Monoallelic CEBPA mutations in normal karyotype acute myeloid leukemia: independent favorable prognostic factor within NPM1 mutated patients. Ann Hematol, 91, 1051-63. https://doi.org/10.1007/s00277-012-1423-4
  5. Fasan A, Haferlach C, Alpermann T (2014). The role of different genetic subtypes of CEBPA mutated AML. Leukemia, 4, 794-803.
  6. Friedman AD (2002). Runx1, c-Myb, and C/EBPalpha couple differentiation to proliferation or growth arrest during hematopoiesis. J Cell Biochem, 86, 624-629. https://doi.org/10.1002/jcb.10271
  7. Friedman AD, McKnight SL (1990). Identification of two polypeptide segments of CCAAT/enhancer-binding protein required for transcriptional activation of the serum albumin gene. Genes Dev, 4, 1416-26. https://doi.org/10.1101/gad.4.8.1416
  8. Frohling S, Dohner H (2004). Disruption of C/EBPalpha function in acute myeloid leukemia. N Engl J Med, 351, 2370-2. https://doi.org/10.1056/NEJMp048241
  9. Frohling S, Scholl C, Gilliland DG, Levine RL (2005). Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol, 23, 6285-95. https://doi.org/10.1200/JCO.2005.05.010
  10. Fuchs O, Kostecka A, Provaznikova D, et al (2010). CCAAT/enhancer-binding protein alpha (CEBPA) polymorphisms and mutations in healthy individuals and in patients with peripheral artery disease, ischaemic heart disease and hyperlipidaemia. Folia Biol, 56, 51-7.
  11. Fuster O, Barragan E, Bolufer P et al (2012). Fragment length analysis screening for detection of CEBPA mutations in intermediate-risk karyotype acute myeloid leukemia. Ann Hematol, 91, 1-7. https://doi.org/10.1007/s00277-011-1234-z
  12. Gombart AF, Hofmann WK, Kawano S, et al (2002). Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood, 99, 1332-40. https://doi.org/10.1182/blood.V99.4.1332
  13. Greif PA, Dufour A, Konstandin NP, et al (2012). GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. Blood, 120, 395-403. https://doi.org/10.1182/blood-2012-01-403220
  14. Grimwade D, Hills RK, Moorman AV et al (2010). Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom medical research council trials. Blood, 116, 354-65. https://doi.org/10.1182/blood-2009-11-254441
  15. Haferlach T, Bacher U, Alpermann T, et al (2012). Amount of bone marrow blasts is strongly orrelated to NPM1 and FLT3-ITD mutation rate in AML with normal karyotype. Leuk Res, 36, 51-8. https://doi.org/10.1016/j.leukres.2011.04.026
  16. Henegariu O, Heerema NA, Lowe WL, et al (2001). Improvements in cytogenetic slide preparation: controlled chromosome spreading, chemical aging and gradual denaturing. Cytometry, 43, 101-9. https://doi.org/10.1002/1097-0320(20010201)43:2<101::AID-CYTO1024>3.0.CO;2-8
  17. Kim S, Kim DH, Jang JH, et al (2012). Novel mutations in CEBPA in Korean Patients with acute myeloid leukemia with a normal karyotype. Ann Lab Med, 32, 153-7. https://doi.org/10.3343/alm.2012.32.2.153
  18. Leecharendkeat A, Tocharoentanaphol C, Auewarakul CU (2008). CCAAT/enhancer binding protein-alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes. Int J Cancer, 123, 2321-6. https://doi.org/10.1002/ijc.23796
  19. Leroy H, Roumier C, Huyghe P, et al (2005). CEBPA point mutations in hematological malignancies. Leukemia, 19, 329-34. https://doi.org/10.1038/sj.leu.2403614
  20. Lin LI, Chen CY, Lin DT, et al (2005). Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res, 11, 1372-9. https://doi.org/10.1158/1078-0432.CCR-04-1816
  21. Li HY, Deng DH, Huang Y, et al (2014). Favorable prognosis of biallelic CEBPA gene mutations in acute myeloid leukemia patients: A meta-analysis. Eur J Haematol, 94, 439-48.
  22. Mueller BU, Pabst T (2006). C/EBPalpha and the pathophysiology of acute myeloid leukemia. Curr Opin Hematol, 13, 7-14. https://doi.org/10.1097/01.moh.0000190110.08156.96
  23. Pabst T, Mueller BU (2009). Complexity of CEBPA dysregulation in human acute myeloid leukemia. Clin Cancer Res, 15, 5303-7. https://doi.org/10.1158/1078-0432.CCR-08-2941
  24. Pabst T, Mueller BU, Zhang P, et al (2001). Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet, 27, 263-70. https://doi.org/10.1038/85820
  25. Pastore F, Kling D, Hoster E, et al (2014). Long-term follow-up of cytogenetically normal CEBPA-mutated AML. J Hematol Oncol, 7, 55. https://doi.org/10.1186/s13045-014-0055-7
  26. Preudhomme C, Sagot C, Boissel N, et al (2002). Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the acute leukemia French association (ALFA). Blood, 100, 2717-23. https://doi.org/10.1182/blood-2002-03-0990
  27. Resende C, Regalo G, Duraes C, Carneiro F, Machado JC (2007). Genetic changes of CEBPA in cancer: mutations or polymorphisms? J Clin Oncol, 25, 2493-4. https://doi.org/10.1200/JCO.2007.10.7227
  28. Ruan M, Zhang L, Han C, et al (2014). NPM1 and CEBPA mutations in pediatric cytogenetically normal acute myeloid leukemia. Zhonghua Er Ke Za Zhi, 52, 303-7.
  29. Schnittger S, Schoch C, Dugas M, et al (2002). Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood, 100, 59-66. https://doi.org/10.1182/blood.V100.1.59
  30. Schnittger S, Schoch C, Kern W, et al (2005). Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood, 106, 3733-9. https://doi.org/10.1182/blood-2005-06-2248
  31. Shaffer LG, Slovak ML, Campbell LJ (eds). ISCN 2009: An International System for Human Cytogenetic Nomenclature (2009). Basel, Karger, 2009.
  32. Su L, Gao SJ, Li W, et al (2013). NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. Hematology, 19, 324-8.
  33. Su L, Gao SJ, TanY H, et al (2013). Associations between age, cytogenetics, FLT3-ITD, and marrow leukemia cells identified by flow cytometry. Asian Pac J Cancer Prev, 14, 5341-3. https://doi.org/10.7314/APJCP.2013.14.9.5341
  34. Su L, Li X, Gao SJ, et al (2014). Cytogenetic and genetic mutation features of de novo acute myeloid leukemia in elderly Chinese patients. Asian Pac J Cancer Prev, 15, 895-8. https://doi.org/10.7314/APJCP.2014.15.2.895
  35. Szankasi P, Ho AK, Bahler DW, Efimova O, Kelley TW (2011). Combined testing for CCAAT/enhancer-binding protein alpha (CEBPA) mutations and promoter methylation in acute myeloid leukemia demonstrates shared phenotypic features. Leuk Res, 35, 200-7. https://doi.org/10.1016/j.leukres.2010.09.018
  36. Tenen DG (2003). Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer, 3, 89-101. https://doi.org/10.1038/nrc989
  37. Thiede C, Steudel C, Mohr B, et al (2002). Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 99, 4326-35. https://doi.org/10.1182/blood.V99.12.4326
  38. Wouters BJ, Louwers I, Valk PJ, Lowenberg B, Delwel R (2007). A recurrent in-frame insertion in a CEBPA transactivation domain is a polymorphism rather than a mutation that does not affect gene expression profiling-based clustering of AML. Blood, 109, 389-90. https://doi.org/10.1182/blood-2006-08-042325
  39. Yohe S (2015). Molecular genetic markers in acute myeloid leukemia. J Clin Med, 4, 460-78. https://doi.org/10.3390/jcm4030460

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