Skip to main content

Advertisement

Log in

Frequency of KRAS mutations in adult Korean patients with acute myeloid leukemia

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Mutation of KRAS genes occurs with a frequency of 0.5–32 % in AML. In the present study, mutations of KRAS codon 12, 13, and 61 were detected by pyrosequencing and direct sequencing in AML. Seven KRAS mutations (7/123, 5.7 %) were detected. The most common mutation was a G-to-A transition in the second base of KRAS codon 13. No mutations were detected in KRAS codon 61. Combinations of KRAS and FLT3 mutation were not found in the same patient. There was no statistically significant difference between patients with KRAS mutations and patients with wild-type KRAS in terms of sex, age, CBC at diagnosis, CD34 positivity, MPO positivity, FLT3 mutation, karyotype, progression-free survival, and overall survival, although this may be attributable to the small sample size. To our knowledge, this is the first report of the detection of KRAS mutation in Asian AML patients using pyrosequencing and direct sequencing. These two methods showed identical efficiencies in their ability to detect KRAS mutations in 84 patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bos JL. RAS oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–9.

    PubMed  CAS  Google Scholar 

  2. Stirewalt DL, Meshinchi S, Radich JP. Molecular targets in acute myelogenous leukemia. Blood Rev. 2003;17:15–23.

    Article  PubMed  Google Scholar 

  3. Byrne JL, Marshall CJ. The molecular pathophysiology of myeloid leukaemias: RAS revisited. Br J Haematol. 1998;100:256–64.

    Article  PubMed  CAS  Google Scholar 

  4. Rockova V, Abbas S, Wouters BJ, Erpelinck CA, Beverloo HB, Delwel R, et al. Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers. Blood. 2011;118:1069–76.

    Article  PubMed  CAS  Google Scholar 

  5. Milella M, Kornblau SM, Estrov Z, Carter BZ, Lapillonne H, Harris D, et al. Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest. 2001;108:851–9.

    PubMed  CAS  Google Scholar 

  6. Neubauer A, Dodge RK, George SL, Davey FR, Silver RT, Schiffer CA, et al. Prognostic importance of mutations in the RAS proto-oncogenes in de novo acute myeloid leukemia. Blood. 1994;83:1603–11.

    PubMed  CAS  Google Scholar 

  7. Preston R, Däbritz J, Hänfler J, Oettle H. Mutational analysis of KRAS codon 12 in blood samples of patients with acute myeloid leukemia. Leuk Res. 2010;34:883–91.

    Article  PubMed  CAS  Google Scholar 

  8. Ahmad EI, Gawish HH, Al Azizi NM, Elhefni AM. The prognostic impact of KRAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine. Onco Targets Ther. 2011;4:115–21.

    PubMed  CAS  Google Scholar 

  9. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93:3074–80.

    PubMed  CAS  Google Scholar 

  10. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL, et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood. 2001;97:3589–95.

    Article  PubMed  CAS  Google Scholar 

  11. Ritter M, Kim TD, Lisske P, Thiede C, Schaich M, Neubauer A. Prognostic significance of N-RAS and KRAS mutations in 232 patients with acute myeloid leukemia. Haematologica. 2004;89:1397–9.

    PubMed  CAS  Google Scholar 

  12. Goemans BF, Zwaan CM, Miller M, Zimmermann M, Harlow A, Meshinchi S, et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia. 2005;19:1536–42.

    Article  PubMed  CAS  Google Scholar 

  13. Bowen DT, Frew ME, Hills R, Gale RE, Wheatley K, Groves MJ, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood. 2005;106:2113–9.

    Article  PubMed  CAS  Google Scholar 

  14. Auewarakul CU, Lauhakirti D, Tocharoentanaphol C. Frequency of RAS gene mutation and its cooperative genetic events in Southeast Asian adult acute myeloid leukemia. Eur J Haematol. 2006;77:51–6.

    Article  PubMed  CAS  Google Scholar 

  15. Schaich M, Ritter M, Illmer T, Lisske P, Thiede C, Schäkel U, et al. Mutations in RAS proto-oncogenes are associated with lower mdr1 gene expression in adult acute myeloid leukaemia. Br J Haematol. 2001;112:300–7.

    Article  PubMed  CAS  Google Scholar 

  16. Liang DC, Shih LY, Fu JF, Li HY, Wang HI, Hung IJ, et al. KRAS mutations and N-RAS mutations in childhood acute leukemias with or without mixed-lineage leukemia gene rearrangements. Cancer. 2006;106:950–6.

    Article  PubMed  CAS  Google Scholar 

  17. Ogino S, Kawasaki T, Brahmandam M, Yan L, Cantor M, Namgyal C, et al. Sensitive sequencing method for KRAS mutation detection by pyrosequencing. J Mol Diagn. 2005;7:413–21.

    Article  PubMed  CAS  Google Scholar 

  18. Sundström M, Edlund K, Lindell M, Glimelius B, Birgisson H, Micke P, et al. KRAS analysis in colorectal carcinoma: analytical aspects of pyrosequencing and allele-specific PCR in clinical practice. BMC Cancer. 2010;10:660–8.

    Article  PubMed  Google Scholar 

  19. Tsiatis AC, Norris-Kirby A, Rich RG, Hafez MJ, Gocke CD, Eshleman JR, et al. Comparison of Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations: diagnostic and clinical implications. J Mol Diagn. 2010;12:425–32.

    Article  PubMed  CAS  Google Scholar 

  20. Gao J, Li YY, Sun PN, Shen L. Comparative analysis of dideoxy sequencing, the KRAS StripAssay and pyrosequencing for detection of KRAS mutation. World J Gastroenterol. 2010;16:4858–64.

    Article  PubMed  CAS  Google Scholar 

  21. Illmer T, Thiede C, Fredersdorf A, Stadler S, Neubauer A, Ehninger G, et al. Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts. Clin Cancer Res. 2005;11:3217–24.

    Article  PubMed  CAS  Google Scholar 

  22. Tyner JW, Erickson H, Deininger MW, Willis SG, Eide CA, Levine RL, et al. High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients. Blood. 2009;113:1749–55.

    Article  PubMed  CAS  Google Scholar 

  23. Misawa S, Horiike S, Kaneko H, Sasai Y, Ueda Y, Nakao M, et al. Significance of chromosomal alterations and mutations of the N-RAS and TP53 genes in relation to leukemogenesis of acute myeloid leukemia. Leuk Res. 1998;22:631–7.

    Article  PubMed  CAS  Google Scholar 

  24. Tien HF, Wang CH, Lin MT, Lee FY, Liu MC, Chuang SM, et al. Correlation of cytogenetic results with immunophenotype, genotype, clinical features, and RAS mutation in acute myeloid leukemia. A study of 235 Chinese patients in Taiwan. Cancer Genet Cytogenet. 1995;84:60–8.

    Article  PubMed  CAS  Google Scholar 

  25. Guo W, Tang B, Xu S, Yao Y, Ye D. N-RAS mutations in 43 Chinese cases of acute myeloid leukemia. Chin Med J (Engl). 1998;111:343–5.

    CAS  Google Scholar 

  26. Sano H, Shimada A, Taki T, Murata C, Park MJ, Sotomatsu M, et al. RAS mutations are frequent in FAB type M4 and M5 of acute myeloid leukemia, and related to late relapse: a study of the Japanese Childhood AML Cooperative Study Group. Int J Hematol. 2012;95:509–15.

    Article  PubMed  Google Scholar 

  27. Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ. Analysis of RAS gene mutations in acute myeloid leukemia by polymeRASe chain reaction and oligonucleotide probes. Proc Natl Acad Sci USA. 1988;85:1629–33.

    Article  PubMed  CAS  Google Scholar 

  28. Bartram CR, Ludwig WD, Hiddemann W, Lyons J, Buschle M, Ritter J, Harbott J, et al. Acute myeloid leukemia: analysis of RAS gene mutations and clonality defined by polymorphic X-linked loci. Leukemia. 1989;3:247–56.

    PubMed  CAS  Google Scholar 

  29. Darley RL, Burnett AK. Mutant RAS inhibits neutrophil but not macrophage differentiation and allows continued growth of neutrophil precursors. Exp Hematol. 1999;27:1599–608.

    Article  PubMed  CAS  Google Scholar 

  30. Chang SH, Lee NY, Kim DH, Sohn SK, Suh JS. FLT3 gene mutations as a prognostic factor for acute myeloid leukemia. Korean J Lab Med. 2006;26:233–40.

    Article  PubMed  CAS  Google Scholar 

  31. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–9.

    Article  PubMed  CAS  Google Scholar 

  32. Langaee T, Ronaghi M. Genetic variation analyses by pyrosequencing. Mutat Res. 2005;573:96–102.

    Article  PubMed  CAS  Google Scholar 

  33. Ahmadian A, Ehn M, Hober S. Pyrosequencing: history, biochemistry and future. Clin Chim Acta. 2005;363:83–94.

    Article  PubMed  Google Scholar 

  34. Bashey A, Gill R, Levi S, Farr CJ, Clutterbuck R, Millar JL, et al. Mutational activation of the N-RAS oncogene assessed in primary clonogenic culture of acute myeloid leukemia (AML): implications for the role of N-RAS mutation in AML pathogenesis. Blood. 1992;79:981–9.

    PubMed  CAS  Google Scholar 

  35. Poehlmann A, Kuester D, Meyer F, Lippert H, Roessner A, Schneider-Stock R. KRAS mutation detection in colorectal cancer using the pyrosequencing technique. Pathol Res Pract. 2007;203:489–97.

    Article  PubMed  CAS  Google Scholar 

  36. Voelkerding KV, Dames SA, Durtschi JD. Next-generation sequencing: from basic research to diagnostics. Clin Chem. 2009;55:641–65.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Our trial was financially supported by QIAGEN Korea and Samil Pharmacy & Trading Company.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jeong-Yeal Ahn.

About this article

Cite this article

Park, MJ., Park, SH., Park, PW. et al. Frequency of KRAS mutations in adult Korean patients with acute myeloid leukemia. Int J Hematol 98, 549–557 (2013). https://doi.org/10.1007/s12185-013-1446-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-013-1446-1

Keywords

Navigation