Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of IDH1G105 polymorphism as prognostic marker in intermediate-risk AML

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

Abstract

Germline polymorphisms in genes mutated in acute myeloid leukemia (AML) may have prognostic impact. Therefore, the relevance of the polymorphism IDH1G105 (IDH1105GGT minor allele) was evaluated in the context of concomitant molecular mutations in a cohort of 507 AML cases with intermediate-risk cytogenetics. In addition, a cohort of 475 healthy controls was analyzed for this polymorphism. IDH1105GGT minor allele was found in 10 % of AML patients and 9 % of healthy controls. While no differences were seen with regard to cytomorphology or cytogenetics, immunophenotyping revealed significantly reduced expression of the progenitor marker CD34 in AML cases harboring IDH1105GGT minor allele. Cases with IDH1105GGT minor allele as compared to those with the IDH1105GGC major allele had significantly longer event-free survival (EFS) (median 16 vs 11 months, p = 0.013) which was most pronounced in the age group >60 years (median 14 vs 9 months, p = 0.007) and in the NPM1 mutated/FLT3-ITD/FLT3wt ratio <0.5 group (median 61 vs 13 months, p = 0.012). However, this association is not independent of other prognostic parameters, and we conclude that IDH1105GGT minor allele has to be considered in the context of the genetic background of the individual AML analyzed.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Arber DA, Brunning RD, Le Beau MM (2008) Acute myeloid leukemia (AML) and related precursor neoplasms. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer (IARC), Lyon, pp 110–123

    Google Scholar 

  2. Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S (2008) Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood 111:2527–2537

    Article  CAS  PubMed  Google Scholar 

  3. Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S (2006) Implications of NRAS mutations in AML: a study of 2502 patients. Blood 107:3847–3853

    Article  CAS  PubMed  Google Scholar 

  4. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1976) Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33:451–458

    Article  CAS  PubMed  Google Scholar 

  5. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103:620–625

    Article  CAS  PubMed  Google Scholar 

  6. Capon F, Allen MH, Ameen M, Burden AD, Tillman D, Barker JN, Trembath RC (2004) A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet 13:2361–2368

    Article  CAS  PubMed  Google Scholar 

  7. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, LoCocco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD (2003) Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21:4642–4649

    Article  PubMed  Google Scholar 

  8. Chou WC, Hou HA, Chen CY, Tang JL, Yao M, Tsay W, Ko BS, Wu SJ, Huang SY, Hsu SC, Chen YC, Huang YN, Chang YC, Lee FY, Liu MC, Liu CW, Tseng MH, Huang CF, Tien HF (2010) Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation. Blood 115:2749–2754

    Article  CAS  PubMed  Google Scholar 

  9. Collins FS, Guyer MS, Charkravarti A (1997) Variations on a theme: cataloging human DNA sequence variation. Science 278:1580–1581

    Article  CAS  PubMed  Google Scholar 

  10. Damm F, Heuser M, Morgan M, Yun H, Grosshennig A, Gohring G, Schlegelberger B, Dohner K, Ottmann O, Lubbert M, Heit W, Kanz L, Schlimok G, Raghavachar A, Fiedler W, Kirchner H, Dohner H, Heil G, Ganser A, Krauter J (2010) Single nucleotide polymorphism in the mutational hotspot of WT1 predicts a favorable outcome in patients with cytogenetically normal acute myeloid leukemia. J Clin Oncol 28:578–585

    Article  CAS  PubMed  Google Scholar 

  11. Damm F, Thol F, Hollink IH, Zimmermann M, Reinhardt K, van den Heuvel-Eibrink MM, Zwaan CM, de Haas V, Creutzig U, Klusmann JH, Krauter J, Heuser M, Ganser A, Reinhardt D, Thiede C (2011) Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups. Leukemia 25:1704–1710

    Article  CAS  PubMed  Google Scholar 

  12. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Dicker F, Haferlach C, Kern W, Haferlach T, Schnittger S (2007) Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. Blood 110:1308–1316

    Article  CAS  PubMed  Google Scholar 

  14. Dohner K, Tobis K, Ulrich R, Frohling S, Benner A, Schlenk RF, Dohner H (2002) Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol 20:3254–3261

    Article  PubMed  Google Scholar 

  15. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, La Starza R, Diverio D, Colombo E, Santucci A, Bigerna B, Pacini R, Pucciarini A, Liso A, Vignetti M, Fazi P, Meani N, Pettirossi V, Saglio G, Mandelli F, Lo-Coco F, Pelicci PG, Martelli MF (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352:254–266

    Article  CAS  PubMed  Google Scholar 

  16. Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K (2004) CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22:624–633

    Article  PubMed  Google Scholar 

  17. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ, Burnett AK (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 116:354–365

    Article  CAS  PubMed  Google Scholar 

  18. Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ, Wheatley K, Burnett AK, Goldstone AH, On behalf of the Medical Research Council Addult and Children’s Leukemia Working Parties (2001) The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML 11 trial. Blood 98:1312–1320

    Article  CAS  PubMed  Google Scholar 

  19. Grossmann V, Schnittger S, Schindela S, Klein HU, Eder C, Dugas M, Kern W, Haferlach T, Haferlach C, Kohlmann A (2011) Strategy for robust detection of insertions, deletions, and point mutations in CEBPA, a GC-rich content gene, using 454 next-generation deep-sequencing technology. J Mol Diagn 13:129–136

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Haferlach T, Kern W, Schoch C, Hiddemann W, Sauerland MC (2003) Morphologic dysplasia in acute myeloid leukemia: importance of granulocytic dysplasia. J Clin Oncol 21:3004–3005

    Article  Google Scholar 

  21. Ho PA, Kopecky KJ, Alonzo TA, Gerbing RB, Miller KL, Kuhn J, Zeng R, Ries RE, Raimondi SC, Hirsch BA, Oehler V, Hurwitz CA, Franklin JL, Gamis AS, Petersdorf SH, Anderson JE, Godwin JE, Reaman GH, Willman CL, Bernstein ID, Radich JP, Appelbaum FR, Stirewalt DL, Meshinchi S (2011) Prognostic implications of the IDH1 synonymous SNP rs11554137 in pediatric and adult AML: a report from the Children’s Oncology Group and SWOG. Blood 118:4561–4566

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Holle R, Happich M, Lowel H, Wichmann HE (2005) KORA—a research platform for population based health research. Gesundheitswesen 67(Suppl 1):S19–S25

    Article  PubMed  Google Scholar 

  23. Im AP, Sehgal AR, Carroll MP, Smith BD, Tefferi A, Johnson DE, Boyiadzis M (2014) DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia 28:1774–1783

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Mitleman F (ed) ISCN (1995) Guidelines for cancer cytogenetics, supplement to an international system for human cytogenetic nomenclature, (S Karger, Basel 1995)

  25. Kern W, Voskova D, Schoch C, Hiddemann W, Schnittger S, Haferlach T (2004) Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood 104:3078–3085

    Article  CAS  PubMed  Google Scholar 

  26. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528

    Article  CAS  PubMed  Google Scholar 

  27. Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B, Dicker F, Schnittger S, Dugas M, Kern W, Haferlach C, Haferlach T (2010) Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol 28:3858–3865

    Article  CAS  PubMed  Google Scholar 

  28. Lander ES (1996) The new genomics: global views of biology. Science 274:536–539

    Article  CAS  PubMed  Google Scholar 

  29. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, DiPersio JF, Wilson RK, Ley TJ (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, Maixner W, Diatchenko L (2006) Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314:1930–1933

    Article  CAS  PubMed  Google Scholar 

  31. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, Behre G, Hiddemann W, Tenen DG (2001) Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 27:263–270

    Article  CAS  PubMed  Google Scholar 

  32. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, De Botton S, Thomas X, Raffoux E, Lamandin C, Castaigne S, Fenaux P, Dombret H (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 100:2717–2723

    Article  CAS  PubMed  Google Scholar 

  33. Ravandi F, Patel K, Luthra R, Faderl S, Konopleva M, Kadia T, Brandt M, Pierce S, Kornblau S, Andreeff M, Wang X, Garcia-Manero G, Cortes J, Kantarjian H (2012) Prognostic significance of alterations in IDH enzyme isoforms in patients with AML treated with high-dose cytarabine and idarubicin. Cancer 118:2665–2673

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517

    Article  CAS  PubMed  Google Scholar 

  35. Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM (2007) The sounds of silence: synonymous mutations affect function. Pharmacogenomics 8:527–532

    Article  CAS  PubMed  Google Scholar 

  36. Schnittger S, Bacher U, Kern W, Alpermann T, Haferlach C, Haferlach T (2011) Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia. Leukemia 25:1297–1304

    Article  CAS  PubMed  Google Scholar 

  37. Schnittger S, Eder C, Jeromin S, Alpermann T, Fasan A, Grossmann V, Kohlmann A, Illig T, Klopp N, Wichmann HE, Kreuzer KA, Schmid C, Staib P, Peceny R, Schmitz N, Kern W, Haferlach C, Haferlach T (2013) ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 27:82–91

    Article  CAS  PubMed  Google Scholar 

  38. Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T (2010) IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood 116:5486–5496

    Article  CAS  PubMed  Google Scholar 

  39. Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T, Buchner T, Wormann B, Hiddemann W, Griesinger F (2000) Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia 14:796–804

    Article  CAS  PubMed  Google Scholar 

  40. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, Loffler H, Sauerland CM, Serve H, Buchner T, Haferlach T, Hiddemann W (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

    Article  CAS  PubMed  Google Scholar 

  41. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF, Haferlach T, Hiddemann W, Falini B (2005) Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106:3733–3739

    Article  CAS  PubMed  Google Scholar 

  42. Schoch C, Haferlach T (2002) Cytogenetics in acute myeloid leukemia. Curr Oncol Rep 4:390–397

    Article  PubMed  Google Scholar 

  43. Steudel C, Wermke M, Schaich M, Schakel U, Illmer T, Ehninger G, Thiede C (2003) Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. Genes Chromosome Cancer 37:237–251

    Article  CAS  Google Scholar 

  44. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, Wermke M, Bornhauser M, Ritter M, Neubauer A, Ehninger G, Illmer T (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 99:4326–4335

    Article  CAS  PubMed  Google Scholar 

  45. Tsai CJ, Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM, Nussinov R (2008) Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J Mol Biol 383:281–291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, Uitterlinden AG, Erpelinck CA, Delwel R, Lowenberg B, Valk PJ (2005) Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 106:3747–3754

    Article  CAS  PubMed  Google Scholar 

  47. Wagner K, Damm F, Gohring G, Gorlich K, Heuser M, Schafer I, Ottmann O, Lubbert M, Heit W, Kanz L, Schlimok G, Raghavachar AA, Fiedler W, Kirchner H, Brugger W, Zucknick M, Schlegelberger B, Heil G, Ganser A, Krauter J (2010) Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol 28:2356–2364

    Article  CAS  PubMed  Google Scholar 

  48. Ward PS, Lu C, Cross JR, Abdel-Wahab O, Levine RL, Schwartz GK, Thompson CB (2013) The potential for isocitrate dehydrogenase mutations to produce 2-hydroxyglutarate depends on allele specificity and subcellular compartmentalization. J Biol Chem 288:3804–3815

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Wichmann HE, Gieger C, Illig T (2005) KORA-gen—resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 67(Suppl 1):S26–S30

    Article  PubMed  Google Scholar 

  51. Wiseman DH, Small HF, Wilks DP, Waddell ID, Dennis MW, Ogilvie DJ, Somervaille TC (2014) Elevated plasma 2-hydroxyglutarate in acute myeloid leukaemia: association with the IDH1 SNP rs11554137 and severe renal impairment3. Br J Haematol 166:145–148

    Article  CAS  PubMed  Google Scholar 

  52. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

CH, WK, TH, and SuS have equity ownership of MLL Munich Leukemia Laboratory GmbH. AF, TA, and CE are employed by MLL Munich Leukemia Laboratory GmbH.

Author information

Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377, Munich, Germany

    Annette Fasan, Claudia Haferlach, Christiane Eder, Tamara Alpermann, Wolfgang Kern, Torsten Haferlach & Susanne Schnittger

  2. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universitat, Munich, Germany

    Anne Quante

  3. German Research Center for Environmental Health, Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, Neuherberg, Germany

    Anne Quante

  4. German Research Center for Environmental Health, Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany

    Annette Peters

  5. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

    Annette Peters

  6. German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

    Annette Peters

Authors
  1. Annette Fasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia Haferlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christiane Eder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tamara Alpermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Quante
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annette Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wolfgang Kern
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Torsten Haferlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Susanne Schnittger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Annette Fasan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fasan, A., Haferlach, C., Eder, C. et al. Evaluation of IDH1G105 polymorphism as prognostic marker in intermediate-risk AML. Ann Hematol 94, 1991–2001 (2015). https://doi.org/10.1007/s00277-015-2488-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-015-2488-7

Keywords

Search

Navigation