Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Wilms' tumor 1 single-nucleotide polymorphism rs16754 does not predict clinical outcome in adult acute myeloid leukemia

Leukemia volume 25, pages 1918–1921 (2011)Cite this article

Subjects

The Wilms' tumor 1 (WT1) gene, located at chromosome band 11p13, encodes a transcriptional regulator with an N-terminal domain (exons 1–6) and a C-terminal domain containing four zinc-finger motifs (exons 7–10). Among the targets of WT1 are many genes involved in apoptosis, cell cycle and proliferation. Originally named for its role in Wilms' tumor, a pediatric kidney malignancy, WT1 has since been found to be implicated in several hematological malignancies, particularly in acute myeloid leukemia (AML). The role of WT1 in AML has been underlined by the finding of WT1 overexpression in 80–90% of AML and WT1 mutations in ∼10% of AML, but its contribution to leukemogenesis has still not been clarified.1 Special attention has been paid to the synonymous (Arg301) single-nucleotide polymorphism (SNP) rs16754 of WT1 (903A>G), due to its location in exon 7, a mutational hotspot of WT1 gene in acute leukemia. Recently, WT1 SNP rs16754 was suggested to predict favorable clinical outcome in adults with cytogenetically normal (CN) AML.2 Conflicting data on the prognostic impact of this SNP have subsequently been reported in pediatric AML.3, 4 In our study, we assessed the prevalence, the main associated features and the prognostic significance of WT1 SNP rs16754 in a large cohort of adult AML patients.

This study was performed in patients with previously untreated de novo AML (M3-AML excluded) and enrolled on the prospective French ALFA-9801 or ALFA-9802 trials. Details of the treatment protocols have been previously described.5, 6 These studies were approved by the ethic committees of Saint-Louis Hospital (ALFA-9801: number 9959) and Lyon B-Hotel Dieu Hospital (ALFA-9802: number 99017B). Informed consent was obtained from all patients in accordance with the Declaration of Helsinki. Overall, 937 patients were included in these trials. This retrospective screening involved 511 patients for whom frozen material collected at time of AML diagnosis was available for molecular analysis. This selected cohort did not significantly differ from the whole cohort in terms of patient characteristics and clinical outcome (data not shown). Genomic DNA was extracted from pre-treatment bone marrow or peripheral blood samples using standard procedures. WT1 exons 7 (including SNP rs16754) and 9 were amplified by PCR, and purified PCR fragments were directly sequenced in both directions, as described elsewhere.7 Mutations of NPM1, CEBPA, IDH1 and IDH2 exon 4, and FLT3 internal tandem duplication (FLT3-ITD) were investigated as previously reported.8 Patient characteristics and complete remission rates comparisons were performed using the Fisher exact test for binary variables and the Mann–Whitney test for continuous variables. Overall survival and relapse risk were estimated by the Kaplan–Meier method. For overall survival, patients were censored at last follow-up if alive or at the time of allogeneic transplantation. All survival analyses were performed using a Cox model regression and adjusted on protocol (ALFA-9801 vs ALFA-9802) as covariate. A P-value ⩽0.05 was considered to indicate statistical significance.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Yang L, Han Y, Suarez Saiz F, Minden MD . A tumor suppressor and oncogene: the WT1 story. Leukemia 2007; 21: 868–876.

    Article  CAS  PubMed  Google Scholar 

  2. Damm F, Heuser M, Morgan M, Yun H, Grosshennig A, Gohring G et al. Single nucleotide polymorphism in the mutational hotspot of WT1 predicts a favorable outcome in patients with cytogenetically normal acute myeloid leukemia. J Clin Oncol 2010; 28: 578–585.

    Article  CAS  PubMed  Google Scholar 

  3. Ho PA, Kuhn J, Gerbing RB, Pollard JA, Zeng R, Miller KL et al. WT1 synonymous SNP rs16754 correlates with higher mRNA expression and predicts significantly improved outcome in favorable-risk pediatric acute myeloid leukemia: a report from the Children′s Oncology Group. J Clin Oncol 2011; 29: 704–711.

    Article  CAS  PubMed  Google Scholar 

  4. Hollink IH, van den Heuvel-Eibrink MM, Zimmermann M, Balgobind BV, Arentsen-Peters ST, Alders M et al. No prognostic impact of the WT1 gene single nucleotide polymorphism rs16754 in pediatric acute myeloid leukemia. J Clin Oncol 2010; 28: e523–e526; author reply e527–e528.

    Article  PubMed  Google Scholar 

  5. Pautas C, Merabet F, Thomas X, Raffoux E, Gardin C, Corm S et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol 2010; 28: 808–814.

    Article  CAS  PubMed  Google Scholar 

  6. Thomas X, Raffoux E, Botton S, Pautas C, Arnaud P, de Revel T et al. Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group. Leukemia 2007; 21: 453–461.

    Article  CAS  PubMed  Google Scholar 

  7. Renneville A, Boissel N, Zurawski V, Llopis L, Biggio V, Nibourel O et al. Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. Cancer 2009; 115: 3719–3727.

    Article  CAS  PubMed  Google Scholar 

  8. Boissel N, Nibourel O, Renneville A, Gardin C, Reman O, Contentin N et al. Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol 2010; 28: 3717–3723.

    Article  CAS  PubMed  Google Scholar 

  9. Neubauer A, Maharry K, Mrozek K, Thiede C, Marcucci G, Paschka P et al. Patients with acute myeloid leukemia and RAS mutations benefit most from postremission high-dose cytarabine: a Cancer and Leukemia Group B study. J Clin Oncol 2008; 26: 4603–4609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM . Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res 2007; 67: 9609–9612.

    Article  CAS  PubMed  Google Scholar 

  11. Milani L, Gupta M, Andersen M, Dhar S, Fryknas M, Isaksson A et al. Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells. Nucleic Acids Res 2007; 35: e34.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mizuno K, Hayashi Y, Tozawa K, Iwatsuki S, Kojima Y, Kohri K . Single-nucleotide polymorphism in WT1 gene in a hyperplastic intralobar nephrogenic rest with botryoid protrusion. Urology 2009; 76: 149–152.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Association Laurette Fugain, the Fondation de France (Leukemia Committee), the French National Cancer Institute (INCa) and North-West Canceropole (Onco-Hematology axis), France.

Author information

Authors and Affiliations

  1. Laboratoire d'Hématologie, CHRU de Lille, Lille, France

    A Renneville, N Helevaut, O Nibourel & C Preudhomme

  2. Inserm, U837, Team 3, Institut de Recherche sur le Cancer de Lille, Lille, France

    A Renneville, N Helevaut, O Nibourel, C Berthon & C Preudhomme

  3. Univ Lille Nord de France, Lille, France

    A Renneville, O Nibourel, C Berthon & C Preudhomme

  4. EA 3518, Université de Paris 7,

    N Boissel & H Dombret

  5. Hématologie Adulte, Hôpital Saint-Louis, Paris, France

    N Boissel & H Dombret

  6. Laboratoire de Cytogénétique, Hôpital André Mignot, Le Chesnay, France

    C Terré

  7. Service d'Hématologie, Hôpital Henri Mondor, Créteil, France

    C Pautas

  8. Service d,

    C Gardin

  9. ′,

    C Gardin

  10. Hématologie Clinique, Hôpital Avicenne, Université Paris, Bobigny, France

    C Gardin

  11. Service d'Hématologie, Hôpital Edouard Herriot, Lyon, France

    X Thomas

  12. Service d'Hématologie, Centre Hospitalier Universitaire Dupuytren, Limoges, France

    P Turlure

  13. Service d'Hématologie, Hôpital de la côte de nacre, Caen, France

    O Reman

  14. Service des Maladies du Sang, CHRU de Lille, Lille, France

    C Berthon

  15. Service d'Hématologie, Hôpital André Mignot, Le Chesnay, France

    S Castaigne

Authors
  1. A Renneville
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Boissel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Helevaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. O Nibourel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Terré
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Pautas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Gardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. X Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Turlure
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. O Reman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C Berthon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. H Dombret
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S Castaigne
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. C Preudhomme
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Preudhomme.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Renneville, A., Boissel, N., Helevaut, N. et al. Wilms' tumor 1 single-nucleotide polymorphism rs16754 does not predict clinical outcome in adult acute myeloid leukemia. Leukemia 25, 1918–1921 (2011). https://doi.org/10.1038/leu.2011.173

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.173

This article is cited by

Search

Advanced search

Quick links