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Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia

Leukemia volume 18, pages 420–425 (2004)Cite this article

Abstract

Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (P<0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.

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Acknowledgements

We thank Professor David Linch for supplying samples from the MRC AML trials tissue bank at University College Hospital, London. These facilities have been supported by the Kay Kendall Leukemia Fund, the Medical Research Council and the Leukemia Research Fund of Great Britain. We thank Dr Cathryn Lewis for advice on statistical analysis and Grover C Bagby Jr who supplied probes for the RQ-PCR assay. MT was funded by Cancer Research UK. DG was supported by the Leukemia Research Fund of Great Britain, and equipment was provided by the Daniel Ayling Fanconi Anemia Trust.

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Authors and Affiliations

  1. Department of Medical and Molecular Genetics, Division of Genetics and Development Guy's, King's and St Thomas' School of Medicine, King's College London, Guy's Hospital, London, UK

    M D Tischkowitz, N V Morgan, D Grimwade, C Eddy, R Stöger, S V Hodgson & C G Mathew

  2. Department of Haematology, University College London, London, UK

    D Grimwade & S Langabeer

  3. Department of Haematology, St George's Hospital, London, UK

    S Ball

  4. Human Genetics Division, School of Medicine, Southampton University Hospital, Tremona Road, Southampton, UK

    I Vorechovsky

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  1. M D Tischkowitz
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Correspondence to M D Tischkowitz.

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Tischkowitz, M., Morgan, N., Grimwade, D. et al. Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia. Leukemia 18, 420–425 (2004). https://doi.org/10.1038/sj.leu.2403280

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