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Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

Leukemia volume 29, pages 1600–1602 (2015)Cite this article

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New sequencing technologies are facilitating the development of large panels of genes that can be screened for mutations in patients with suspected hematological malignancies. Emerging evidence, however, has indicated that some malignancy-associated mutations are detectable in the general population, raising questions about the utility of broad mutation screening of peripheral blood or bone marrow DNA as a diagnostic tool. Analysis of intensity data tracks from single-nucleotide polymorphism (SNP) array analysis of peripheral blood DNA from older individuals (typically >60 years) in population cohorts has revealed large somatically acquired chromosomal duplications, deletions and regions of acquired uniparental disomy (aUPD; also known as copy number neutral loss of heterozygosity) similar to those seen in individuals with a hematological malignancy.1, 2, 3, 4 Such variants are typically present in a proportion of peripheral blood cells at a specific time-point, but their frequency can increase or decrease over time and even disappear, suggesting a dynamic pattern of clonal change.1 Consistent with this data, mutations in genes, such as TET2, DNMT3A, ASXL1 and JAK2, that are often mutated in myeloid malignancy, have also been described in elderly individuals with no evidence of hematological malignancy.5, 6, 7, 8 Increasing age is accompanied by the changes to the hematopoietic stem cell compartment, a process known as myeloid shift, with a bias toward the myeloid lineage at the expense of the lymphoid lineage.9 In addition, acquired skewing of X-chromosome inactivation patterns in elderly women suggests that there is a reduction in stem cell usage over time that might in principle be stochastic or driven by subclinical clonal expansion.10 These combined factors may help to explain the higher frequency of myeloid neoplasia in the elderly population.

To investigate the presence of mutations in elderly populations further, we studied two independent cohorts: (i) the Uppsala Longitudinal Study of Adult Men (ULSAM), an ongoing epidemiologic study of all available men born between 1920 and 1924 in Uppsala County, Sweden who have been analyzed by SNP arrays;1, 4 and (ii) 56 elderly women with normal blood counts and paired DNA from both neutrophils and T cells.10

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Authors and Affiliations

  1. Wessex Regional Genetics Laboratory, Salisbury, UK

    J Score, A Chase, L Feng, K Waghorn, A V Jones & N C P Cross

  2. Faculty of Medicine, University of Southampton, Southampton, UK

    J Score, A Chase, K Waghorn, A V Jones & N C P Cross

  3. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    L A Forsberg, C Rasi & J P Dumanski

  4. Department of Haematology, UCL Cancer Institute, London, UK

    D C Linch & R E Gale

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  1. J Score
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  2. A Chase
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  10. R E Gale
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Correspondence to N C P Cross.

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Score, J., Chase, A., Forsberg, L. et al. Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals. Leukemia 29, 1600–1602 (2015). https://doi.org/10.1038/leu.2015.13

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