Article

Detectable clonal mosaicism from birth to old age and its relationship to cancer

Department of Biostatistics, University of Washington, Seattle, Washington, USA.
Nature Genetics (Impact Factor: 29.65). 05/2012; 44(6):642-50. DOI: 10.1038/ng.2271
Source: PubMed

ABSTRACT We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18).

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    • "In any case, our results concur with recent reports (Jacobs et al., 2012; Laurie et al., 2012) and show that the burden of amplifications and deletions increases with age, a trend that is similar to that reported for point mutations, loss of heterozygosity, and ploidy changes (Maslov et al., 2013; Matsuo et al., 1982; Pedersen et al., 2013a; Tomasetti et al., 2013; Vogelstein et al., 2013). Age-dependent increases in genomic changes could reflect the occurrence of new mutations, alterations in selection (positive selection for some changes and/or reduced purifying selection against others), and/or bottlenecks that lead to reduced clonal diversity. "
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    • "eral tissues in mice (Dolle and Vijg 2002) and also in peripheral blood in cancer-free humans (Forsberg et al. 2012; Jacobs et al. 2012; Laurie et al. 2012), we assumed that single nucleotide somatic mutations might also increase with age. Therefore, we chose a healthy person of extreme age as our subject, anticipating that during a long lifetime, mutations leading to the fittest HSCs might lead to clonal selection and thus the detectability of somatic mutations (Naylor et al. 2005; Gibson et al. 2009). "
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