Laurie, C. C. et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nature Genet. 44, 642-650

Department of Biostatistics, University of Washington, Seattle, Washington, USA.
Nature Genetics (Impact Factor: 29.35). 05/2012; 44(6):642-50. DOI: 10.1038/ng.2271
Source: PubMed


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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    • "This behaviour is not unique to TET2 mutations, but is also a feature of other somatic mutations, such as large chromosomal deletions or amplifications, which also increase in frequency with age (Jacobs et al., 2012; Laurie et al., 2012; Schick et al., 2013). In fact, there is a 5–10-fold increase in the risk of developing a haematological malignancy in the decade after the detection of mosaicism for such chromosomal changes in blood leukocyte DNA (Laurie et al., 2012; Schick et al., 2013). "
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    ABSTRACT: Acute myeloid leukaemia (AML) is an uncontrolled clonal proliferation of abnormal myeloid progenitor cells in the bone marrow and blood. Advances in cancer genomics have revealed the spectrum of somatic mutations that give rise to human AML and drawn our attention to its molecular evolution and clonal architecture. It is now evident that most AML genomes harbour small numbers of mutations, which are acquired in a stepwise manner. This characteristic, combined with our ability to identify mutations in individual leukaemic cells and our detailed understanding of normal human and murine haematopoiesis, makes AML an excellent model for understanding the principles of cancer evolution. Furthermore, a better understanding of how AML evolves can help us devise strategies to improve the therapy and prognosis of AML patients. Here, we draw from recent advances in genomics, clinical studies and experimental models to describe the current knowledge of the clonal evolution of AML and its implications for the biology and treatment of leukaemias and other cancers.
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    • "Further, a study of copy-number variants (CNVs) in somatic human tissues revealed a significant number of intra-individual genomic changes between tissues [19]. Other studies of chromosomal abnormalities, including CNVs have revealed clonal mosaicism associated with aging and cancer [14], as well as related it to a higher risk of hematological cancer [20]. "
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    ABSTRACT: Understanding genotype/phenotype relationships has become more complicated as increasing amounts of inter- and intra-tissue genetic heterogeneity have been revealed through next-generation sequencing and evidence showing that factors such as epigenetic modifications, non-coding RNAs and RNA editing can play an important role in determining phenotype. Such findings have challenged a number of classic genetic assumptions including (i) analysis of genomic sequence obtained from blood is an accurate reflection of the genotype responsible for phenotype expression in an individual; (ii) that significant genetic alterations will be found only in diseased individuals, in germline tissues in inherited diseases, or in specific diseased tissues in somatic diseases such as cancer; and (iii) that mutation rates in putative disease-associated genes solely determine disease phenotypes. With the breakdown of our traditional understanding of genotype to phenotype relationships, it is becoming increasingly apparent that new analytical tools will be required to determine the relationship between genotype and phenotypic expression. To this end, we are proposing that next-generation genetic database (NGDB) platforms be created that include new bioinformatics tools based on algorithms that can evaluate genetic heterogeneity, as well as powerful systems biology analysis tools to actively process and evaluate the vast amounts of both genomic and genomic-modifying information required to reveal the true relationships between genotype and phenotype.
    Full-text · Article · May 2014 · Human genomics
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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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    ABSTRACT: Little is understood about the occurrence of somatic genomic alterations in normal tissues and their significance in the context of disease. Here, we identified potential somatic copy number alterations (pSCNAs) in apparently normal ovarian tissue and peripheral blood of 423 ovarian cancer patients. There were, on average, two to four pSCNAs per sample detectable at a tissue-level resolution, although some individuals had orders of magnitude more. Accordingly, we estimated the lower bound of the rate of pSCNAs per cell division. Older individuals and BRCA mutation carriers had more pSCNAs than others. pSCNAs significantly overlapped with Alu and G-quadruplexes, and the affected genes were enriched for signaling and regulation. Some of the amplification/deletion hotspots in pan-cancer genomes were hot spots of pSCNAs in normal tissues as well, suggesting that those regions might be inherently unstable. Prevalence of pSCNA in peripheral blood predicted survival, implying that mutations in normal tissues might have consequences for cancer patients.
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