Detectable clonal mosaicism and its relationship to aging and cancer

Abstract

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.

Clonal hematopoiesis in acquired aplastic anemia

“…41,43,44 A substantial proportion of patients with persistent cytopenia lack conclusive morphology and cytogenetics and may presumptively be classified as ICUS. 45,46 The difficulty in diagnosing MDS among AA patients lies in the fact that both conditions often show indistinguishable phenotypes and may even coexist in the same patients, although patients with AA are nevertheless at high risk for MDS development.…”

“…It was originally suggested by the studies on NRXI 53,54 and has recently been investigated more extensively using advanced genomics. By reanalyzing SNP array data generated for .50 000 individuals who did not carry hematologic cancer, Jacobs et al 43 and Laurie et al 44 demonstrated that CNAs and UPDs were observed at increasing frequencies in peripheral blood from elderly people (;2% to 3%) compared with those from younger people (;,0.5%) (ARCH). Some authors describe the same phenomenon under the term "CHIP" (CH with indeterminate potential), although the potential may not be totally indeterminate.…”

“…41,[67][68][69][70] Importantly, ARCH is shown to be associated with a substantially high incidence of developing hematologic cancer (hazard ratio,10-35.4). 19,20,43,44 Busque et al reported TET2 mutations in PNMs (not in lymphoid cells) from 10 of 182 (5.6%) elderly women (.65 years old) with NRXI, but not in 95 younger women (,60 years old) or 105 elderly women without NRXI. 71 More comprehensive surveys of leukemia/ MDS-associated mutations in the general population were conducted by repurposing WES data of peripheral blood DNA from large population-based studies.…”

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

“…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 .…”

Low-grade chromosomal mosaicism in human somatic and embryonic stem cell populations

“…In recent years, many groups have performed high-resolution screening of somatic cell populations 1,6,11,12 as well as hiPSC and hESC 7,8 and have reported de novo CNVs ranging from 10 kb to several Mb. It is important to bear in mind that these studies are based on the analysis of DNA from extractions from large numbers of cells, which only allows detection of CNVs if they are present in at least 5-10% of the cells 11,12 .…”