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 from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Figure 1. Characteristics of detectable clonal mosaic events

Detectable clonal mosaic events plotted by proportion of abnormal cells (p) and Log R Ratio (LRR) for 681 events in 517 individuals.

Figure 2. Circular genomic plot of detectable clonal mosaic events

Genomic location of detectable clonal mosaic events. Outer rings are the autosomes 1 to 22. Yellow region denotes events of copy neutral loss of heterozygosity. Blue region denotes copy gain events. Red region denotes copy loss events. Panel A includes events in cancer free controls. Panel B includes events in cancer cases.

Figure 3. Frequency of detectable clonal mosaic events by age and cancer status

Analysis excluded 1,000 individuals with unknown age at DNA collection. 95% confidence intervals are shown.