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Detectable clonal mosaicism and its relationship to aging and cancer


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.

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Figure 1: Characteristics of detectable clonal mosaic events.
Figure 2: Circular genomic plot of detectable clonal mosaic events.
Figure 3: Frequency of detectable clonal mosaic events by age and cancer status.


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This research was supported by the Intramural Research Program and by contract number HHSN261200800001E of the US National Institutes of Health (NIH), NCI. Support for each contributing study is listed in the Supplementary Note. We thank C. Laurie and B. Weir for constructive discussion and a comparison of methodology and results for the GENEVA study. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Cancer Institute, the National Institute for Occupational Safety and Health or the Maryland Cancer Registry.

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Authors and Affiliations



K.B.J., M.Y., W. Zhou, Z.W., X.D., C.L., S.W., N.E.C., M.T., N.R. and S.J.C. designed the study. K.B.J., M.Y., L.A.P.-J., W. Zhou, Z.W., S.W., N.E.C., N.R., M. Cullen, M.C.D., D.A., B.I.G., R.N.H., F.X.R. and S.J.C. interpreted the primary results. K.B.J., M.Y., L.A.P.-J., B.R.-S. and J.R.G. developed the study methods. K.B.J., M.Y., L.A.P.-J., W. Zhou, Z.W., X.D., C.L., M. Cullen, C.G.E., M.C.D., N.C., J.S. and C.C.C. analyzed the data. K.B.J., M.Y., W. Zhou, Z.W., X.D., C.L., A.H., L.B. and J.K. were responsible for production and analysis of the genotype data. K.B.J., M.Y. and S.W. performed statistical analysis. K.B.J., M.Y., S.W., M.-J.H. and S.J.C. drafted the manuscript. M.T., R.N.H., S.J.C. and J.F.F. provided vital programmatic and institutional support. J.R.G., N.E.C., M.T., N.R., S.J.C., S.M.G., V.L.S., L.T.T., M.M.G., D.A., S.J.W., J.V., P.R.T., N.D.F., C.C.A., A.M.G., N.H., K.Y., J.-M.Y., L.L., T.D., Y.-L.Q., Y.-T.G.,W.-P.K., Y.-B.X., Z.-Z.T., J.-H.F., M.C.A., C.A., W.J.B., C.H.B., E.M.G., C.C.H., C.A.H., B.E.H., L.N.K., L.L.M., L.H.M., B.A.R., A.G.S., L.B.S., M.R.S., J.K.W., M.W., X.W., K.A.Z., R.G.Z., J.D.F., M.G.-C., N.M., G.M., L.P.-O., D.B., M.S., A.J., M.T.L., L.G., D.C., P.A.B., M.R., P.R., U.A., L.E.B.F., C.D.B., J.E.B., M.A.B., T.C., M.F., A.A., J.M.G., G.G.G., G.H., S.E.H., P.H., R.H., P.D.I., C.J., A. Landgren, R.M.-C., D.S.M., B.S.M., U.P., A.M.R., H.D.S., G.S., X.-O.S., K.V., E.W., A.W., A.Z.-J., W. Zheng, D.T.S., M.K., O.V., D.L., E.J.D., H.A.R., S.H.O., C.K., B.M.W., L.J., M.H., W.W., A.A.A., H.B.B.-d.-M., C.S.F., S.G., M.D.G., E.A.H., A.P.K., A. LaCroix, M.T.M., G.P., M.-C.B.-R., P.M.B., F.C., K.C., M. Cotterchio, E.L.G., M.G., J.A.H.B., M.J., K.-T.K., V.K., R.C.K., R.R.M., J.B.M., K.G.R., E.R., A.T., G.S.T., D.T., J.W.E., H.Y., L.A., R.Z.S.-S., P.K., F.S., D.S., S.A.S., L.M., I.L.A., J.S.W., A.P.G., L.S., D.A.B., R.G.G., M.P., W.-H.C., L.E.M., K.L.S., F.G.D., A.W.H., S.I.B., A.B., N.W., L.A.B., J.L., B.P., K.A.M., M.B.C., B.I.G., C.P.K., M.H.G., R.L.E., D.J.H., G.T., R.N.H., F.X.R. and J.F.F. contributed data or samples. All authors contributed critical feedback, review and approval of the manuscript.

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Correspondence to Stephen J Chanock.

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Competing interests

B.R.-S. and O.V. are currently employees of qGenomics, and L.A.P.-J. is a member of its scientific advisory board.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–3, Supplementary Figures 1–3 and Supplementary Note (PDF 1478 kb)

Supplementary Data

Excel file containing an anonymized listing of coordinates for all detectable clonal mosaic events and their attributes (XLS 149 kb)

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Jacobs, K., Yeager, M., Zhou, W. et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet 44, 651–658 (2012).

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