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


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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Figure 1: Expected values of BAF and LRR for discrete copy-number states.
Figure 2: BAF and LRR metrics for clonal mosaic anomalies detected in GENEVA subjects.
Figure 3: BAF and LRR plots of four representative mosaic anomalies.
Figure 4: The lengths and chromosomal positions of the 514 clonal mosaic anomalies detected in GENEVA subjects.
Figure 5: The percentage of subjects having one or more mosaic anomaly within 5-year age bins.
Figure 6: Fixed-effects meta-analysis for effect of age at DNA sampling on mosaic status.
Figure 7: A Kaplan-Meier plot of the proportion of living subjects who remain free of hematological cancer as a function of time since the time of DNA sampling and determination of mosaic status.


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The GENEVA Consortium thanks the subjects and the staff of all GENEVA studies for their important contributions. We thank the following state cancer registries for their help: Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington and Wyoming. We thank C. Laird and G. Marti for helpful comments on the manuscript and B. Wakimoto and D. Gottschling for enlightening discussions. We also thank K. Jacobs for exchanging ideas and for working with us to estimate cross-method concordance of mosaic detection using the PLCO/GENEVA Lung Cancer study. Support for the GENEVA genome-wide association studies was provided through the US National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI). Some studies also received support from individual NIH Institutes. The grant numbers are: Melanoma (NCI R29CA70334, R01CA100264 and P50CA093459); Lung Health (U01HG004738); Cleft Lip/Palate (National Institute Dental and Craniofacial Research (NIDCR): U01DE018993 and NIH contract: HHSN268200782096C); Addiction (U01HG004422, National Institute on Alcohol Abuse and Alcoholism (NIAAA): U10AA008401, National Cancer Institute (NCI): P01CA089392, National Institute on Drug Abuse (NIDA): R01DA013423 and R01DA019963); Lung Cancer (Z01CP010200); Blood Clotting (R37 HL 039693); Prostate Cancer (U01HG004726, NCI: CA63464, CA54281, CA1326792 and RC2 CA148085); Venous Thromboembolism (U01HG004735); Birth Weight (U01HG004415); Dental Caries (NIDCR: U01DE018903 and R01DE014899, NIH Center for Inherited Disease Research (CIDR) contract: HHSN268200-782096C); Prematurity (U01HG004423); Glaucoma (U01HG004728, National Eye Institute (NEI): R01EY015473 and R01EY015872); GENEVA Coordinating Center (U01 HG004446); CIDR (U01HG004438 and HHSN268200782096C); Broad Center for Genotyping and Analysis (U01HG04424); the Intramural Research Program of the NIH, the National Library of Medicine; and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. L.R.P. was also supported by a Physician Scientist award from Research to Prevent Blindness in NYC and an Ophthalmology Scholar Award from Harvard Medical School and from the Harvard Glaucoma Center of Excellence. L.R.Z. was supported by the NCI (T32 CA09168).

Author information




K.F.D., H.L., K.N.H. and E.W.P. initiated the detection of chromosomal anomalies in GENEVA GWAS data. C.A.L. developed the automated methods of anomaly detection, with assistance from C.C.L., L.R.Z., C.P.M., V.E.S. and A.N.M. C.C.L., C.A.L., K.R., L.R.Z., C.P.M., J.S., D.R.C., D.M.L., X.Z., S.C.N., S.M.G., M.P.C., J.I.U. and S.B. performed data analyses. C.A., Q.W., L.W., J.E.L., K.C.B., N.N.H., R.M., T.H.B., A.F.S., L.J.B., M.T.L., L.R.G., D.G., K.C.D., S.S.S., W.J.B., L.B.S., S.A.I., S.J.C., S.I.B., L.L.M., B.E.H., J.A.H., S.M.A., C.R., W.L.L., M.L.M., J.C.M., M.M., B.F., J.H.K., J.L.W., L.R.P., C.A.H. and N.C. contributed sample collections and phenotypic data. K.F.D., H.L., K.N.H., E.W.P., D.B.M. and A.C. performed genotyping. L.R.P., J.H.K., N.C., C.A.H., B.E.H. and K.R.M. provided data and interpretation for analysis of incident hematological cancer. C.C.L., C.A.L., L.R.Z., K.F.D., K.R., C.A., D.D., T.H.B., A.F.S., I.R., R.B.S., L.J.B., S.M.H., N.D.F., J.L., B.E.H., K.R.M., M.d.A., W.L.L., M.G.H., M.L.M., E.F., J.C.M., M.M., B.F., J.L.W., A.W., C.P.M., J.S., D.R.C., D.M.L., X.Z., J.I.U., S.B., S.C.N., S.M.G., P.H., G.P.J., A.N.M., V.E.S., H.L., K.N.H., E.W.P., D.B.M., A.C., N.S., T.M., L.R.P., C.A.H., N.C. and B.S.W. contributed ideas and advice during regular discussions of the project. C.C.L. coordinated the study and wrote the first draft of the manuscript, with guidance from a writing committee consisting of C.A.L., K.R., K.F.D., T.M., L.R.P., N.C. and B.S.W. All authors contributed to review and revision of the manuscript.

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Correspondence to Cathy C Laurie.

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Competing interests

L.J.B. served as a consultant for Pfizer Inc. in 2008 and is an inventor on the patent Markers for Addiction (US 20070258898) covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction.

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Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1, 2, 4, 5 and 7 and Supplementary Figures 1–13 (PDF 5308 kb)

Supplementary Table 3

Breakpoints and other characteristics of autosomal mosaic anomalies (XLSX 64 kb)

Supplementary Table 6

Site and histology descriptions and hematological cancer category (XLSX 13 kb)

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Laurie, C., Laurie, C., Rice, K. et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 44, 642–650 (2012).

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