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

Nature Genetics volume 44, pages 642650 (2012) | Download Citation


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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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

Author notes

    • Cathy C Laurie
    •  & Cecelia A Laurie

    These authors contributed equally to this work.

    • Cathy C Laurie
    • , Teri Manolio
    • , Louis R Pasquale
    • , Christopher A Haiman
    • , Neil Caporaso
    •  & Bruce S Weir

    These authors jointly directed this work.


  1. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Cathy C Laurie
    • , Cecelia A Laurie
    • , Kenneth Rice
    • , Leila R Zelnick
    • , Caitlin P McHugh
    • , Jess Shen
    • , David R Crosslin
    • , David M Levine
    • , Xiuwen Zheng
    • , Jenna I Udren
    • , Siiri Bennett
    • , Sarah C Nelson
    • , Stephanie M Gogarten
    • , Matthew P Conomos
    • , Patrick Heagerty
    •  & Bruce S Weir
  2. The Center for Inherited Disease Research, Johns Hopkins University, Baltimore, Maryland, USA.

    • Kimberly F Doheny
    • , Hua Ling
    • , Kurt N Hetrick
    •  & Elizabeth W Pugh
  3. Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Chris Amos
    • , Qingyi Wei
    •  & Li-e Wang
  4. Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Jeffrey E Lee
  5. Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Kathleen C Barnes
    • , Nadia N Hansel
    •  & Rasika Mathias
  6. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

    • Denise Daley
  7. Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

    • Terri H Beaty
  8. Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Alan F Scott
  9. Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA.

    • Ingo Ruczinski
  10. Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Rob B Scharpf
  11. Department of Psychiatry, School of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.

    • Laura J Bierut
    •  & Sarah M Hartz
  12. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Maria Teresa Landi
    • , Neal D Freedman
    • , Lynn R Goldin
    • , Stephen J Chanock
    • , Sonja I Berndt
    •  & Neil Caporaso
  13. Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA.

    • David Ginsburg
  14. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • David Ginsburg
  15. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Jun Li
  16. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.

    • Karl C Desch
  17. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Sara S Strom
  18. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, Tennessee, USA.

    • William J Blot
    •  & Lisa B Signorello
  19. Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA.

    • Sue A Ingles
    • , Brian E Henderson
    • , Kristine R Monroe
    •  & Christopher A Haiman
  20. Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii, USA.

    • Loic Le Marchand
  21. Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

    • John A Heit
  22. Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.

    • Mariza de Andrade
    •  & Sebastian M Armasu
  23. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

    • Cynthia Regnier
  24. Mayo Hyperoxaluria Center, Mayo Clinic, Rochester, Minnesota, USA.

    • Cynthia Regnier
  25. Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, Illinois, USA.

    • William L Lowe
    •  & M Geoffrey Hayes
  26. Center for Craniofacial and Dental Genetics, Department of Oral Biology School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Mary L Marazita
  27. Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Eleanor Feingold
  28. Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.

    • Jeffrey C Murray
  29. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

    • Mads Melbye
    •  & Bjarke Feenstra
  30. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Jae H Kang
  31. Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.

    • Janey L Wiggs
    •  & Louis R Pasquale
  32. Division of Medical Genetics, University of Washington, Seattle, Washington, USA.

    • Gail P Jarvik
  33. Cancer Prevention Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Andrew N McDavid
  34. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Venkatraman E Seshan
  35. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Daniel B Mirel
    •  & Andrew Crenshaw
  36. National Center for Biotechnology Information, Bethesda, Maryland, USA.

    • Nataliya Sharopova
  37. Office of Population Genomics, National Human Genome Research Institute at the National Institutes of Health, Bethesda, Maryland, USA.

    • Anastasia Wise
    •  & Teri Manolio


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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.

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.

Corresponding author

Correspondence to Cathy C Laurie.

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    Supplementary Note, Supplementary Tables 1, 2, 4, 5 and 7 and Supplementary Figures 1–13

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    Breakpoints and other characteristics of autosomal mosaic anomalies

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    Site and histology descriptions and hematological cancer category

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