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

Cathy C. Laurie; Cecelia A. Laurie; Kenneth Rice; Kimberly F. Doheny; Leila R. Zelnick; Caitlin P. McHugh; Hua Ling; Kurt N. Hetrick; Elizabeth W. Pugh; Chris Amos; Qingyi Wei; Li E. Wang; Jeffrey E. Lee; Kathleen C. Barnes; Nadia N. Hansel; Rasika Mathias; Denise Daley; Terri H. Beaty; Alan F. Scott; Ingo Ruczinski; Rob B. Scharpf; Laura J. Bierut; Sarah M. Hartz; Maria Teresa Landi; Neal D. Freedman; Lynn R. Goldin; David Ginsburg; Jun Li; Karl C. Desch; Sara S. Strom; William J. Blot; Lisa B. Signorello; Sue A. Ingles; Stephen J. Chanock; Sonja I. Berndt; Loic Le Marchand; Brian E. Henderson; Kristine R. Monroe; John A. Heit; Mariza De Andrade; Sebastian M. Armasu; Cynthia Regnier; William L. Lowe; M. Geoffrey Hayes; Mary L. Marazita; Eleanor Feingold; Jeffrey C. Murray; Mads Melbye; Bjarke Feenstra; Jae H. Kang; Janey L. Wiggs; Gail P. Jarvik; Andrew N. McDavid; Venkatraman E. Seshan; Daniel B. Mirel; Andrew Crenshaw; Nataliya Sharopova; Anastasia Wise; 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; Teri Manolio; Louis R. Pasquale; Christopher A. Haiman; Neil Caporaso; Bruce S. Weir

doi:10.1038/ng.2271

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

Cathy C. Laurie, Cecelia A. Laurie, Kenneth Rice, Kimberly F. Doheny, Leila R. Zelnick, Caitlin P. McHugh, Hua Ling, Kurt N. Hetrick, Elizabeth W. Pugh, Chris Amos, Qingyi Wei, Li E. Wang, Jeffrey E. Lee, Kathleen C. Barnes, Nadia N. Hansel, Rasika Mathias, Denise Daley, Terri H. Beaty, Alan F. Scott, Ingo RuczinskiRob B. Scharpf, Laura J. Bierut, Sarah M. Hartz, Maria Teresa Landi, Neal D. Freedman, Lynn R. Goldin, David Ginsburg, Jun Li, Karl C. Desch, Sara S. Strom, William J. Blot, Lisa B. Signorello, Sue A. Ingles, Stephen J. Chanock, Sonja I. Berndt, Loic Le Marchand, Brian E. Henderson, Kristine R. Monroe, John A. Heit, Mariza De Andrade, Sebastian M. Armasu, Cynthia Regnier, William L. Lowe, M. Geoffrey Hayes, Mary L. Marazita, Eleanor Feingold, Jeffrey C. Murray, Mads Melbye, Bjarke Feenstra, Jae H. Kang, Janey L. Wiggs, Gail P. Jarvik, Andrew N. McDavid, Venkatraman E. Seshan, Daniel B. Mirel, Andrew Crenshaw, Nataliya Sharopova, Anastasia Wise, 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, Teri Manolio, Louis R. Pasquale, Christopher A. Haiman, Neil Caporaso, Bruce S. Weir

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Abstract

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).

Original language	English
Pages (from-to)	642-650
Number of pages	9
Journal	Nature Genetics
Volume	44
Issue number	6
DOIs	https://doi.org/10.1038/ng.2271
State	Published - Jun 2012

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Laurie, C. C., Laurie, C. A., Rice, K., Doheny, K. F., Zelnick, L. R., McHugh, C. P., Ling, H., Hetrick, K. N., Pugh, E. W., Amos, C., Wei, Q., Wang, L. E., Lee, J. E., Barnes, K. C., Hansel, N. N., Mathias, R., Daley, D., Beaty, T. H., Scott, A. F., ... Weir, B. S. (2012). Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nature Genetics, 44(6), 642-650. https://doi.org/10.1038/ng.2271

@article{110897c34c5d430ba51642c62609f291,

title = "Detectable clonal mosaicism from birth to old age and its relationship to cancer",

abstract = "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).",

author = "Laurie, {Cathy C.} and Laurie, {Cecelia A.} and Kenneth Rice and Doheny, {Kimberly F.} and Zelnick, {Leila R.} and McHugh, {Caitlin P.} and Hua Ling and Hetrick, {Kurt N.} and Pugh, {Elizabeth W.} and Chris Amos and Qingyi Wei and Wang, {Li E.} and Lee, {Jeffrey E.} and Barnes, {Kathleen C.} and Hansel, {Nadia N.} and Rasika Mathias and Denise Daley and Beaty, {Terri H.} and Scott, {Alan F.} and Ingo Ruczinski and Scharpf, {Rob B.} and Bierut, {Laura J.} and Hartz, {Sarah M.} and Landi, {Maria Teresa} and Freedman, {Neal D.} and Goldin, {Lynn R.} and David Ginsburg and Jun Li and Desch, {Karl C.} and Strom, {Sara S.} and Blot, {William J.} and Signorello, {Lisa B.} and Ingles, {Sue A.} and Chanock, {Stephen J.} and Berndt, {Sonja I.} and {Le Marchand}, Loic and Henderson, {Brian E.} and Monroe, {Kristine R.} and Heit, {John A.} and {De Andrade}, Mariza and Armasu, {Sebastian M.} and Cynthia Regnier and Lowe, {William L.} and Hayes, {M. Geoffrey} and Marazita, {Mary L.} and Eleanor Feingold and Murray, {Jeffrey C.} and Mads Melbye and Bjarke Feenstra and Kang, {Jae H.} and Wiggs, {Janey L.} and Jarvik, {Gail P.} and McDavid, {Andrew N.} and Seshan, {Venkatraman E.} and Mirel, {Daniel B.} and Andrew Crenshaw and Nataliya Sharopova and Anastasia Wise and Jess Shen and Crosslin, {David R.} and Levine, {David M.} and Xiuwen Zheng and Udren, {Jenna I.} and Siiri Bennett and Nelson, {Sarah C.} and Gogarten, {Stephanie M.} and Conomos, {Matthew P.} and Patrick Heagerty and Teri Manolio and Pasquale, {Louis R.} and Haiman, {Christopher A.} and Neil Caporaso and Weir, {Bruce S.}",

note = "Funding Information: 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 Funding Information: (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).",

year = "2012",

month = jun,

doi = "10.1038/ng.2271",

language = "English",

volume = "44",

pages = "642--650",

journal = "Nature Genetics",

issn = "1061-4036",

number = "6",

}

Laurie, CC, Laurie, CA, Rice, K, Doheny, KF, Zelnick, LR, McHugh, CP, Ling, H, Hetrick, KN, Pugh, EW, Amos, C, Wei, Q, Wang, LE, Lee, JE, Barnes, KC, Hansel, NN, Mathias, R, Daley, D, Beaty, TH, Scott, AF, Ruczinski, I, Scharpf, RB, Bierut, LJ , Hartz, SM, Landi, MT, Freedman, ND, Goldin, LR, Ginsburg, D, Li, J, Desch, KC, Strom, SS, Blot, WJ, Signorello, LB, Ingles, SA, Chanock, SJ, Berndt, SI, Le Marchand, L, Henderson, BE, Monroe, KR, Heit, JA, De Andrade, M, Armasu, SM, Regnier, C, Lowe, WL, Hayes, MG, Marazita, ML, Feingold, E, Murray, JC, Melbye, M, Feenstra, B, Kang, JH, Wiggs, JL, Jarvik, GP, McDavid, AN, Seshan, VE, Mirel, DB, Crenshaw, A, Sharopova, N, Wise, A, Shen, J, Crosslin, DR, Levine, DM, Zheng, X, Udren, JI, Bennett, S, Nelson, SC, Gogarten, SM, Conomos, MP, Heagerty, P, Manolio, T, Pasquale, LR, Haiman, CA, Caporaso, N & Weir, BS 2012, 'Detectable clonal mosaicism from birth to old age and its relationship to cancer', Nature Genetics, vol. 44, no. 6, pp. 642-650. https://doi.org/10.1038/ng.2271

TY - JOUR

T1 - Detectable clonal mosaicism from birth to old age and its relationship to cancer

AU - Laurie, Cathy C.

AU - Laurie, Cecelia A.

AU - Rice, Kenneth

AU - Doheny, Kimberly F.

AU - Zelnick, Leila R.

AU - McHugh, Caitlin P.

AU - Ling, Hua

AU - Hetrick, Kurt N.

AU - Pugh, Elizabeth W.

AU - Amos, Chris

AU - Wei, Qingyi

AU - Wang, Li E.

AU - Lee, Jeffrey E.

AU - Barnes, Kathleen C.

AU - Hansel, Nadia N.

AU - Mathias, Rasika

AU - Daley, Denise

AU - Beaty, Terri H.

AU - Scott, Alan F.

AU - Ruczinski, Ingo

AU - Scharpf, Rob B.

AU - Bierut, Laura J.

AU - Hartz, Sarah M.

AU - Landi, Maria Teresa

AU - Freedman, Neal D.

AU - Goldin, Lynn R.

AU - Ginsburg, David

AU - Li, Jun

AU - Desch, Karl C.

AU - Strom, Sara S.

AU - Blot, William J.

AU - Signorello, Lisa B.

AU - Ingles, Sue A.

AU - Chanock, Stephen J.

AU - Berndt, Sonja I.

AU - Le Marchand, Loic

AU - Henderson, Brian E.

AU - Monroe, Kristine R.

AU - Heit, John A.

AU - De Andrade, Mariza

AU - Armasu, Sebastian M.

AU - Regnier, Cynthia

AU - Lowe, William L.

AU - Hayes, M. Geoffrey

AU - Marazita, Mary L.

AU - Feingold, Eleanor

AU - Murray, Jeffrey C.

AU - Melbye, Mads

AU - Feenstra, Bjarke

AU - Kang, Jae H.

AU - Wiggs, Janey L.

AU - Jarvik, Gail P.

AU - McDavid, Andrew N.

AU - Seshan, Venkatraman E.

AU - Mirel, Daniel B.

AU - Crenshaw, Andrew

AU - Sharopova, Nataliya

AU - Wise, Anastasia

AU - Shen, Jess

AU - Crosslin, David R.

AU - Levine, David M.

AU - Zheng, Xiuwen

AU - Udren, Jenna I.

AU - Bennett, Siiri

AU - Nelson, Sarah C.

AU - Gogarten, Stephanie M.

AU - Conomos, Matthew P.

AU - Heagerty, Patrick

AU - Manolio, Teri

AU - Pasquale, Louis R.

AU - Haiman, Christopher A.

AU - Caporaso, Neil

AU - Weir, Bruce S.

N1 - Funding Information: 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 Funding Information: (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).

PY - 2012/6

Y1 - 2012/6

N2 - 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).

AB - 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).

UR - http://www.scopus.com/inward/record.url?scp=84861591789&partnerID=8YFLogxK

U2 - 10.1038/ng.2271

DO - 10.1038/ng.2271

M3 - Article

C2 - 22561516

AN - SCOPUS:84861591789

SN - 1061-4036

VL - 44

SP - 642

EP - 650

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

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