title: Mosaic loss of chromosome Y is associated with common variation near TCL1A.
abstract: Mosaic loss of chromosome Y (mLOY) leading to gonosomal XY/XO commonly occurs during aging, particularly in smokers. We investigated whether mLOY was associated with non-hematological cancer in three prospective cohorts (8,679 cancer cases and 5,110 cancer-free controls) and genetic susceptibility to mLOY. Overall, mLOY was observed in 7% of men, and its prevalence increased with age (per-year odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.12-1.15; P < 2 × 10(-16)), reaching 18.7% among men over 80 years old. mLOY was associated with current smoking (OR = 2.35, 95% CI = 1.82-3.03; P = 5.55 × 10(-11)), but the association weakened with years after cessation. mLOY was not consistently associated with overall or specific cancer risk (for example, bladder, lung or prostate cancer) nor with cancer survival after diagnosis (multivariate-adjusted hazard ratio = 0.87, 95% CI = 0.73-1.04; P = 0.12). In a genome-wide association study, we observed the first example of a common susceptibility locus for genetic mosaicism, specifically mLOY, which maps to TCL1A at 14q32.13, marked by rs2887399 (OR = 1.55, 95% CI = 1.36-1.78; P = 1.37 × 10(-10)).
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
authors.forename: Weiyin
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authors.lastname: Zhou
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Mitchell J
authors.identifier: 0000-0001-6538-9705
authors.initials: MJ
authors.lastname: Machiela
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Freedman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Nathaniel
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authors.lastname: Rothman
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Malats
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Dagnall
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
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authors.lastname: Caporaso
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
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authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
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authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
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authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Stevens
authors.affiliation: Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.|Bioinformed, LLC, Gaithersburg, Maryland, USA.
authors.forename: Kevin B
authors.initials: KB
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
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authors.lastname: Albanes
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Stephanie
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authors.lastname: Weinstein
authors.affiliation: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jarmo
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authors.lastname: Virtamo
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Sonja
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Robert N
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Amanda
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authors.lastname: Black
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Debra
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authors.lastname: Silverman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
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authors.lastname: Figueroa
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.|Division of Genetics and Epidemiology, Institute for Cancer Research, London, UK.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Francisco X
authors.identifier: 0000-0001-9501-498X
authors.initials: FX
authors.lastname: Real
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
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authors.initials: J
authors.lastname: Earl
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Marenne
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Quantitative Genomic Medicine Laboratory, qGenomics, Barcelona, Spain.
authors.forename: Benjamin
authors.initials: B
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authors.affiliation: Biostatistics and Epidemiology Section, Dartmouth Medical School, Lebanon, New Hampshire, USA.
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authors.affiliation: Vermont Cancer Registry, Burlington, Vermont, USA.
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authors.affiliation: Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
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authors.affiliation: Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yuanqing
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Hutchinson
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Tucker
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
authors.forename: Luis A
authors.identifier: 0000-0002-1988-3005
authors.initials: LA
authors.lastname: Perez-Jurado
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.|Laboratory of Experimental Immunology, Center for Cancer Research, NCI-Frederick, Frederick, Maryland, USA.
authors.forename: Michael
authors.identifier: 0000-0003-2234-0631
authors.initials: M
authors.lastname: Dean
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
authors.forename: Meredith
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authors.lastname: Yeager
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
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mesh_terms: D000368:Aged; D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14; D041322:Chromosomes, Human, Y; D015331:Cohort Studies; D004273:DNA, Neoplasm; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009030:Mosaicism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012044:Regression Analysis; D016019:Survival Analysis
chemical_list: D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human