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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).

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Figure 1: Fraction of men with mLOY across 5-year age groups for all subjects (n = 13,729).
Figure 2: mLOY and smoking analysis.
Figure 3: Association between mLOY and overall and cancer survival among participants with DNA collected at least 1 year before cancer diagnosis.
Figure 4: Regional plot of the association P values from mLOY meta-analysis on chromosome 14.

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Acknowledgements

This project has been funded in whole or in part with federal funds from the National Cancer Institute, US National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

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Authors and Affiliations

Authors

Contributions

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

Corresponding authors

Correspondence to Meredith Yeager or Stephen J Chanock.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1–16. (PDF 1904 kb)

Supplementary Data Set

List of mLOY events. (XLSX 71 kb)

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Zhou, W., Machiela, M., Freedman, N. et al. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat Genet 48, 563–568 (2016). https://doi.org/10.1038/ng.3545

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