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).
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pierre, R.V. & Hoagland, H.C. Age-associated aneuploidy: loss of Y chromosome from human bone marrow cells with aging. Cancer 30, 889–894 (1972).
United Kingdom Cancer Cytogenetics Group (UKCCG). Loss of the Y chromosome from normal and neoplastic bone marrows. Genes Chromosom. Cancer 5, 83–88 (1992).
Guttenbach, M., Koschorz, B., Bernthaler, U., Grimm, T. & Schmid, M. Sex chromosome loss and aging: in situ hybridization studies on human interphase nuclei. Am. J. Hum. Genet. 57, 1143–1150 (1995).
Jacobs, P.A., Brunton, M., Court Brown, W.M., Doll, R. & Goldstein, H. Change of human chromosome count distribution with age: evidence for a sex differences. Nature 197, 1080–1081 (1963).
Abeliovich, D., Yehuda, O., Ben-Neriah, S. & Or, R. Loss of Y chromosome. An age-related event or a cytogenetic marker of a malignant clone? Cancer Genet. Cytogenet. 76, 70–71 (1994).
Herens, C. et al. Loss of the Y chromosome in bone marrow cells: results on 1907 consecutive cases of leukaemia and preleukaemia. Clin. Lab. Haematol. 21, 17–20 (1999).
Wiktor, A. et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosom. Cancer 27, 11–16 (2000).
Wong, A.K. et al. Loss of the Y chromosome: an age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome? Arch. Pathol. Lab. Med. 132, 1329–1332 (2008).
Zhang, L.J., Shin, E.S., Yu, Z.X. & Li, S.B. Molecular genetic evidence of Y chromosome loss in male patients with hematological disorders. Chin. Med. J. (Engl.) 120, 2002–2005 (2007).
Chanock, S. Cancer biology: genome-wide association studies. in World Cancer Report 2014 (eds. Stewart, B. & Wild, C.P.) 193–202 (International Agency for Research on Cancer, 2014).
Conrad, D.F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).
González, J.R. et al. A fast and accurate method to detect allelic genomic imbalances underlying mosaic rearrangements using SNP array data. BMC Bioinformatics 12, 166 (2011).
Itsara, A. et al. Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84, 148–161 (2009).
Jacobs, K.B. et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44, 651–658 (2012).
Laurie, C.C. et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44, 642–650 (2012).
Machiela, M.J. et al. Characterization of large structural genetic mosaicism in human autosomes. Am. J. Hum. Genet. 96, 487–497 (2015).
McCarroll, S.A. & Altshuler, D.M. Copy-number variation and association studies of human disease. Nat. Genet. 39 (suppl. 7), S37–S42 (2007).
Peiffer, D.A. et al. High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res. 16, 1136–1148 (2006).
Dumanski, J.P. et al. Smoking is associated with mosaic loss of chromosome Y. Science 347, 81–83 (2015).
Forsberg, L.A. et al. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat. Genet. 46, 624–628 (2014).
Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).
Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).
Fernández, L.C., Torres, M. & Real, F.X. Somatic mosaicism: on the road to cancer. Nat. Rev. Cancer 16, 43–55 (2016).
Machiela, M.J. & Chanock, S.J. Detectable clonal mosaicism in the human genome. Semin. Hematol. 50, 348–359 (2013).
Skaletsky, H. et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423, 825–837 (2003).
Laine, J., Künstle, G., Obata, T., Sha, M. & Noguchi, M. The protooncogene TCL1 is an Akt kinase coactivator. Mol. Cell 6, 395–407 (2000).
Virgilio, L. et al. Deregulated expression of TCL1 causes T cell leukemia in mice. Proc. Natl. Acad. Sci. USA 95, 3885–3889 (1998).
Olcaydu, D. et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat. Genet. 41, 450–454 (2009).
Olcaydu, D. et al. The 'GGCC' haplotype of JAK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera. Leukemia 23, 1924–1926 (2009).
Jones, A.V. et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat. Genet. 41, 446–449 (2009).
Kilpivaara, O. et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms. Nat. Genet. 41, 455–459 (2009).
Machiela, M.J. & Chanock, S.J. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31, 3555–3557 (2015).
Rothman, N. et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat. Genet. 42, 978–984 (2010).
Wu, X. et al. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat. Genet. 41, 991–995 (2009).
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.
Author information
Authors and Affiliations
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
Ethics declarations
Competing interests
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.3545
This article is cited by
-
Loss of chromosome Y in regulatory T cells
BMC Genomics (2024)
-
Characterization of loss of chromosome Y in peripheral blood cells in male Han Chinese patients with schizophrenia
BMC Psychiatry (2023)
-
Y chromosome toxicity does not contribute to sex-specific differences in longevity
Nature Ecology & Evolution (2023)
-
Loss of Y chromosome in leukocytes can be regarded as a male-specific age predictor for age group estimation in forensic genetics
Molecular Genetics and Genomics (2023)
-
Personalized health risk assessment based on single-cell RNA sequencing analysis of a male with 45, X/48, XYYY karyotype
Scientific Reports (2022)