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  • Correspondence
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Reply to ‘Mosaic loss of chromosome Y in leukocytes matters’

Nature Genetics volume 51, pages 7–9 (2019)Cite this article

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Zhou et al. reply — A revised Correspondence by Forsberg et al.1 (whose authors include the founders of CRAY Innovation, L. A. Forsberg and J. P. Dumanski) posits that the methodological differences in our analysis of mosaic chromosome-Y loss (mLOY) in a substantially larger sample set2 could explain the lack of replication of a borderline association of mLOY with all-cause as well as overall cancer survival3. The authors offer an interpretive hypothesis of their association study that mLOY is mechanistically linked to disease risk and mortality through immune-cell function3,4,5. They suggest that (i) associations between mLOY in blood-derived DNA and disease risk or mortality could have been diluted by the inclusion of buccal derived samples in the analysis; (ii) the inclusion of lower-completion-rate samples could have skewed the overall results; and (iii) an inappropriate threshold for the log2 R ratio (LRR) deviation was used for mLOY scoring. Herein, we address these concerns by performing a series of sensitivity analyses of our study. Our expanded analysis indicates limited tissue-specific differences in the causes or consequences of mLOY, no evidence that the inclusion of lower-completion-rate samples influenced the results, and no differences in the association with mLOY and cancer risk or mortality under a range of LRR mLOY scoring thresholds.

To address the first issue regarding buccal cell samples potentially attenuating evidence for an association with cancer risk and mortality, we performed analyses stratified by DNA source for both blood and buccal samples (Table 1). In total, 9,697 samples were in the blood-derived DNA analyses, and 4,029 samples were in the buccal-derived DNA analyses. As in our published paper2, we observed strong associations between both age and smoking and the risk of developing mLOY, yet little difference in the patterns observed for the analyses of blood- and buccal-derived DNA. To our knowledge, this is the first report of an age and smoking effect on mLOY observed in buccal-derived DNA, thus suggesting that the effects of smoking and age on mLOY can be observed in at least two tissue sources. As in the published combined analysis, stratified analyses of cancer risk suggest limited evidence for an association in the prospectively collected samples but a potential association in the samples collected after cancer diagnosis (Table 1). Owing to the ample potential for confounding by disease or treatment, great caution is warranted when interpreting the effect of mLOY on cancer risk in postdiagnostic samples. As previously reported, we observed no effect of mLOY on all-cause mortality or cancer-specific mortality in either the blood or buccal strata (Table 1). In addition, no evidence for heterogeneity between blood- or buccal-derived DNA was observed in the cancer-risk or mortality analyses. Similar results were observed for the association between the 14q32.13 locus (marker SNP rs2887399 near TCL1A) and mean chromosome-Y LRR in blood-derived (β = 0.0114, P = 5.86 × 10−8) and buccal-derived (β = 0.0199, P = 2.01 × 10−5) DNA. This trend of similar association results by DNA tissue type has also been observed for loci from a recent larger genome-wide association study of mosaic Y loss6 (Supplementary Table 1).

Table 1 Association of mLOY with age, smoking, cancer risk and mortality
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Author information

Author notes

  1. These authors contributed equally: Weiyin Zhou, Mitchell J. Machiela, Neal D. Freedman.

  2. These authors jointly supervised this work: Meredith Yeager, Stephen J. Chanock.

Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA

    Weiyin Zhou, Mitchell J. Machiela, Neal D. Freedman, Nathaniel Rothman, Casey Dagnall, Neil Caporaso, Joshua Sampson, Demetrius Albanes, Stephanie Weinstein, Sonja Berndt, Robert N. Hoover, Amanda Black, Debra Silverman, Jonine Figueroa, Montserrat Garcia-Closas, Amy Hutchinson, Margaret Tucker, Michael Dean, Meredith Yeager & Stephen J. Chanock

  2. Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD, USA

    Weiyin Zhou, Casey Dagnall, Kevin B. Jacobs, Amy Hutchinson & Meredith Yeager

  3. Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Nuria Malats, Francisco X. Real, Julie Earl & Gaelle Marenne

  4. Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA

    Lauren T. Teras, Mia M. Gaudet, Susan M. Gapstur & Victoria L. Stevens

  5. Bioinformed, LLC, Gaithersburg, MD, USA

    Kevin B. Jacobs

  6. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland

    Jarmo Virtamo

  7. Division of Genetics and Epidemiology, Institute for Cancer Research, London, UK

    Montserrat Garcia-Closas

  8. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

    Francisco X. Real, Benjamin Rodriguez-Santiago & Luis A. Perez-Jurado

  9. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain

    Benjamin Rodriguez-Santiago & Luis A. Perez-Jurado

  10. Quantitative Genomic Medicine Laboratory, qGenomics, Esplugues de Llobregat, Spain

    Benjamin Rodriguez-Santiago

  11. Biostatistics and Epidemiology Section, Dartmouth Medical School, Lebanon, NH, USA

    Margaret Karagas

  12. Vermont Cancer Registry, Burlington, VT, USA

    Alison Johnson

  13. Maine Cancer Registry, Augusta, ME, USA

    Molly Schwenn

  14. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Xifeng Wu, Jian Gu & Yuanqing Ye

  15. Hospital del Mar Research Institute (IMIM), Barcelona, Spain

    Luis A. Perez-Jurado

  16. Women’s and Children’s Hospital, South Australia Medical and Health Research Institute and University of Adelaide, Adelaide, South Australia, Australia

    Luis A. Perez-Jurado

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Correspondence to Stephen J. Chanock.

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Zhou, W., Machiela, M.J., Freedman, N.D. et al. Reply to ‘Mosaic loss of chromosome Y in leukocytes matters’. Nat Genet 51, 7–9 (2019). https://doi.org/10.1038/s41588-018-0310-x

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