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. 2016 May;48(5):563-8.
doi: 10.1038/ng.3545. Epub 2016 Apr 11.

Mosaic loss of chromosome Y is associated with common variation near TCL1A

Weiyin Zhou  1   2 , Mitchell J Machiela  1 , Neal D Freedman  1 , Nathaniel Rothman  1 , Nuria Malats  3 , Casey Dagnall  1   2 , Neil Caporaso  1 , Lauren T Teras  4 , Mia M Gaudet  4 , Susan M Gapstur  4 , Victoria L Stevens  4 , Kevin B Jacobs  2   5 , Joshua Sampson  1 , Demetrius Albanes  1 , Stephanie Weinstein  1 , Jarmo Virtamo  6 , Sonja Berndt  1 , Robert N Hoover  1 , Amanda Black  1 , Debra Silverman  1 , Jonine Figueroa  1 , Montserrat Garcia-Closas  1   7 , Francisco X Real  3   8 , Julie Earl  3 , Gaelle Marenne  3 , Benjamin Rodriguez-Santiago  8   9   10 , Margaret Karagas  11 , Alison Johnson  12 , Molly Schwenn  13 , Xifeng Wu  14 , Jian Gu  14 , Yuanqing Ye  14 , Amy Hutchinson  1   2 , Margaret Tucker  1 , Luis A Perez-Jurado  8   9   15 , Michael Dean  1   16 , Meredith Yeager  1   2 , Stephen J Chanock  1
Affiliations

Mosaic loss of chromosome Y is associated with common variation near TCL1A

Weiyin Zhou et al. Nat Genet. 2016 May.

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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Conflict of interest statement

Conflict of Interest Statement

The authors declare no relevant conflicts of interest.

Figures

Figure 1
Figure 1. Fraction of men with mLOY across 5-year age groups for all subjects (n = 13,729)
Fraction of men with Y loss is calculated as men in the age group with Y loss divided by the total number of men in that age group. Error bars represent 95% Jeffery’s confidence intervals around the proportion estimate. (A) Mosaic chromosome Y loss is associated with older age at DNA collection, with frequencies of 1.18% in individuals less than 60 years and 18.71% in those 80 years or older (OR per year of age = 1.13, 95% CI = 1.12–1.15; P < 2×10−16). Chi-squared test for trend among 6 age groups shows there is significant evidence that the fraction of men with Y loss increases with age (P < 2.2×10−16). (B) Scatterplot for age versus fraction of men with Y loss. There is an overall increasing trend for the fraction of men with Y loss until age 80. After age 80, the trend became unstable reflecting the limited number of subjects in this age group in our study (Supplementary Table 4). All statistical tests are two-sided.
Figure 2
Figure 2. mLOY and Smoking Analysis
(A) Proportion of males with mLOY across strata of 5-year age group and smoking status for subjects from PLCO and CPSII studies (n = 9,859). Non-smokers are in grey, former smokers are in blue, and current smokers are in red. Error bars represent 95% Jeffery’s confidence intervals around the proportion estimate. Current smoking men in the 75+ age group are at a 13.90 times increased odds of having mosaic Y loss as compared to non-smoking men less than 65 years old (95% CI =6.60–29.26, P = 4.13 × 10−12). (B) Association between current smoking and years since cessation and mosaic Y loss from adjusted logistic regression models (n=8,825). The dotted line reflects an odds ratio of 1.0 for the referent never smokers. All statistical tests are two-sided.
Figure 3
Figure 3. Association between mLOY and overall and cancer survival among participants with DNA collected at least one year prior to cancer diagnosis
Kaplan-Meier survival curves are for (A) all-cause mortality for all cancer cases (n=5,340), (B) overall cancer survival (died of cancer) for all cancer cases (n=5,340), (C) cancer survival of bladder cancer cases (n=721), (D) cancer survival of lung cancer cases (n=1744), and (E) cancer survival of prostate cancer cases (n=2711). Subjects without Y loss are in blue and with Y loss are in red. All statistical tests are two-sided.
Figure 4
Figure 4. Regional plot for chromosome 14 mLOY meta-analysis association p-values
The GWAS for mLOY included 895 men with detected mLOY and 11,474 men with no detected mLOY. The top panel is a Manhattan plot showing −log10 P-values on the Y axis and chromosomal position on the X axis. A 500 Kb region around the top SNP (rs2887399, blue) is highlighted (orange) and zoomed in using LDlink to investigate LD (middle panel) and nearby genes (bottom panel). Numbers encapsulated within points in the middle plot represent RegulomeDB values. All statistical tests are two-sided.
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Comment in

  • Mosaic loss of chromosome Y in leukocytes matters.
    Forsberg LA, Halvardson J, Rychlicka-Buniowska E, Danielsson M, Moghadam BT, Mattisson J, Rasi C, Davies H, Lind L, Giedraitis V, Lannfelt L, Kilander L, Ingelsson M, Dumanski JP. Forsberg LA, et al. Nat Genet. 2019 Jan;51(1):4-7. doi: 10.1038/s41588-018-0267-9. Nat Genet. 2019. PMID: 30374072 No abstract available.
  • Reply to 'Mosaic loss of chromosome Y in leukocytes matters'.
    Zhou W, Machiela MJ, Freedman ND, Rothman N, Malats N, Dagnall C, Caporaso N, Teras LT, Gaudet MM, Gapstur SM, Stevens VL, Jacobs KB, Sampson J, Albanes D, Weinstein S, Virtamo J, Berndt S, Hoover RN, Black A, Silverman D, Figueroa J, Garcia-Closas M, Real FX, Earl J, Marenne G, Rodriguez-Santiago B, Karagas M, Johnson A, Schwenn M, Wu X, Gu J, Ye Y, Hutchinson A, Tucker M, Perez-Jurado LA, Dean M, Yeager M, Chanock SJ. Zhou W, et al. Nat Genet. 2019 Jan;51(1):7-9. doi: 10.1038/s41588-018-0310-x. Nat Genet. 2019. PMID: 30514911 Free PMC article. No abstract available.

References

    1. Pierre RV, Hoagland HC. Age-associated aneuploidy: loss of Y chromosome from human bone marrow cells with aging. Cancer. 1972;30:889–94. - PubMed
    1. Loss of the Y chromosome from normal and neoplastic bone marrows. United Kingdom Cancer Cytogenetics Group (UKCCG) Genes Chromosomes Cancer. 1992;5:83–8. - PubMed
    1. 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. 1995;57:1143–50. - PMC - PubMed
    1. Jacobs PA, Brunton M, Court Brown WM, Doll R, Goldstein H. Change of human chromosome count distribution with age: evidence for a sex differences. Nature. 1963;197:1080–1. - PubMed
    1. 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. 1994;76:70–1. - PubMed

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