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

2016; Nature Portfolio; Volume: 48; Issue: 5 Linguagem: Inglês

10.1038/ng.3545

1546-1718

Weiyin Zhou, Mitchell J. Machiela, Neal D. Freedman, Nathaniel Rothman, Núria Malats, Casey Dagnall, Neil E. Caporaso, Lauren T. Teras, Mia M. Gaudet, Susan M. Gapstur, Victoria L. Stevens, Kevin B. Jacobs, Joshua N. Sampson, Demetrius Albanes, Stephanie J. Weinstein, Jarmo Virtamo, Sonja I. Berndt, Robert N. Hoover, Amanda Black, Debra T. Silverman, Jonine D. Figueroa, Montserrat García‐Closas, Francisco X. Real, Julie Earl, Gaëlle Marenne, Benjamín Rodríguez‐Santiago, Margaret R. Karagas, Alison Johnson, Molly Schwenn, Xifeng Wu, Jian Gu, Yuanqing Ye, Amy Hutchinson, Margaret A. Tucker, Luis A. Pérez‐Jurado, Michael Dean, Meredith Yeager, Stephen J. Chanock,

Genomics and Chromatin Dynamics

Meredith Yeager, Stephen Chanock and colleagues analyze mosaic loss of the Y chromosome in three prospective cohorts and observe association with age and smoking but not with cancer survival. They also identify common variation at TCL1A associated with increased risk of mosaic loss of the Y chromosome. 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).