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

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

Research output: Contribution to journalArticlepeer-review

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)).

Original languageEnglish
Pages (from-to)563-8
Number of pages6
JournalNature Genetics
Volume48
Issue number5
Early online date11 Apr 2016
DOIs
Publication statusE-pub ahead of print - 11 Apr 2016

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