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

Mosaic loss of the Y chromosome (mLOY) leading to gonosomal XY/XO commonly occurs during aging, particularly in smokers. We investigated whether mLOY was associated with non-hematologic 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 increased with age (per year OR=1.13, 95%CI=1.12–1.15; P<2×10(−16)), reaching 18.7% among men over age 80. mLOY was associated with current smoking (OR=2.35, 95%CI=1.82–3.03; P=5.55×10(−11)); however, the association weakened with years after cessation. mLOY was not consistently associated with overall or specific cancer risk (e.g. for bladder, lung, or prostate) 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 the T-cell leukemia/lymphoma 1A (TCL1A) gene on 14q32.13, marked by rs2887399 (OR=1.55, 95%CI=1.36–1.78; P=1.37×10(−10)).