Association of Mosaic Loss of Chromosome Y with Lung Cancer Risk and Prognosis in a Chinese Population

Introduction: Mosaic loss of chromosome Y (mLOY) is the most commonly detectable mosaic chromosomal event in cancers; however, its underlying relationship with tumorigenesis is still unclear. Methods: We conducted a mendelian randomization study to systematically investigate the effect of mLOY on lung cancer based on a published genome-wide association study and inferred the causal relationship between mLOY and lung cancer. Kaplan-Meier and Cox regression analyses were used to evaluate the effect of mLOY on lung cancer prognosis. Results: We discovered that genetically defined mLOY was a protective factor against lung cancer development in nonsmokers but not in smokers (lifelong nonsmokers: OR = 0.80, 95% confidence interval [CI]: 0.69-0.93, p = 4.03 x 10(-3); smokers: OR = 0.96, 95% CI: 0.89-1.04, p = 2.90 x 10(-1), p(Heterogeneity) = 3.83 x 10(-2)). A U-shaped curve between the copy number level of chromosome Y and lung cancer risk was fitted (p for linearity Wald = 8.81 x 10(-10)) to support the idea that heavy mLOY caused by acquired damaging environmental factors may have effects on lung cancer that are different from those of genetically defined mLOY, whereas genetically predicted mLOY was linearly associated with a decreased lung cancer risk (p for linearity Wald = 0.15). In addition, increased genetically defined mLOY was also significantly associated with a better outcome of lung cancer (HR = 0.86, 95% CI: 0.75-0.98, p = 2.03 x 10(-2)). Conclusions: In summary, we propose a "two-sides" model: "natural" mLOY reduces the risk and ensures a better prognosis of lung cancer, although the effect can be abolished by an aberrant loss of chromosome Y caused by environmental risk factors. Our results reveal a complex relationship between mLOY and lung cancer and provide important implications for the prevention of lung cancer. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.