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Association of Mosaic Loss of Chromosome Y with Lung Cancer Risk and Prognosis in a Chinese Population
aDepartment of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China
bJiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, People’s Republic of China cState Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, People’s Republic of China dNational Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
eDepartment of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, People’s Republic of China
Introduction: Mosaic loss of chromosome Y (mLOY) is the most commonly detectable mosaic chromosomal event in cancers; however, its underlying relationship with tumori-genesis 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.
lung cancer risk was fitted (p for linearity Wald ¼ 8.81 10–10) to support the idea that heavy mLOY caused by ac-quired 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 ¼ 0.15). In addition, increased genetically defined mLOY was also significantly associated with a
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 abol-ished 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.
2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Keywords: Lung cancer; Mosaic loss of chromosome Y; Smoking; Mendelian randomization
Mosaic loss of chromosome Y (mLOY) is the most commonly detectable mosaic chromosomal event in males and has been associated with aging and risk of
Drs. Qin, Li, Wang, and Pu equally contributed to this work.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Hongbing Shen, MD, PhD, Nanjing Medical University, 818 Tianyuan East Road, Nanjing 211166, People’s Republic of China. E-mail: [email protected]
ª 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
hematological diseases.1–3 Recent observational studies investigated the association between the mLOY status and etiology of nonhematological cancers but failed to draw consistent conclusions: Forsberg et al.4 proposed that men with mLOY have a substantially higher risk of cancer, whereas Wright et al.5 and Zhou et al.6 found little evidence of an association between mLOY and cancer risk. Zhou et al.6 also showed inconsistent results within cancer types: mLOY was a risk factor for prostate and bladder cancer but exerted a protective effect against lung cancer risk, with a nonsignificant p value. However, because smoking can causally lead to lung cancer7 and alter the status of mLOY,8 the effect of mLOY on lung cancer could be biased by smoking status. In addition, the ordinary observational case-control studies cannot evaluate the causal relationship between mLOY and lung cancer.
Mendelian randomization provides an alternative approach to unbiasedly infer the causal relationship between exposure and outcome with genetic variants9 that can be easily and accurately detected in a large-scale epidemiological study. Recently, a genome-wide association study (GWAS) was conducted to compre-hensively evaluate the genetic influence on individual mLOY on the basis of a large-scale cohort.5 These find-ings provided us with genetic markers that could be used to investigate the association between mLOY and risk of lung cancer by using the mendelian randomiza-tion approach.