Age at Menarche, age at Natural Menopause, and Risk of Lung and Colorectal Cancers: A Mendelian Randomization Study

BACKGROUND: The roles of age at menarche and age at menopause in the etiology of lung and colorectal cancers are unclear. OBJECTIVE: We aimed to investigate potential causal associations between age at menarche, age at natural menopause, and risk of lung and colorectal cancers using a Mendelian randomization (MR) approach. METHODS: From the Trøndelag Health Study in Norway, we defined two cohorts of 35 477 and 17 118 women to study the effects of age at menarche and age at natural menopause, respectively. We ran univariable MR to evaluate the potential causal associations. We performed multivariable MR adjusting for genetic variants of adult body mass index (BMI) to estimate the direct effect of age at menarche. RESULTS: Genetically predicted 1-year increase in age at menarche was associated with a lower risk of lung cancer overall (hazard ratio [HR, 0.64; 95% CI, 0.48-0.86), lung adenocarcinoma (HR, 0.61; 95% CI, 0.38-0.99), and lung non-adenocarcinoma (HR, 0.66; 95% CI, 0.45-0.95). After adjusting for adult BMI using a multivariable MR model, the direct effect estimates reduced to HR 0.72 (95% CI, 0.54-0.95) for lung cancer overall, HR 0.67 (95% CI, 0.43-1.03) for lung adenocarcinoma, and HR 0.77 (95% CI, 0.54-1.09) for lung non-adenocarcinoma. Age at menarche was not associated with colorectal cancer. Moreover, genetically predicted age at natural menopause was not associated with lung and colorectal cancers. CONCLUSION: Our MR study suggested that later age at menarche was causally associated with a decreased risk of lung cancer overall and its subtypes, and adult BMI might be a mediator.