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

Marion Denos; Yi-Qian Sun; Lin Jiang; Ben Michael Brumpton; Xiao-Mei Mai

doi:10.1210/jendso/bvad077

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

J Endocr Soc. 2023 Jun 7;7(8):bvad077. doi: 10.1210/jendso/bvad077. eCollection 2023 Jul 3.

Authors

Marion Denos¹, Yi-Qian Sun^{2

3

4}, Lin Jiang¹, Ben Michael Brumpton^{5

6}, Xiao-Mei Mai¹

Affiliations

¹ Department of Public Health and Nursing, Norwegian University of Science and Technology, 7030 Trondheim, Norway.
² Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7030 Trondheim, Norway.
³ Department of Pathology, Clinic of Laboratory Medicine, St. Olavs Hospital, 7030 Trondheim, Norway.
⁴ Center for Oral Health Services and Research Mid-Norway (TkMidt), 7030 Trondheim, Norway.
⁵ Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway.
⁶ K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, 7030 Trondheim, Norway.

Abstract

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.

Keywords: HUNT; Mendelian randomization; colorectal cancer; lung cancer; menarche; menopause.