Effects of reproductive factors and sex hormones on risk of lung and colorectal cancers in women. Prospective cohort and Mendelian randomization studies using data from the Trøndelag Health Study (HUNT)

Abstract

Lung and colorectal cancers are the two most common cancers in women after breast cancer. The high incidence and mortality of these two cancers in women prompt us to study the causes. Female reproductive factors and sex hormones have been reported to be associated with both cancers. However, their causal roles remain unclear. The aim of this thesis was to investigate the role of reproductive factors and sex hormones on risk of lung cancer and its subtypes as well as colon, rectal and colorectal cancers in women. We conducted conventional observational and Mendelian randomization (MR) analyses, using primarily individual-level data from the Trøndelag Health Study (HUNT) and secondarily summary-level data from genome-wide association studies when available. In the first study, we explored several reproductive factors in relation to lung and colorectal cancers in a HUNT prospective cohort. In the second and third studies, we focused on age at menarche, age at menopause, and sex hormones, respectively, and investigated their potential causal associations with lung and colorectal cancers using an MR approach. We found that early menarche was associated with an increased risk of lung adenocarcinoma in our prospective cohort study. This was supported by our MR analyses suggesting a later age at menarche to be causally associated with a decreased risk of lung cancer and its subtypes. Adult body mass index may have mediated these associations. Our cohort study also suggested that women with one or no child had an increased incidence of colon cancer, and hormone therapy was associated with a decreased incidence of rectal cancer. In addition, our two-sample MR study did not provide convincing evidence for a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry. The main finding of this thesis regarding a causal association between age at menarche and lung cancer risk warrants further confirmation. If the observed association is corroborated by future studies, age at menarche could be incorporated into clinical assessment to help identify women at higher risk of lung cancer.