Investigating the interplay of reproductive, menstrual and adiposity factors in relation to breast cancer risk

Abstract

Observational studies have identified associations between a later age at menarche, earlier age at menopause, having children and an earlier first pregnancy, and decreased breast cancer risk. Studies have largely investigated the role of individual reproductive factors in isolation. This thesis aims to consider the causal role of reproductive factors and the interplay that may occur between them, and with adiposity, an established breast cancer risk factor. Chapter 1 describes breast cancer epidemiology and the current understanding of the relationships among reproductive factors and adiposity. It also highlights the gaps in current literature regarding the causal effects of reproductive factors on breast cancer risk. Chapter 2 details the data, particularly from the UK Biobank, and methodology, particularly linkage disequilibrium score regression and Mendelian randomization, used in this thesis. Using these approaches, I identify high genetic correlation and numerous causal effects among reproductive factors and adiposity (chapter 3,4). Notably, I find evidence for opposing effects of childhood and adulthood adiposity on several reproductive factors. The evidence from chapters 3 and 4 inform a multivariable approach investigating reproductive factors on breast cancer risk (chapter 5,6). I do not identify evidence for the proposed protective effect of an earlier age at first birth but do find an adverse effect on estrogen-receptor negative breast cancer risk, which warrants further investigation. Additionally, I identify an earlier age at menarche, and later age at menopause increases estrogen-receptor positive breast cancer risk, and that an earlier age at menarche also increases triple negative. Chapter 7 provides a summary of the findings, strengths and limitations of this work, alongside possible future directions. While weak instruments when using multivariable Mendelian randomization warrants caution, this thesis demonstrates the importance of considering relationships among reproductive factors and adiposity, when investigating their role in breast cancer risk, which could aid risk prediction.

Date of Award	1 Oct 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Rebecca Richmond (Supervisor), Abigail Fraser (Supervisor), Laura D Howe (Supervisor) & Gemma C Sharp (Supervisor)