Long-Term Impact of Stressful Life Events on Breast Cancer Risk: A 36-Year Genetically Informed Prospective Study in the Finnish Twin Cohort

Abstract

ABSTRACTTo investigate potential interactions between stress, genetic predisposition, and breast cancer, we employed a multifaceted approach, analysing polygenic risk scores (PRS), DNA methylation (DNAm) patterns, stressful life events, and breast cancer risk using data from 10342 women in the Finnish Twin Cohort, including 719 breast cancer cases. Stressful life events data was gathered from a 1981 questionnaire while cancer and mortality data were obtained from Finnish Cancer Registry, Finnish Population Register and Statistics Finland. DNAm data from breast cancer discordant twin pairs was used to explore within-pair differences between 212 breast cancer associated CpG sites and stressful life events. A hazard ratio (HR) of 1.05 (95%CI 1.02-1.08) was observed for breast cancer per one-event increase in total stressful life events. Women exposed to over 10 stressful life events exhibited an almost two-fold increase in risk of breast cancer (HR=1.93, 95%CI 1.19-3.14). Stratifying by birth decade revealed a lower HR for those born after 1950 (HR 1.01; 95%CI 0.96-1.06) compared to those born between 1940-1949 (HR 1.07; 95%CI 1.01-1.12). In a subsample with genetic data, no association with breast cancer PRS was seen (HR = 1.03, 95%CI 0.92-1.15 per SD of PRS). Stressful life events exposure associated with breast cancer related DNAm in 42 of the 212 CpG sites. This 36-year genetically informed study highlights the long-term association between stressful life events and breast cancer risk. These findings suggest epigenetic changes, but not polygenic risk may mediate the impact the effects of stressful life events on breast cancer incidence.