Mendelian randomization analyses of 23 known and suspected risk factors and biomarkers for breast cancer overall and by molecular subtypes

Abstract

Many risk factors have been identified for breast cancer. The potential causality for some of them remains uncertain, and few studies have comprehensively investigated these associations by molecular subtypes. We performed a two-sample Mendelian randomization (MR) study to evaluate potential causal associations of 23 known and suspected risk factors and biomarkers with breast cancer risk overall and by molecular subtypes using data from the Breast Cancer Association Consortium. The inversevariance weighted method was used to estimate odds ratios (OR) and 95% confidence interval (CI) for association of each trait with breast cancer risk. Significant associations with breast cancer risk were found for 15 traits, including age at menarche, age at menopause, body mass index, waist-to-hip ratio, height, physical activity, cigarette smoking, sleep duration, and morning-preference chronotype, and six blood biomarkers (estrogens, insulin-like growth factor-1, sex hormone-binding globulin [SHBG], telomere length, HDL-cholesterol and fasting insulin). Noticeably, an increased circulating SHBG was associated with a reduced risk of estrogen receptor (ER)-positive cancer (OR = 0.83, 95% CI: 0.73-0.94), but an elevated risk of ER-negative (OR = 1.12, 95% CI: 0.93-1.36) and triple negative cancer (OR = 1.19, 95% CI: 0.92-1.54) (P heterogeneity = 0.01). Fasting insulin was most strongly associated with an increased risk of HER2-negative cancer (OR = 1.94, 95% CI: 1.18-3.20), but a reduced risk of HER2-enriched cancer (OR = 0.46, 95% CI: 0.26-0.81) (P heterogeneity = 0.006). Results from sensitivity analyses using MR-Egger and MR-PRESSO were generally consistent. Our study provides strong evidence supporting potential causal associations of several risk factors for breast cancer and suggests potential heterogeneous associations of SHBG and fasting insulin levels with subtypes of breast cancer.

Integrating Mendelian randomization and literature-mined evidence for breast cancer risk factors

“…Age at menopause is an established risk factor for breast cancer in observational studies [45] and MR studies [40], [46]. In our analysis, we observed a strong causal effect on both versions of the overall breast cancer sample, ER+ sample, Luminal A and Luminal B1 subtype (ER+ subtypes), but little evidence of an effect on ER-sample, TNBC and HER-enriched (both ER-subtypes) and Luminal B2.…”

“…adult and childhood body size and other anthropometric measures [44], [47], [48] reproductive traits [40], sleep traits [49], height [50], IGF-1 [41], smoking [51], lipids [52], [53]), or in MR studies analysing multiple exposure traits as potential risk factors or biomarkers, e.g. identified with a traditional literature search [46] or focusing on a subset of molecular traits [54] [55]. The final set of traits also included many that have robust (FDR corrected) causal estimates of the effect on breast cancer but have not been reported in MR studies before.…”

Morning chronotype and digestive tract cancers: Mendelian randomization study

“…Chronotype can be influenced by genetic and environmental factors including cultural and social influences, urban lifestyle, exposure to light, sleep schedule and so on. 44 Given the protective effects of a morning chronotype on several cancer outcomes, [14][15][16]31 strategies that formulate a morning type, like limiting evening screen time and maintaining a regular sleep schedule, should be promoted to reduce the disease burden of these cancers. In addition, chronotype may influence the disease risk via altering diet preference and pattern.…”

Sleep and breast and prostate cancer risk in the MCC-Spain study

“…Results when combining findings from previous studies of prostate cancer were 0.95 (95% CI 0.86–1.04) and 0.75 (95% CI 0.54–1.05) respectively. Results of Mendelian randomisation studies in contrast reported adverse effects of genetic variants associated with increased sleep duration and incident oestrogen receptor positive and oestrogen receptor negative breast cancer risk, suggesting that further research using objectively measured metrics of sleep duration, including biological metrics (as opposed to questionnaire data), maybe useful 40 , 41 .…”