The Emerging Role of the Microbiota in Breast Cancer Progression.
Cells
Emerging evidence suggests a profound association between the microbiota composition in the gastrointestinal tract and breast cancer progression. The gut microbiota plays a crucial role in modulating the immune response, releasing metabolites, and modulating estrogen levels, all of which have implications for breast cancer growth. However, recent research has unveiled a novel aspect of the relationship between the microbiota and breast cancer, focusing on microbes residing within the mammary tissue, which was once considered sterile. These localized microbial communities have been found to change in the presence of a tumor as compared to healthy mammary tissue, unraveling their potential contribution to tumor progression. Studies have identified specific bacterial species that are enriched within breast tumors and have highlighted the mechanisms by which even these microbes influence cancer progression through immune modulation, direct carcinogenic activity, and effects on cellular pathways involved in cell proliferation or apoptosis. This review aims to provide an overview of the current knowledge on the mechanisms of crosstalk between the gut/mammary microbiota and breast cancer. Understanding this intricate interplay holds promise for developing innovative therapeutic approaches.
10.3390/cells12151945
Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.
Cell death and differentiation
The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
10.1038/s41418-021-00784-1
Mendelian randomization studies of cancer risk: a literature review.
Current epidemiology reports
PURPOSE OF REVIEW:In this paper, we summarize prior studies that have used Mendelian Randomization (MR) methods to study the effects of exposures, lifestyle factors, physical traits, and/or biomarkers on cancer risk in humans. Many such risk factors have been associated with cancer risk in observational studies, and the MR approach can be used to provide evidence as to whether these associations represent causal relationships. MR methods require a risk factor of interest to have known genetic determinants that can be used as proxies for the risk factor (i.e., "instrumental variables" or IVs), and these can be used to obtain an effect estimate that, under certain assumptions, is not prone to bias caused by unobserved confounding or reverse causality. This review seeks to describe how MR studies have contributed to our understanding of cancer causation. RECENT FINDINGS:We searched the published literature and identified 76 MR studies of cancer risk published prior to October 31, 2017. Risk factors commonly studied included alcohol consumption, Vitamin D, anthropometric traits, telomere length, lipid traits, glycemic traits, and markers of inflammation. Risk factors showing compelling evidence of a causal association with risk for at least one cancer type include alcohol consumption (for head/neck and colorectal), adult body mass index (increases risk for multiple cancers, but decreases risk for breast), height (increases risk for breast, colorectal, and lung; decreases risk for esophageal), telomere length (increases risk for lung adenocarcinoma, melanoma, renal cell carcinoma, glioma, B-cell lymphoma subtypes, chronic lymphocytic leukemia, and neuroblastoma), and hormonal factors (affects risk for sex-steroid sensitive cancers). SUMMARY:This review highlights alcohol consumption, body mass index, height, telomere length, and the hormonal exposures as factors likely to contribute to cancer causation. This review also highlights the need to study specific cancer types, ideally subtypes, as the effects of risk factors can be heterogeneous across cancer types. As consortia-based genome-wide association studies increase in sample size and analytical methods for MR continue to become more sophisticated, MR will become an increasingly powerful tool for understanding cancer causation.
10.1007/s40471-018-0144-1
Exploring the contribution of lifestyle to the impact of education on the risk of cancer through Mendelian randomization analysis.
Scientific reports
Educational attainment (EA) has been linked to the risk of several types of cancer, despite having no expected direct biological connection. In this paper, we investigate the mediating role of alcohol consumption, smoking, vegetable consumption, fruit consumption and body mass index (BMI) in explaining the effect of EA on 7 cancer groupings. Large-scale genome wide association study (GWAS) results were used to construct the genetic instrument for EA and the lifestyle factors. We conducted GWAS in the UK Biobank sample in up to 335,024 individuals to obtain genetic association data for the cancer outcomes. Univariable and multivariable two-sample Mendelian randomization (MR) analyses and mediation analyses were then conducted to explore the causal effect and mediating proportions of these relations. MR mediation analysis revealed that reduced lifetime smoking index accounted for 81.7% (49.1% to 100%) of the protective effect of higher EA on lower respiratory cancer. Moreover, the effect of higher EA on lower respiratory cancer was mediated through vegetable consumption by 10.2% (4.4% to 15.9%). We found genetic evidence that the effect of EA on groups of cancer is due to behavioural changes in avoiding well established risk factors such as smoking and vegetable consuming.
10.1038/s41598-024-54259-7
Coffee consumption and risk of breast cancer: A Mendelian randomization study.
PloS one
BACKGROUND:Observational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer. METHODS:We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations. RESULTS:One cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR = 0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07). CONCLUSIONS:The results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak association.
10.1371/journal.pone.0236904
Causal relationship between endometrial cancer and risk of breast cancer: A 2-sample Mendelian randomization study.
Medicine
Several studies have confirmed the important role of endometrial cancer (EC) in the development and progression of breast cancer (BC), and this study will explore the causal relationship between EC and BC by 2-sample Mendelian randomization analysis. Pooled data from published genome-wide association studies were used to assess the association between EC and BC risk in women using 5 methods, namely, inverse variance weighting (IVW), MR-Egger, weighted median (WME), simple multimaximetry (SM) and weighted multimaximetry (WM) with the EC-associated genetic loci as the instrumental variables (IV) and sensitivity analyses were used to assess the robustness of the results. The statistical results showed a causal association between EC and BC (IVW: OR = 1.07, 95% CI = 1.01-1.32, P = .02; MR-Egger: OR = 1.21, 95% CI = 0.71-1.51, P = .11; weighted median: OR = 1.05, 95% CI = 0.97-1.31, P = .19; simple plurality method: OR = 0.98, 95% CI = 0.81-1.15, P = .78; weighted plurality method: OR = 0.98, 95% CI = 0.81-1.14, P = .75), and the results of the sensitivity analyses showed that there was no significant heterogeneity or multiplicity, and the results were stable. EC is associated with an increased risk of developing BC. The results of this MR analysis can be used as a guideline for screening for BC in women with EC and to help raise awareness of screening for early detection and treatment.
10.1097/MD.0000000000038732
Causal relationship between dietary factors and breast cancer risk: A Mendelian randomization study.
Heliyon
Background:Previous studies have discovered an association between dietary factors and breast cancer. However, few studies have used Mendelian randomization (MR) to assess the potential causal relationship between dietary factors and breast cancer. Methods:The exposure datasets for fresh fruit intake, dried fruit intake, salad/raw vegetable intake, cooked vegetable intake, oily fish intake, non-oily fish intake, cheese intake, and bread intake were obtained from the UK Biobank. The outcome dataset was extracted from the Breast Cancer Association Consortium (BCAC). We used the inverse variance weighted (IVW) method as the primary approach for the two-sample MR analysis. To ensure the accuracy of the results, we conducted heterogeneity and horizontal pleiotropy analyses. Additionally, multivariable MR analysis was conducted to ensure the stability of the results. Results:Dried fruit intake was found to be a protective factor for overall breast cancer (outliers excluded: OR: 0.549; 95 % CI: 0.429-0.702; p = 1.75 × 10). Subtype analyses showed that dried fruit intake was inversely associated with both estrogen receptor-positive (ER+) breast cancer (outliers excluded: OR: 0.669; 95 % CI: 0.512-0.875; p = 0.003) and ER-negative (ER-) breast cancer (OR: 0.559; 95 % CI: 0.379-0.827; p = 0.004), while fresh fruit intake was inversely associated with ER- breast cancer (excluded outliers: OR: 0.510; 95 % CI: 0.308-0.846; p = 0.009). No significant causal relationship was found between other dietary intakes and breast cancer. After adjusting for the effects of possible confounders, the causal relationships found by the two-sample MR analysis remained. Conclusion:Our study provides evidence that dried fruit intake may reduce the risk of both ER+ and ER- breast cancer, and fresh fruit intake may reduce the risk of ER- breast cancer. Other factors included in this study were not linked to breast cancer.
10.1016/j.heliyon.2023.e20980
Bidirectional Mendelian randomization analysis investigating the genetic association between primary breast cancer and colorectal cancer.
Frontiers in immunology
Purpose:With the advancement in early diagnosis and treatment, the prognosis for individuals diagnosed with breast cancer (BC) has improved significantly. The prognosis of primary breast cancer (PBC) survivors can be significantly influenced by the occurrence of colorectal cancer (CRC) as a secondary primary cancer (SPC). The objective of this study is to explore the possible genetic association between PBC and CRC, aiming to lay a groundwork for the development of preventive strategies against SPC-CRC following BC surgery. Methods:We employed a bidirectional two-sample Mendelian randomization (MR) approach to thoroughly examine genetic instrumental variables (IVs) derived from genome-wide association studies (GWAS) conducted on PBC and CRC. And applied inverse variance weighted (IVW) and multiple other MR methods (weighted median, simple median, MR-PRESSO and MR-RAPS) to evaluate the association between the two cancers (PBC and CRC) at genetic level. Furthermore, the robustness of the findings was further confirmed through the utilization of the genetic risk score (GRS) method in a secondary analysis. Results:Forward MR analysis, a total of 179 BC genetic IVs, 25 estrogen receptor-negative (ER-) genetic IVs and 135 ER-positive (ER+) genetic IVs were screened. Reverse MR analysis, 179 genetic IVs of CRC, 25 genetic IVs of colon cancer, 135 genetic IVs of rectal cancer, 25 genetic IVs of left colon cancer and 135 genetic IVs of right colon cancer were screened. IVW and other MR methods found no significant genetic association between PBC and CRC ( > 0.05). Subgroup analysis also showed that ER- BC and ER+ BC were not correlated with the occurrence of CRC ( > 0.05). The findings of the secondary analysis using GRS were consistent with those obtained from the primary analysis, thereby confirming the robustness and reliability of this study. Conclusions:Our findings do not provide any evidence supporting the association between PBC and CRC at the genetic level. Further large-scale prospective studies are warranted to replicate our findings.
10.3389/fimmu.2023.1260941
Mendelian randomisation analysis of circulating adipokines and C-reactive protein on breast cancer risk.
International journal of cancer
Circulating adipokines and C-reactive protein (CRP) have been linked to breast cancer risk in observational epidemiological studies. The causal nature of these associations is unclear because of the susceptibility of conventional observational designs to residual confounding, reverse causation and other forms of bias. Mendelian randomisation (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational settings. We performed a MR analysis to evaluate the causal relevance of six previously reported circulating adipokines [adiponectin, hepatocyte growth factor (HGF), interleukin-6, leptin receptor, plasminogen activator inhibitor-1 and resistin] and CRP in risk of overall and oestrogen receptor-stratified breast cancer in up to 122,977 cases and 105,974 controls of European ancestry. Genetic instruments were constructed from single-nucleotide polymorphisms robustly (p < 5 × 10 ) associated with risk factors in genome-wide association studies. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding. In MR analyses, there was evidence for an association of HGF with oestrogen receptor-negative cancer (odds ratio per standard deviation increase: 1.17, 95% confidence interval: 1.01-1.35; p = 0.035) but little evidence for associations of other adipokines or CRP with overall or oestrogen receptor-stratified breast cancer. Colocalisation analysis suggested that the association of HGF with oestrogen receptor-negative breast cancer was unlikely to reflect a causal association. Collectively, these findings do not support an important aetiological role of various adipokines or CRP in overall or oestrogen receptor-specific breast cancer risk.
10.1002/ijc.32947
The association between immune cells and breast cancer: insights from mendelian randomization and meta-analysis.
International journal of surgery (London, England)
BACKGROUND:Breast cancer (BC) is the most common cancer among women worldwide, with 2.3 million new cases and 685,000 deaths annually. It has the highest incidence in North America, Europe, and Australia and lower rates in parts of Asia and Africa. Risk factors include age, family history, hormone replacement therapy, obesity, alcohol consumption, and lack of physical activity. BRCA1 and BRCA2 gene mutations significantly increase the risk. The five-year survival rate is over 90% in developed countries but lower in developing ones. Early screening and diagnosis, using mammography and MRI, are crucial for reducing mortality. In recent years, significant progress has been made in studying BC immunophenotyping, particularly in multicolor flow cytometry, molecular imaging techniques, and tumor microenvironment analysis. These technologies improve diagnosis, classification, and detection of minimal residual disease. Novel immunotherapies targeting the tumor microenvironment, like CAR-T cell therapy, show high efficiency and fewer side effects. High levels of tumor-infiltrating lymphocytes (TILs) correlate with better prognosis, while immune checkpoint molecules (PD-1, PD-L1) help cancer cells evade the immune system. Tumor-associated macrophages (TAMs) promote invasion and metastasis. Blocking molecules like CTLA-4, LAG-3, and TIM-3 enhance anti-tumor responses, and cytokines like IL-10 and TGF-β aid tumor growth and immune evasion. Mendelian randomization (MR) studies use genetic variants to reduce confounding bias and avoid reverse causation, providing robust causal inferences about immune cell phenotypes and BC. This approach supports the development of precision medicine and personalized treatment strategies for BC. METHODS:This study aims to conduct Mendelian Randomization (MR) analysis on 731 immune cell phenotypes with BC in the BCAC and Finngen R10 datasets, followed by a meta-analysis of the primary results using the inverse-variance weighted (IVW) method and multiple corrections for the significance p values from the meta-analysis. Specifically, the study is divided into three parts: First, data on 731 immune cell phenotypes and BC are obtained and preprocessed from the GWAS Catalog and Open GWAS (BCAC) and the Finngen R10 databases. Second, MR analysis is performed on the 731 immune cell phenotypes with BC data from the BCAC and Finngen R10 databases, followed by a meta-analysis of the primary results using the IVW method, with multiple corrections for the significance p values from the meta-analysis. Finally, the positively identified immune cell phenotypes are used as outcome variables, and BC as the exposure variable for reverse MR validation. RESULTS:The study found that two immune phenotypes exhibited strong significant associations in MR analysis combined with meta-analysis and multiple corrections. For the immune phenotype CD3 on CD28+ CD4-CD8- T cells, the results were as follows: In the BCAC dataset, the IVW result was Odds Ratio (OR) = 0.942 (95% confidence interval (CI) = 0.915 ~ 0.970, P = 6.76 × 10-5), β = -0.059; MR Egger result was β = -0.095; and the weighted median result was β = -0.060. In the Finngen R10 dataset, the IVW result was OR = 0.956 (95% CI = 0.907 ~ 1.01, P = 0.092), β = -0.045; MR Egger result was β = -0.070; and weighted median result was β = -0.035. The β values were consistent in direction across all three MR methods in both datasets. The meta-analysis of the IVW results from both datasets showed OR = 0.945 (95% CI = 0.922 ~ 0.970, P = 1.70 × 10-5). After Bonferroni correction, the significant P-value was P = 0.01, confirming the immune phenotype as a protective factor against BC. For the immune phenotype HLA DR on CD33- HLA DR+, the results were as follows: In the BCAC dataset, the IVW result was OR = 0.977 (95% CI = 0.964 ~ 0.990, P = 7.64 × 10-4), β = -0.023; MR Egger result was β = -0.016; and the weighted median result was β = -0.019. In the Finngen R10 dataset, the IVW result was OR = 0.960 (95% CI = 0.938 ~ 0.983, P = 6.51 × 10-4), β = -0.041; MR Egger result was β = -0.064; and weighted median result was β = -0.058. The β values were consistent in direction across all three MR methods in both datasets. The meta-analysis of the IVW results from both datasets showed OR = 0.973 (95% CI = 0.961 ~ 0.984, P = 3.80 × 10-6). After Bonferroni correction, the significant P-value was P = 0.003, confirming this immune phenotype as a protective factor against BC. When the immune cell phenotypes CD3 on CD28+ CD4-CD8- T cells and HLA DR on CD33- HLA DR+ were used as outcomes and BC was used as exposure, the data processing and analysis procedures were the same. The MR analysis results are as follows: Data from the FinnGen database regarding the effect of positive immune phenotypes on malignant neoplasm of the breast indicated a β coefficient of -0.011, OR = 0.99 (95% CI = -0.117 ~ 0.096, P = 0.846); data from the BCAC database regarding favorable immune phenotypes for BC demonstrated a β coefficient of -0.052, OR = 0.095 (95% CI = -0.144 ~ 0.040, P = 0.266). The results suggest insufficient evidence in both databases to indicate that BC inversely affects these two immune cell phenotypes. CONCLUSIONS:Evidence suggests that the immune cell phenotypes CD3 on CD28+ CD4-CD8- T cells and HLA DR on CD33- HLA DR+ protect against BC. This protective effect may be achieved through various mechanisms, including enhancing immune surveillance to recognize and eliminate tumor cells; secreting cytokines to inhibit tumor cell proliferation and growth directly; triggering apoptotic pathways in tumor cells to reduce their number; modulating the tumor microenvironment to make it unfavorable for tumor growth and spread; activating other immune cells to boost the overall immune response; and inhibiting angiogenesis to reduce the tumor's nutrient supply. These mechanisms work together to help protect BC patients and slow disease progression. Both immune cell phenotypes are protective factors for BC patients and can be targeted to enhance their function and related pathways for BC treatment.
10.1097/JS9.0000000000001840
Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis.
Frontiers in oncology
Background:Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC. Methods:Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking. Results:Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN. Conclusion:Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.
10.3389/fonc.2024.1407795
Breast cancer risk factors and their effects on survival: a Mendelian randomisation study.
BMC medicine
BACKGROUND:Observational studies have investigated the association of risk factors with breast cancer prognosis. However, the results have been conflicting and it has been challenging to establish causality due to potential residual confounding. Using a Mendelian randomisation (MR) approach, we aimed to examine the potential causal association between breast cancer-specific survival and nine established risk factors for breast cancer: alcohol consumption, body mass index, height, physical activity, mammographic density, age at menarche or menopause, smoking, and type 2 diabetes mellitus (T2DM). METHODS:We conducted a two-sample MR analysis on data from the Breast Cancer Association Consortium (BCAC) and risk factor summary estimates from the GWAS Catalog. The BCAC data included 86,627 female patients of European ancestry with 7054 breast cancer-specific deaths during 15 years of follow-up. Of these, 59,378 were estrogen receptor (ER)-positive and 13,692 were ER-negative breast cancer patients. For the significant association, we used sensitivity analyses and a multivariable MR model. All risk factor associations were also examined in a model adjusted by other prognostic factors. RESULTS:Increased genetic liability to T2DM was significantly associated with worse breast cancer-specific survival (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.03-1.17, P value [P] = 0.003). There were no significant associations after multiple testing correction for any of the risk factors in the ER-status subtypes. For the reported significant association with T2DM, the sensitivity analyses did not show evidence for violation of the MR assumptions nor that the association was due to increased BMI. The association remained significant when adjusting by other prognostic factors. CONCLUSIONS:This extensive MR analysis suggests that T2DM may be causally associated with worse breast cancer-specific survival and therefore that treating T2DM may improve prognosis.
10.1186/s12916-020-01797-2
Modifiable pathways for colorectal cancer: a mendelian randomisation analysis.
The lancet. Gastroenterology & hepatology
BACKGROUND:Epidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer. METHODS:We used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (OR) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10 was considered significant, and p values less than 0·05 were considered to be suggestive of an association. FINDINGS:No putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (OR 1·14 [95% CI 1·03-1·25]; p=0·0086), body-mass index (1·09 [1·01-1·17]; p=0·023), waist circumference (1·13 [1·02-1·26]; p=0·018), basal metabolic rate (1·10 [1·03-1·18]; p=0·0079), and concentrations of LDL cholesterol (1·14 [1·04-1·25]; p=0·0056), total cholesterol (1·09 [1·01-1·18]; p=0·025), circulating serum iron (1·17 [1·00-1·36]; p=0·049), and serum vitamin B12 (1·21 [1·04-1·42]; p=0·016), although potential pleiotropy among genetic variants used as instruments for vitamin B12 constrains the finding. A suggestive association was also noted between adult height and increased risk of colorectal cancer (OR 1·04 [95% CI 1·00-1·08]; p=0·032). Low blood selenium concentration had a suggestive association with decreased risk of colorectal cancer (OR 0·85 [95% CI 0·75-0·96]; p=0·0078) based on a single variant, as did plasma concentrations of interleukin-6 receptor subunit α (also based on a single variant; 0·98 [0·96-1·00]; p=0·035). Risk of colorectal cancer was not associated with any sex hormone or reproductive factor, serum calcium, or circulating 25-hydroxyvitamin D concentrations. INTERPRETATION:This analysis identified several modifiable targets for primary prevention of colorectal cancer, including lifestyle, obesity, and cardiometabolic factors, that should inform public health policy. FUNDING:Cancer Research UK, UK Medical Research Council Human Genetics Unit Centre, DJ Fielding Medical Research Trust, EU COST Action, and the US National Cancer Institute.
10.1016/S2468-1253(19)30294-8