Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study.

BACKGROUND Previous research has demonstrated that a morning-preference chronotype is protective against both breast and prostate cancer. Sex hormones have been implicated in relation to both chronotype and the development of both cancers. This study aims to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer risk using a Mendelian Randomization (MR) framework. METHODS We obtained genetic variants strongly (p<5x10-8) associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin (SHBG), and oestradiol from previously published genome-wide association studies (GWAS) that had been undertaken in UK Biobank and 23andMe (n=244,207 females and n=205,527 males). These variants were used to investigate causal relationships with risk of breast and prostate cancer using summary data from the largest available consortia in breast (nCases/nControls=133,384/ 113,789) and prostate cancer (nCases/nControls=79,148/61,106). This was achieved using a series of MR approaches: univariable, bidirectional and multivariable. Results Overall, we found evidence for a protective effect of genetically predicted tendency towards morning preference on both breast (OR=0.93, 95% CI:0.88, 1.00) and prostate (OR=0.90, 95% CI:0.83, 0.97) cancer risk. There was evidence that an increased tendency to morning preference reduces bioavailable testosterone levels in both females (mean SD difference=-0.08, 95% CI:-0.12, -0.05) and males (mean SD difference=-0.06, 95% CI:-0.09, -0.03), and reduces total testosterone levels in females (mean SD difference=-0.07, 95% CI:-0.10, -0.03). We also found evidence to support higher total and bioavailable testosterone increasing the risk of breast cancer (OR=1.15, 95% CI:1.07, 1.23, OR=1.10, 95% CI:1.01, 1.19 respectively) and higher bioavailable testosterone increasing prostate cancer risk (OR=1.22, 95% CI:1.08, 1.37). While findings from univariable and bidirectional MR analyses indicated that testosterone may lie on the causal pathway between chronotype and cancer risk, there was evidence for a bidirectional association between chronotype and testosterone in females, implicating testosterone as both a confounder and mediator of the chronotype effect on breast cancer risk. However, the effects of chronotype remained largely unchanged when accounting for testosterone in multivariable MR, suggesting that any confounding or mediating effect is likely to be minimal. Conclusions This study has extended previous findings regarding the protective effect of chronotype on breast cancer and found evidence to suggest that morning preference also reduces prostate cancer risk in men. While testosterone levels were found to be closely linked with both chronotype and cancer risk, there was inconsistent evidence for the role of testosterone in mediating the effect of morning preference chronotype on both breast and prostate cancer. Findings regarding the potential protective effect of chronotype on both breast and prostate cancer risk are clinically interesting. However, this may not serve as a direct target for intervention, since it is difficult to modify someone's morning/evening preference. Given this, further studies are needed to investigate the mechanisms underlying this effect and to identify other potential modifiable intermediates.

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Interactions Between Genome-wide Significant Genetic Variants and Circulating Concentrations of Insulin-like Growth Factor 1, Sex Hormones, and Binding Proteins in Relation to Prostate Cancer Risk in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

American Journal of Epidemiology ◽

10.1093/aje/kwr423 ◽

2012 ◽

Vol 175 (9) ◽

pp. 926-935 ◽

Cited By ~ 12

Author(s):

Konstantinos K. Tsilidis ◽

Ruth C. Travis ◽

Paul N. Appleby ◽

Naomi E. Allen ◽

Sara Lindstrom ◽

...

Keyword(s):

Prostate Cancer ◽

Growth Factor ◽

Cancer Risk ◽

Sex Hormones ◽

National Cancer Institute ◽

Genetic Variants ◽

Binding Proteins ◽

Prostate Cancer Risk ◽

Genome Wide ◽

Breast And Prostate Cancer

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Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000872 ◽

2019 ◽

Vol 7 (1) ◽

pp. e000872 ◽

Cited By ~ 6

Author(s):

Shiu Lun Au Yeung ◽

Catherine Mary Schooling

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Type 2 Diabetes ◽

Cancer Risk ◽

Fasting Glucose ◽

Prostate Cancer Risk ◽

Immortal Time Bias ◽

Log Odds ◽

Breast And Prostate Cancer

ObjectivesObservational studies suggest glycemic traits and type 2 diabetes are positively associated, and metformin inversely associated with breast and prostate cancer risk. However, observational studies are susceptible to unmeasured confounding while studies of metformin use are also vulnerable to immortal time bias. The use of Mendelian randomization may reduce confounding due to random allocation of relevant genetic markers at birth, and may reduce immortal time bias (for metformin-related variants analysis) since the start of exposure is at birth.Research design and methodsWe identified strong genetic predictors of fasting glucose, glycated hemoglobin, and type 2 diabetes from the Meta-Analyses of Glucose and Insulin-related traits Consortium and Diabetes Genetics Replication And Meta-analysis Consortium (n=140 595 for glucose; n=123 665 for HbA1c; n=898 130 for type 2 diabetes) and of AMPK-instrumented HbA1c reduction as a proxy of metformin and applied them to large genome-wide association studies of breast cancer (Breast Cancer Association Consortium; BCAC) and prostate cancer (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome; PRACTICAL). We used inverse variance weighting to obtain estimates. Sensitivity analyses included use of MR-Egger, weighted median, exclusion of pleiotropic instruments, and validation using UK Biobank (breast cancer only).ResultsThere was no association of fasting glucose (OR 1.03 per mmol/L, 95% CI 0.85 to 1.25), HbA1c (OR 1.02 per %, 95% CI 0.73 to 1.45), or type 2 diabetes (OR 0.98 per log odds, 95% CI 0.95 to 1.01) with breast cancer in BCAC, with similar findings from UK Biobank. There was no association of fasting glucose (OR 0.93 per mmol/L, 95% CI 0.73 to 1.17), HbA1c (OR 0.90 per %, 95% CI 0.58 to 1.40) or type 2 diabetes (OR 1.02 per log odds, 95% CI 0.97 to 1.07) with prostate cancer in PRACTICAL. No strong evidence was observed for AMPK-instrumented HbA1c reduction on cancer risk.ConclusionGlycemic traits and type 2 diabetes unlikely cause breast and prostate cancer. Whether metformin can be repurposed for cancer prevention remains unclear.

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Increased adiposity is protective for breast and prostate cancer: a Mendelian randomisation study using up to 132,413 breast cancer cases and 85,907 prostate cancer cases

10.1101/2020.04.02.20049031 ◽

2020 ◽

Author(s):

H. A. Amin ◽

P. Kaewsri ◽

A. M. Yiorkas ◽

H. Cooke ◽

A. I. Blakemore ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Cancer Risk ◽

Causal Effect ◽

Prostate Cancer Risk ◽

Mendelian Randomisation ◽

Health Campaigns ◽

Fat Percentage ◽

Published Evidence ◽

Breast And Prostate Cancer

ABSTRACTBackgroundBreast and prostate cancer are the first and second most common types of cancer in women and men, respectively. A recent campaign by Cancer Research UK emphasised obesity as being a causal risk factor for cancer, although previously published evidence is heterogenous. We aimed to explore the causal effect of adiposity on breast and prostate cancer risk in the UK Biobank (UKB), a large prospective cohort study, and published data.MethodsWe used Mendelian randomisation (MR) to assess the causal effect of body mass index (BMI), body fat percentage (BFP), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) on breast and prostate cancer risk.ResultsWe obtained estimates (odds ratios, OR, per SD unit increase) of the causal effect of the adiposity measures on breast and prostate cancer risk. BMI and HC decrease the risk of breast cancer (OR 0.776 [95% CIs 0.661-0.91] and OR 0.781 [95% CIs 0.649-0.94], respectively). WC, BFP, and BMI decrease the risk of prostate cancer (OR 0.602 [95% CIs 0.439-0.825], OR 0.629 [95% CIs 0.414-0.956], and OR 0.695 [95% CIs 0.553-0.874], respectively). The protective effect of adiposity on prostate cancer risk is enhanced in men who are exposed to potentially hazardous substances at work, and the association between BMI and breast cancer is confounded by variables associated with general health.ConclusionsIn conclusion, increasing adiposity is causally protective for breast and prostate cancer and the effects in prostate cancer may, at least partly, be due to the safe storage of chemicals in adipose cells. It is necessary to explore the mechanisms through which adiposity may protect against or be a risk factor for cancer, to identify how the latter can be minimised without sacrificing the former, and to base public health campaigns around sound evidence.HIGHLIGHTSPreviously published evidence regarding the effect of adiposity on prostate and breast cancer risk is heterogenousIncreasing BMI and hip circumference decrease the risk of breast cancer in womenIncreasing waist circumference, body fat percentage, and BMI decrease the risk of prostate cancerThe protective effect of adiposity on prostate cancer is stronger in men who are exposed to carcinogens at workPublic health campaigns need to target the negative aspects of adiposity whilst preserving the positive aspects

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Evaluating the Association between Artificial Light-at-Night Exposure and Breast and Prostate Cancer Risk in Spain (MCC-Spain Study)

Environmental Health Perspectives ◽

10.1289/ehp1837 ◽

2018 ◽

Vol 126 (4) ◽

pp. 047011 ◽

Cited By ~ 43

Author(s):

Ariadna Garcia-Saenz ◽

Alejandro Sánchez de Miguel ◽

Ana Espinosa ◽

Antonia Valentin ◽

Núria Aragonés ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Prostate Cancer Risk ◽

Artificial Light ◽

Light At Night ◽

Breast And Prostate Cancer

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First-degree family history of breast cancer is associated with prostate cancer risk: a systematic review and meta-analysis

BMC Cancer ◽

10.1186/s12885-019-6055-9 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Zheng-Ju Ren ◽

De-Hong Cao ◽

Qin Zhang ◽

Peng-Wei Ren ◽

Liang-Ren Liu ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Systematic Review ◽

Family History ◽

Cancer Risk ◽

Meta Analysis ◽

Prostate Cancer Risk ◽

History Of

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Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Journal of Clinical Oncology ◽

10.1200/jco.2016.69.4935 ◽

2017 ◽

Vol 35 (20) ◽

pp. 2240-2250 ◽

Cited By ~ 69

Author(s):

Julie Lecarpentier ◽

Valentina Silvestri ◽

Karoline B. Kuchenbaecker ◽

Daniel Barrowdale ◽

Joe Dennis ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Cancer Susceptibility ◽

Prostate Cancer Risk ◽

Risk Scores ◽

Cancer Risks ◽

Prostate Cancer Susceptibility ◽

Common Genetic Variants ◽

Breast And Prostate Cancer ◽

Male Carriers

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated—for the first time to our knowledge—associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10−6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10−9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

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Testosterone therapy may reduce prostate cancer risk due to testosterone deficiency at a young age via stabilizing serum testosterone levels

The Aging Male ◽

10.1080/13685538.2019.1578739 ◽

2019 ◽

Vol 23 (2) ◽

pp. 112-118 ◽

Cited By ~ 4

Author(s):

Xiao Zhang ◽

Yan Zhong ◽

Farid Saad ◽

Karim Sultan Haider ◽

Ahmad Haider ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Prostate Cancer Risk ◽

Serum Testosterone ◽

Young Age ◽

Testosterone Deficiency ◽

Testosterone Therapy ◽

Testosterone Levels

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Hormonal Predictors of Prostate Cancer: A Meta-Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.4.847 ◽

2000 ◽

Vol 18 (4) ◽

pp. 847-847 ◽

Cited By ~ 199

Author(s):

Terrence Shaneyfelt ◽

Rozita Husein ◽

Glenn Bubley ◽

Christos S. Mantzoros

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Confidence Interval ◽

Population Distribution ◽

Serum Insulin ◽

Meta Analysis ◽

Prostate Cancer Risk ◽

Sex Hormone Binding Globulin ◽

Total Testosterone

PURPOSE: Although there is strong circumstantial evidence that androgens are implicated in the etiology of prostate cancer, epidemiologic investigations have failed to demonstrate consistently that one or more steroid hormones are implicated. In contrast, recent epidemiologic studies unequivocally link serum insulin-like growth factor 1 (IGF-1) levels with risk for prostate cancer. METHODS: We have performed the first meta-analysis of all previously published studies on hormonal predictors of risk for prostate cancer. RESULTS: A meta-analysis restricted to studies that performed mutual adjustment for all measured serum hormones, age, and body mass index indicated that men whose total testosterone is in the highest quartile are 2.34 times more likely to develop prostate cancer (95% confidence interval, 1.30 to 4.20). In contrast, levels of dihydrotestosterone and estradiol do not seem to play a role of equal importance. The only study that provides multivariably adjusted sex hormone–binding globulin data indicates that this binding protein is inversely related to prostate cancer risk (odds ratio, 0.46; 95% confidence interval, 0.24 to 0.89). Finally, all three studies that examined the role of serum IGF-1 have consistently demonstrated a positive and significant association with prostate cancer risk that is similar in magnitude to that of testosterone. CONCLUSION: Men with either serum testosterone or IGF-1 levels in upper quartile of the population distribution have an approximately two-fold higher risk for developing prostate cancer.

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