Cancer is the cause of death for one in seven individuals worldwide. It is widely acknowledged that screening and early diagnosis are of vital importance for improving the likelihood of recovery. However, given the costly, time-consuming, and invasive nature of the many methods currently in use, patients often do not take advantage of the services available to them. Consequently, many researchers are exploring the possibility of developing fast, reliable, and non-invasive diagnostic tools that can be used directly or by local physicians at the point-of-care. Herein, we look at the use of established biomarkers in cancer therapy and investigate emerging biomarkers exhibiting future potential. The incorporation of these biomarkers into point-of-care devices could potentially reduce the strain currently experienced by screening programs in hospitals and healthcare systems. Results derived from point-of-care tests should be accurate, sensitive, and generated rapidly to assist in the selection of the best course of treatment for optimal patient care. Essentially, point-of-care diagnostics should enhance the well-being of patients and lead to a reduction in cancer-related deaths.

Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p<5×10−8) were obtained from published genome-wide association studies (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with breast (nCases/nControls = 133,384/113,789) and prostate (nCases/nControls = 79,148/61,106) cancer using univariable, bidirectional and multivariable MR. In females, we found evidence for: I) Reduced risk of breast cancer per category increase in morning-preference (OR = 0.93, 95% CI:0. 88, 1.00); II) Increased risk of breast cancer per SD increase in bioavailable testosterone (OR = 1.10, 95% CI: 1.01, 1.19) and total testosterone (OR = 1.15, 95% CI:1.07, 1.23); III) Bidirectional effects between morning-preference and both bioavailable and total testosterone (e.g. mean SD difference in bioavailable testosterone = -0.08, 95% CI:-0.12, -0.05 per category increase in morning-preference vs difference in morning-preference category = -0.04, 95% CI: -0.08, 0.00 per SD increase in bioavailable testosterone). In males, we found evidence for: I) Reduced risk of prostate cancer per category increase in morning-preference (OR = 0.90, 95% CI: 0.83, 0.97) and II) Increased risk of prostate cancer per SD increase in bioavailable testosterone (OR = 1.22, 95% CI: 1.08, 1.37). No bidirectional effects were found between morning-preference and testosterone in males. While testosterone levels were causally implicated with both chronotype and cancer, there was inconsistent evidence for testosterone as a mediator of the relationship. The protective effect of morning-preference on both breast and prostate cancer is clinically interesting, although it may be difficult to effectively modify chronotype. Further studies are needed to investigate other potentially modifiable intermediates.

Aims/hypothesis Podocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, particularly in the early stages of disease progression. The aim of this study was to investigate the potential roles of IGFBPs in the development of type 2 DKD, focusing on podocytes. Methods IGFBP expression was analysed in the Pima DKD cohort, alongside data from the Nephroseq database, and in ex vivo human glomeruli. Conditionally immortalised human podocytes and glomerular endothelial cells were studied in vitro, where IGFBP-1 expression was analysed using quantitative PCR and ELISAs. Cell responses to IGFBPs were investigated using migration, cell survival and adhesion assays; electrical cell-substrate impedance sensing; western blotting; and high-content automated imaging. Results Data from the Pima DKD cohort and from the Nephroseq database demonstrated a significant reduction in glomerular IGFBP-1 in the early stages of human type 2 DKD. In the glomerulus, IGFBP-1 was predominantly expressed in podocytes and controlled by phosphoinositide 3-kinase (PI3K)–forkhead box O1 (FoxO1) activity. In vitro, IGFBP-1 signalled to podocytes via β1-integrins, resulting in increased phosphorylation of focal-adhesion kinase (FAK), increasing podocyte motility, adhesion, electrical resistance across the adhesive cell layer and cell viability. Conclusions/interpretation This work identifies a novel role for IGFBP-1 in the regulation of podocyte function and that the glomerular expression of IGFBP-1 is reduced in the early stages of type 2 DKD, via reduced FoxO1 activity. Thus, we hypothesise that strategies to maintain glomerular IGFBP-1 levels may be beneficial in maintaining podocyte function early in DKD. Graphical abstract

Background: Variation in the human gut microbiome may influence cancer progression and therapy response through various mechanisms including modulation of both immune and cell signalling pathways. Whilst observational epidemiological studies have provided evidence that the gut microbiome may play a role in cancer risk, such studies are prone to residual confounding, reverse causation, and other forms of bias. Therefore, the nature of these associations still remains unclear. Mendelian randomization (MR) is a causal methodology that uses genetic variants as instruments (“proxies”) for risk factors to eliminate such biases when questioning causality in observational epidemiological associations. The statistical power and precision of MR analyses can be increased by employing a “two-sample MR” (2SMR) framework in which summary data – usually from large, independent, genome-wide association studies (GWASs) reporting associations of genetic variants with exposures (here, the gut microbiome) and outcomes (here, cancer) – are synthesised to estimate causal effects of each exposure on each outcome of interest. In this study, we utilised 2SMR to interrogate causal relationships between the gut microbiome and breast cancer (BC) risk using the largest published GWASs of the gut microbiome and of clinically utilised subtypes of BC. Methods: We performed 2SMR using summary-level data from the GWAS of the host genetic contribution to gut microbiome variation amongst European individuals (the Flemish Gut Flora Project and two German cohorts (n=3890)) combined with summary-level data from the GWAS of BC risk (Breast Cancer Association Consortium (133,384 cases stratified by Luminal A, Luminal B, Human Epidermal Growth Factor 2 (Her2) positive, Her2 negative and triple negative status and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with BC)). Sensitivity analyses were also conducted to assess pleiotropy of genetic variants on BC risk, independent of gut microbiota. Analyses were conducted in R Studio using the TwoSampleMR and the MR-TRYX packages. Results: Of the 14 microbial traits (MTs) with evidence for a host genetic contribution in the GWAS of the gut microbiome, we found evidence that abundance of a genus within a certain bacterial order decreased the risk of triple negative BC (odds ratio per standard deviation increase: 0.84; 95% CI: 0.71, 0.9; p=0.03). In addition, we demonstrated that the risk of all molecular subtypes of BC may be altered by variation in these MTs, and that these relationships differed according to subtype. Sensitivity analyses demonstrated that pleiotropy was unlikely to explain these relationships Conclusions: In our study, we utilised two recent and novel GWASs in an MR context to appraise causality in relationships between the gut microbiome and BC risk and found evidence that certain bacteria may alter BC risk, effects of which vary according to molecular subtype. These important results generate hypotheses about mechanisms underlying the causal biology of BC subtypes and potentially facilitate the design of BC risk-reducing interventions and prevention strategies. Citation Format: Tim Robinson, Grace Edmunds, Bryony Hayes, Kaitlin Wade. Exploring the causal role of the human gut microbiome in breast cancer risk using mendelian randomization [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-06.

Objective: The aim of this study was to systematically evaluate the direction of any potential causal effect between sleep and adiposity traits. Methods: Two-sample Mendelian randomization was used to assess the association of genetically predicted sleep traits with adiposity and vice versa. Using data from UK Biobank and 23andMe, the sleep traits explored were morning preference (chronotype; N = 697,828), insomnia (N = 1,331,010), sleep duration (N = 446,118), napping (N = 452,633), and daytime sleepiness (N = 452,071). Using data from the Genetic Investigation of ANthropometric Traits (GIANT) and Early Growth Genetics (EGG) consortia, the adiposity traits explored were adult BMI, hip circumference (HC), waist circumference (WC), waist-hip ratio (WHR; N = 322,154), and childhood BMI (N = 35,668).