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Abstract Circulating proteins can reveal key pathways to cancer and identify therapeutic targets for cancer prevention. We investigate 2,074 circulating proteins and risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) using cis protein Mendelian randomisation and colocalization. We conduct additional analyses to identify adverse side-effects of altering risk proteins and map cancer risk proteins to drug targets. Here we find 40 proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment: 2.27, 1.88-2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [0.79, 0.73-0.85]. We also identify potential adverse effects of protein-altering interventions to reduce cancer risk, such as hypertension. Additionally, we report 18 proteins associated with cancer risk that map to existing drugs and 15 that are not currently under clinical investigation. In sum, we identify protein-cancer links that improve our understanding of cancer aetiology. We also demonstrate that the wider consequence of any protein-altering intervention on well-being and morbidity is required to interpret any utility of proteins as potential future targets for therapeutic prevention.

Summary: Background: Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. Methods: We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. Findings: We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54–2.93], PYY [OR = 1.87, 95% CI: 1.43–2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73–0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99–4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67–0.86] and TPM3 [OR = 0.47, 95% CI: 0.34–0.64]. We confirmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80–0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82–0.86] and early onset disease [OR = 0.71, 95% CI: 0.68–0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions. Interpretation: Our findings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer. Funding: This work was supported by Cancer Research UK (grant no. C8221/A29017).

Background Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.9 million new cases in 2020 and a predicted rise to 3.2 million in 2040. Screening programmes are already in place to aid early detection and secondary prevention of CRC, but the rising prevalence means additional approaches are required in both primary and secondary prevention settings. Preventive therapy, whereby natural or synthetic agents are used to prevent, reverse or delay disease development, could be an effective strategy to further reduce cancer risk and potential agents have already been identified in conventional observational studies. However, as such studies are vulnerable to confounding and reverse causation, we aim to evaluate these observed relationships using Mendelian randomization (MR), an alternative causal inference approach which should be less susceptible to these biases. Methods and analysis We will use two-sample MR, which uses two independent samples for the exposure and outcome data, to investigate previously reported observational associations of multiple potential preventive agents with CRC risk. We define preventive agents as any synthetic (e.g. approved medication) or natural (e.g. micronutrient, endogenous hormone) molecule used to reduce the risk of cancer. We will first extract potential preventive agents that have been previously linked to CRC risk in observational studies from reviews of the literature. We will then evaluate whether we can develop a genetic instrument for each preventive agent from previously published genome-wide association studies (GWASs) of direct measures of molecular traits (e.g. circulating levels of protein drug targets, blood-based biomarkers of dietary vitamins). The summary statistics from these GWASs, and a large GWAS of CRC, will be used in two-sample MR analyses to investigate the causal effect of putative preventive therapy agents on CRC risk. Sensitivity analyses will be conducted to evaluate the robustness of findings to potential violations of MR assumptions.

Abstract Background Some modifiable risk factors for cancer originate during adolescence. While there is evidence indicating relationships between adverse childhood experiences and health risk behaviours generally, little is known about how childhood adversity influences the engagement of adolescents in cancer risk behaviours. This study aimed to determine the relationship between adverse childhood experiences and adolescent cancer risk behaviours. Methods Data were collected prospectively from birth to age 18 years on children born to mothers enrolled into the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort study. Multivariable linear regression models assessed relationships of a composite exposure measure comprised of adverse childhood experiences (total number of childhood adversities experienced from early infancy until age 9 years) with multiple cancer risk behaviours. The latter was expressed as a single continuous score for tobacco smoking, alcohol consumption, obesity, unsafe sex, and physical inactivity, at ages 11, 14, 16 and 18 years. Analysis was carried out on the complete case and imputation samples of 1,368 and 7,358 participants respectively. Results All adolescent cancer risk behaviours increased in prevalence as the adolescents grew older, except for obesity. Each additional adverse childhood experience was associated with a 0.25 unit increase in adolescent cancer risk behaviour (95% CI 0.16–0.34; p

Summary: Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion’s Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Abstract Background The associations of adiposity with aggressive prostate cancer risk are unclear. Using two‐sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer. Methods We examined the association of these genetically predicted adiposity‐related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases). Results In inverse‐variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61–1.19), 0.80 (0.53–1.23) and 0.97 (0.88–1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer. Conclusions We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies.

Abstract Background Screening men for prostate cancer using prostate-specific antigen (PSA) testing remains controversial. We aimed to estimate the likely budgetary impact on secondary care in England and Wales to inform screening decision makers. Methods The Cluster randomised triAl of PSA testing for Prostate cancer study (CAP) compared a single invitation to men aged 50–69 for a PSA test with usual care (no screening). Routinely collected hospital care data were obtained for all men in CAP, and NHS reference costs were mapped to each event via Healthcare Resource Group (HRG) codes. Secondary-care costs per man per year were calculated, and cost differences (and population-level estimates) between arms were derived annually for the first five years following randomisation. Results In the first year post-randomisation, secondary-care costs averaged across all men (irrespective of a prostate cancer diagnosis) in the intervention arm (n = 189279) were £44.80 (95% confidence interval: £18.30-£71.30) higher than for men in the control arm (n = 219357). Extrapolated to a population level, the introduction of a single PSA screening invitation could lead to additional secondary care costs of £314 million. Conclusions Introducing a single PSA screening test for men aged 50–69 across England and Wales could lead to very high initial secondary-care costs.

Introduction Compared with the traditional drug development pathway, investigating alternative uses for existing drugs (ie, drug repurposing) requires substantially less time, cost and resources. Immune checkpoint inhibitors are licensed for the treatment of certain breast, colorectal, head and neck, lung and melanoma cancers. These drugs target immune checkpoint proteins to reduce the suppression of T cell activation by cancer cells. As T cell suppression is a hallmark of cancer common across anatomical sites, we hypothesise that immune checkpoint inhibitors could be repurposed for the treatment of additional cancers beyond the ones already indicated.Methods and analysis We will use two-sample Mendelian randomisation to investigate the effect of genetically proxied levels of protein targets of two immune checkpoint inhibitors—programmed cell death protein 1 and programmed death ligand 1—on survival of seven cancer types (breast, colorectal, head and neck, lung, melanoma, ovarian and prostate). Summary genetic association data will be obtained from prior genome-wide association studies of circulating protein levels and cancer survival in populations of European ancestry. Various sensitivity analyses will be performed to examine the robustness of findings to potential violations of Mendelian randomisation assumptions, collider bias and the impact of alternative genetic instrument construction strategies. The impact of treatment history and tumour stage on the findings will also be investigated using summary-level and individual-level genetic data where available.Ethics and dissemination No separate ethics approval will be required for these analyses as we will be using data from previously published genome-wide association studies which individually gained ethical approval and participant consent. Results from analyses will be submitted as an open-access peer-reviewed publication and statistical code will be made freely available on the completion of the analysis.

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Abstract Background Sedentary behaviours have been associated with increased risks of some common cancers in epidemiological studies; however, it is unclear if these associations are causal. Methods We used univariable and multivariable two‐sample Mendelian randomisation (MR) to examine potential causal relationships between sedentary behaviours and risks of breast, colorectal and prostate cancer. Genetic variants associated with self‐reported leisure television watching and computer use were identified from a recent genome‐wide association study (GWAS). Data related to cancer risk were obtained from cancer GWAS consortia. A series of sensitivity analyses were applied to examine the robustness of the results to the presence of confounding. Results A 1‐standard deviation (SD: 1.5 h/day) increment in hours of television watching increased risk of breast cancer (OR per 1‐SD: 1.15, 95% confidence interval [CI]: 1.05–1.26) and colorectal cancer (OR per 1‐SD: 1.32, 95% CI: 1.16–1.49) while there was little evidence of an association for prostate cancer risk (OR per 1‐SD: 0.94, 95% CI: 0.84–1.06). After adjusting for years of education, the effect estimates for television watching were attenuated (breast cancer, OR per 1‐SD: 1.08, 95% CI: 0.92–1.27; colorectal cancer, OR per 1‐SD: 1.08, 95% CI: 0.90–1.31). Post hoc analyses showed that years of education might have a possible confounding and mediating role in the association between television watching with breast and colorectal cancer. Consistent results were observed for each cancer site according to sex (colorectal cancer), anatomical subsites and cancer subtypes. There was little evidence of associations between genetically predicted computer use and cancer risk. Conclusions Our univariable analysis identified some positive associations between hours of television watching and risks of breast and colorectal cancer. However, further adjustment for additional lifestyle factors especially years of education attenuated these results. Future studies using objective measures of exposure can provide new insights into the possible role of sedentary behaviour in cancer development.

Abstract Genetic evidence suggests glioma risk is altered by leukocyte telomere length, allergic disease (asthma, hay fever or eczema), alcohol consumption, childhood obesity, low-density lipoprotein cholesterol (LDLc) and triglyceride levels. DNA methylation (DNAm) variation influences many of these glioma-related traits and is an established feature of glioma. Yet the causal relationship between DNAm variation with both glioma incidence and glioma risk factors is unknown. We applied a two-step Mendelian randomization (MR) approach and several sensitivity analyses (including colocalization and Steiger filtering) to assess the association of DNAm with glioma risk factors and glioma incidence. We used data from a recently published catalogue of germline genetic variants robustly associated with DNAm variation in blood (32,851 participants) and data from a genome-wide association study of glioma risk (12,488 cases and 18,169 controls, sub-divided into 6191 glioblastoma cases and 6305 non-glioblastoma cases). MR evidence indicated that DNAm at 3 CpG sites (cg01561092, cg05926943, cg01584448) in one genomic region (HEATR3) had a putative association with glioma and glioblastoma risk (False discovery rate [FDR]

Summary: Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention.

Abstract Background Evidence from observational studies have shown that moderate intensity physical activity can reduce risk of progression and cancer-specific mortality in participants with prostate cancer. Epidemiological studies have also shown participants taking metformin to have a reduced risk of prostate cancer. However, data from randomised controlled trials supporting the use of these interventions are limited. The Prostate cancer–Exercise and Metformin Trial examines that feasibility of randomising participants diagnosed with localised or locally advanced prostate cancer to interventions that modify physical activity and blood glucose levels. The primary outcomes are randomisation rates and adherence to the interventions over 6 months. The secondary outcomes include intervention tolerability and retention rates, measures of insulin-like growth factor I, prostate-specific antigen, physical activity, symptom-reporting, and quality of life. Methods Participants are randomised in a 2 × 2 factorial design to both a physical activity (brisk walking or control) and a pharmacological (metformin or control) intervention. Participants perform the interventions for 6 months with final measures collected at 12 months follow-up. Discussion Our trial will determine whether participants diagnosed with localised or locally advanced prostate cancer, who are scheduled for radical treatments or being monitored for signs of cancer progression, can be randomised to a 6 months physical activity and metformin intervention. The findings from our trial will inform a larger trial powered to examine the clinical benefits of these interventions. Trial registration Prostate Cancer Exercise and Metformin Trial (Pre-EMpT) is registered on the ISRCTN registry, reference number ISRCTN13543667 . Date of registration 2nd August 2018–retrospectively registered. First participant was recruited on 11th September 2018.

Summary: Background: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. Methods: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. Findings: Genetically elevated PUFA desaturase activity was associated (P

Abstract Background Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. Methods Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10−8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. Results In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10−31), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10−12), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10−9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10−7) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10−4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10−2) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10−3), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10−8) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10−2) in the relationship between BMI and endometrial cancer risk. Conclusions Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

Abstract Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Abstract The Rho GTPase family consists of 20 genes encoding intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. They are implicated in breast cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR). MR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER−) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. As a sensitivity analysis, we undertook co-localisation to examine whether findings reflected shared causal variants or genomic confounding. We identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI) 1.03, 1.09; P = 5.65 × 10–5) and OR 1.22 (95% CI 1.11, 1.35; P = 5.22 × 10–5) in normal breast tissue and blood respectively). There was a consistent direction of association for ER− breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was negatively associated with overall and ER + breast cancer risk. The evidence from colocalization analyses strongly supported our MR results particularly for RHOD. Our study suggests a potential causal role of increased RHOD gene expression, and, although the evidence is weaker, a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.

Abstract Background Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). Methods Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. Results In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p =

Abstract Background An estimated 40% of cancer cases in the UK in 2015 were attributable to cancer risk behaviours. Tobacco smoking, alcohol consumption, obesity, and unprotected sexual intercourse are known causes of cancer and there is strong evidence that physical inactivity is associated with cancer. These cancer risk behaviours co-occur however little is known about how they pattern longitudinally across adolescence and early adulthood. Using data from ALSPAC, a prospective population-based UK birth cohort study, we explored patterns of adolescent cancer risk behaviours and their associations with cancer risk behaviours in early adulthood. Methods Six thousand three hundred fifty-one people (46.0% of ALSPAC participants) provided data on all cancer risk behaviours at one time during adolescence, 1951 provided data on all cancer risk behaviours at all time points. Our exposure measure was quartiles of a continuous score summarising cumulative exposure to cancer risk behaviours and longitudinal latent classes summarising distinct categories of adolescents exhibiting similar patterns of behaviours, between age 11 and 18 years. Using both exposure measures, odds of harmful drinking (Alcohol Use Disorders Identification Test-C ≥ 8),daily tobacco smoking, nicotine dependence (Fagerström test ≥4), obesity (BMI ≥30), high waist circumference (females: ≥80 cm and males: ≥94 cm, and high waist-hip ratio (females: ≥0.85 and males: ≥1.00) at age 24 were estimated using logistic regression analysis. Results We found distinct groups of adolescents characterised by consistently high and consistently low engagement in cancer risk behaviours. After adjustment, adolescents in the top quartile had greater odds of all outcomes in early adulthood: nicotine dependency (odds ratio, OR = 5.37, 95% confidence interval, CI = 3.64–7.93); daily smoking (OR = 5.10, 95% CI =3.19–8.17); obesity (OR = 4.84, 95% CI = 3.33–7.03); high waist circumference (OR = 2.48, 95% CI = 1.94–3.16); harmful drinking (OR = 2.04, 95% CI = 1.57–2.65); and high waist-hip ratio (OR = 1.88, 95% CI = 1.30–2.71), compared to the bottom quartile. In latent class analysis, adolescents characterised by consistently high-risk behaviours throughout adolescence were at higher risk of all cancer risk behaviours at age 24, except harmful drinking. Conclusions Exposure to adolescent cancer risk behaviours greatly increased the odds of cancer risk behaviours in early adulthood. Interventions to reduce these behaviours should target multiple rather than single risk behaviours and should focus on adolescence.

A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Abstract Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.

Abstract Obesity is associated with an increased risk of advanced, recurrent and fatal prostate cancer. Adipokines may mediate this relationship. We conducted a systematic review and meta-analysis of associations of leptin and adiponectin with overall and aggressive prostate cancer. Bibliographic databases were systematically searched up to 1st April 2017. Log Odds Ratios (ORs) per 2.5 unit increase in adiponectin or leptin levels were derived and pooled. All analyses were stratified by study type (cross-sectional/prospective). 746 papers were retrieved, 34 eligible studies identified, 31 of these could be included in the meta-analysis. Leptin was not consistently associated with overall prostate cancer (pooled OR 1.00, 95%CI 0.98–1.02, per 2.5 ng/ml increase, prospective study OR 0.97, 95%CI 0.95–0.99, cross-sectional study OR 1.19, 95%CI 1.13–1.26) and there was weak evidence of a positive association with aggressive disease (OR 1.03, 95%CI 1.00–1.06). There was also weak evidence of a small inverse association of adiponectin with overall prostate cancer (OR 0.96, 95%CI 0.93–0.99, per 2.5 µg/ml increase), but less evidence of an association with aggressive disease (OR 0.98, 95%CI 0.94–1.01). The magnitude of any effects are small, therefore levels of circulating adiponectin or leptin alone are unlikely to be useful biomarkers of risk or prognosis.

Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671–13,879; N controls = 173,493–372,016), FinnGen (N cases = 719–8401; N controls = 74,685–174,006) and several international cancer genetic consortia (N cases = 11,348–122,977; N controls = 15,861–105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04–1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09–1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97–1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. Funding: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic’s Operational Programme ‘Competitiveness, Entrepreneurship & Innovation’ (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer’s Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol.

Alcohol and smoking are both associated with oral/oropharyngeal cancer risk, but independent effects are unclear given their relatedness. Here, the authors use multivariable Mendelian randomization to show that both alcohol and smoking are independently causal for oral/oropharyngeal cancer.

Abstract Background The workplace environment potentially provides access to a large population who are employed, and it is an employer's responsibility to provide appropriate conditions for its employees. Whilst the aetiology of cardiovascular disease is multifactorial, it is generally acknowledged that working conditions, gender and age are involved in its development. Male-dominated industries (comprising > 70% male workers, e.g., agriculture, construction, manufacturing, mining, transport and technology) have a higher prevalence of health risk behaviours than other population subgroups. Working in a gender-dominated industry can impact an employee's health and wellbeing, particularly for the opposite sex. This systematic review examines workplace interventions that address the health and wellbeing of employees in male-dominated industries. Methods We will include randomised controlled trials and studies with non-randomised intervention groups. The interventions must aim to improve employee physical and/or mental health and wellbeing implemented in the workplace in male-dominated industries. There will be no limits on date. The following electronic databases will be searched for published studies: Web of Science, Embed, MedLine, PsycInfo and the Cochrane Database. The search strategy will include free-text terms and MeSH vocabulary, including ‘male-dominated industries’, ‘workplace interventions’, ‘occupational stress’, ‘mental health’, ‘cardiovascular disease’, ‘blood pressure’, ‘body mass index’ and ‘exercise’. Two authors will independently select, review and extract data from studies that meet the inclusion criteria. The Cochrane's Risk of Bias tool will be used to assess risk of bias. We will perform structured summaries of the included studies and, if possible, conduct meta-analyses or construct an Albatross plot. Discussion There are an increasing number of interventions designed to improve employee health and wellbeing in the workplace, but no prior review that systematically evaluates their effectiveness. A systematic review is required to prioritise the future implementation of those interventions found to be most effective. Systematic review registration PROSPERO CRD42019161283

Abstract Background Lifestyle factors, including diet and physical activity, are associated with prostate cancer progression and mortality. However, it is unclear how men would like lifestyle information to be delivered following primary treatment. This study aimed to identify men’s preferences for receiving lifestyle information. Methods We conducted a cross-sectional pilot best-worst discrete choice experiment which was nested within a feasibility randomised controlled trial. Our aim was to explore men’s preferences of receiving diet and physical activity advice following surgery for localised prostate cancer. Thirty-eight men with a mean age of 65 years completed best-worst scenarios based on four attributes: (1) how information is provided; (2) where information is provided; (3) who provides information; and (4) the indirect cost of receiving information. Data was analysed using conditional logistic regression. Men’s willingness to pay (WTP) for aspects of the service was calculated using an out-of-pocket cost attribute. Results The combined best-worst analysis suggested that men preferred information through one-to-one discussion β = 1.07, CI = 0.88 to 1.26) and not by email (β = − 1.02, CI = − 1.23 to − 0.80). They preferred information provided by specialist nurses followed by dietitians (β = 0.76, CI = 0.63 to 0.90 and − 0.16, CI = − 0.27 to − 0.05 respectively) then general nurses (β = − 0.60, CI = − 0.73 to − 0.48). Three groups were identified based on their preferences. The largest group preferred information through individual face-to-face or group discussions (β = 1.35, CI = 1.05 to 1.63 and 0.70, CI = 0.38 to 1.03 respectively). The second group wanted information via one-to-one discussions or telephone calls (β = 1.89, CI = 1.41 to 2.37 and 1.03, CI = 0.58 to 1.48 respectively), and did not want information at community centres (β = − 0.50, CI = − 0.88 to − 0.13). The final group preferred individual face-to-face discussions (β = 0.45, CI = 0.03 to 0.88) but had a lower WTP value (£17). Conclusions Men mostly valued personalised methods of receiving diet and physical activity information over impersonal methods. The out-of-pocket value of receiving lifestyle information was important to some men. These findings could help inform future interventions using tailored dietary and physical activity advice given to men by clinicians following treatment for prostate cancer, such as mode of delivery, context, and person delivering the intervention. Future studies should consider using discrete choice experiments to examine information delivery to cancer survivor populations.

The role of impaired lung function in lung cancer etiology is complex due to the relation of cigarette smoking to both conditions. Here, supported by Mendelian randomization analysis the authors find a link between pulmonary function impairment and lung cancer risk beyond smoking, implicating immune-related pathways

Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.

BackgroundEpidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes.Methods and findingsWe performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry.ConclusionsIn this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.

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

Abstract Background Evidence from studies on prostate cancer progression have identified vitamin D to be a potentially important nutrient. However, the World Cancer Research Fund and American Institute for Cancer Research have reported the quality of this evidence to be limited and warrant further investigation. We plan to use the recently developed WCRF International/University of Bristol mechanistic systematic review framework to determine whether the observed association between vitamin D and prostate cancer exists through a plausible biological pathway. Methods This protocol sets out how we will perform a systematic review of the literature in human and animal studies. We will search the electronic databases MEDLINE, EMBASE, PubMed, and BIOSIS Citation Index without restrictions on year of publication or language. We will extract data from observational and experimental studies examining two inter-linked pathways in the relationship between vitamin D and prostate cancer progression: (1) vitamin D and testosterone, and (2) testosterone and prostate cancer progression. We focus on testosterone as its actions form a potentially novel intermediate mechanism that was identified via our online literature mining tools. The outcomes of interest include incidence or prevalence of prostate cancer, measures of prostate cancer progression (including biochemical recurrence, local, or distal metastases), and prostate cancer-specific mortality. We will assess study quality and the level of certainty of the evidence. We will analyse data where possible, using meta-analysis with forest plots or albatross plots; otherwise, a narrative synthesis will be performed. Discussion To our knowledge, this will be the first systematic synthesis of the evidence underpinning the vitamin D-testosterone-prostate cancer mechanistic pathway. The results of the review may inform future research, intervention trials, and public health messages.

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.

Objectives To confirm the association of previously reported prognostic factors with future progression of localised prostate cancer using primary care data and identify new potential prognostic factors for further assessment in prognostic model development and validation.Design Retrospective cohort study, employing Cox proportional hazards regression controlling for age, prostate specific antigen (PSA), and Gleason score, was stratified by diagnostic stage.Setting Primary care in England.Participants Males with localised prostate cancer diagnosedbetween 01/01/1987 and 31/12/2016 within the Clinical Practice ResearchDatalink database, with linked data from the National Cancer Registration andAnalysis Service and Office for National Statistics.Primary and secondary outcomes Primary outcome measure was prostate cancer mortality. Secondary outcome measures were all-cause mortality and commencing systemic therapy. Up-staging after diagnosis was not used as a secondary outcome owing to significant missing data.Results 10 901 men (mean age 74.38±9.03 years) with localised prostate cancer were followed up for a mean of 14.12 (±6.36) years. 2331 (21.38%) men underwent systemic therapy and 3450 (31.65%) died, including 1250 (11.47%) from prostate cancer. Factors associated with an increased risk of prostate cancer mortality included age; high PSA; current or ex-smoker; ischaemic heart disease; high C reactive protein; high ferritin; low haemoglobin; high blood glucose and low albumin.Conclusions This study identified several new potential prognostic factors for prostate cancer progression, as well as confirming some known prognostic factors, in an independent primary care data set. Further research is needed to develop and validate a prognostic model for prostate cancer progression.

BackgroundObservational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.MethodsWe 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.ResultsOne 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).ConclusionsThe 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.

Background: Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments. Objectives: To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50–69 years. Design: A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up. Setting: Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK. Participants: Between 2001 and 2009, 228,966 men aged 50–69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (n = 545), radical prostatectomy (n = 553) or radical radiotherapy (n = 545) and 997 chose a treatment. Interventions: The interventions were active monitoring, radical prostatectomy and radical radiotherapy. Trial primary outcome measure: Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants. Secondary outcome measures: Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes. Results: There were no statistically significant differences between the groups for 17 prostate cancer-specific (p = 0.48) and 169 all-cause (p = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p

Background: Smoking is the leading avoidable cause of illness and premature mortality. The first-line treatments for smoking cessation are nicotine replacement therapy and varenicline. Meta-analyses of experimental studies have shown that participants allocated to the varenicline group were 1.57 times (95% confidence interval 1.29 to 1.91 times) as likely to be abstinent 6 months after treatment as those allocated to the nicotine replacement therapy group. However, there is limited evidence about the effectiveness of varenicline when prescribed in primary care. We investigated the effectiveness and rate of adverse events of these medicines in the general population. Objective: To estimate the effect of prescribing varenicline on smoking cessation rates and health outcomes. Data sources: Clinical Practice Research Datalink. Methods: We conducted an observational cohort study using electronic medical records from the Clinical Practice Research Datalink. We extracted data on all patients who were prescribed varenicline or nicotine replacement therapy after 1 September 2006 who were aged ≥ 18 years. We investigated the effects of varenicline on smoking cessation, all-cause mortality and cause-specific mortality and hospitalisation for: (1) chronic lung disease, (2) lung cancer, (3) coronary heart disease, (4) pneumonia, (5) cerebrovascular disease, (6) diabetes, and (7) external causes; primary care diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression, or prescription for anxiety; weight in kg; general practitioner and hospital attendance. Our primary outcome was smoking cessation 2 years after the first prescription. We investigated the baseline differences between patients prescribed varenicline and patients prescribed nicotine replacement therapy. We report results using multivariable-adjusted, propensity score and instrumental variable regression. Finally, we developed methods to assess the relative bias of the different statistical methods we used. Results: People prescribed varenicline were healthier at baseline than those prescribed nicotine replacement therapy in almost all characteristics, which highlighted the potential for residual confounding. Our instrumental variable analysis results found little evidence that patients prescribed varenicline had lower mortality 2 years after their first prescription (risk difference 0.67, 95% confidence interval –0.11 to 1.46) than those prescribed nicotine replacement therapy. They had similar rates of all-cause hospitalisation, incident primary care diagnoses of myocardial infarction and chronic obstructive pulmonary disease. People prescribed varenicline subsequently attended primary care less frequently. Patients prescribed varenicline were more likely (odds ratio 1.46, 95% confidence interval 1.42 to 1.50) to be abstinent 6 months after treatment than those prescribed nicotine replacement therapy when estimated using multivariable-adjusted for baseline covariates. Patients from more deprived areas were less likely to be prescribed varenicline. However, varenicline had similar effectiveness for these groups. Conclusion: Patients prescribed varenicline in primary care were more likely to quit smoking than those prescribed nicotine replacement therapy, but there was little evidence that they had lower rates of mortality or morbidity in the 4 years following the first prescription. There was little evidence of heterogeneity in effectiveness across the population. Future work: Future research should investigate the decline in prescribing of smoking cessation products; develop an optimal treatment algorithm for smoking cessation; use methods for using instruments with survival outcomes; and develop methods for comparing multivariable-adjusted and instrumental variable estimates. Limitations: Not all of our code lists were validated, body mass index and Index of Multiple Deprivation had missing values, our results may suffer from residual confounding, and we had no information on treatment adherence. Trial registration: This trial is registered as NCT02681848. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 9. See the NIHR Journals Library website for further project information.

Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

Abstract Background Drugs for dementia have been available in England since 1997. Since their launch, there have been several changes to national guidelines and initiatives that may have influenced prescribing. These include changes in National Institute for Health and Care Excellence (NICE) guidance, several government dementia strategies, the addition of dementia to the Quality and Outcomes Framework (QOF), and the expiry of drug patents. Despite this, there has been little research into the effect of these events on prescribing. This paper examines prescribing trends in England using data from the U.K. Clinical Practice Research Datalink since the launch of drugs for dementia up to 1st January 2016. Methods We considered the monthly proportion of patients eligible for treatment, with a diagnosis of probable Alzheimer’s disease, receiving their first prescription for each drug class—namely, acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and N-methyl-d-aspartate (NMDA) receptor antagonists (memantine). Trend analysis using joinpoint models was then applied to identify up to two trend changes per treatment of interest. Results The overall trend was for increasing prescriptions in each drug class over the period in which they were studied. This was indicated by the average monthly percentage change, which was 6.0% (95% CI, − 6.4 to 19.9; June 1997 to December 2015) for AChE inhibitors and 15.4% (95% CI, − 77.1 to 480.9; January 2003 to December 2015) for NMDA receptor antagonists. Prescriptions of AChE inhibitors increased at the end of 2012, probably in response to the patent expiry of these drugs earlier that year. The Prime Minister’s Dementia Challenge launched in May 2012 may also have contributed to the observed increase. However, neither this strategy nor patent expiry appeared to influence prescriptions of NMDA receptor antagonists. Instead trend changes in this drug class were driven by NICE guidance released in 2011 that allowed access to these drugs outside of clinical trials. Conclusions Dementia drug prescribing does not always respond to factors such as regulatory guidance, recommendations, or patent expiry, and when it does, not necessarily in a predictable way. This suggests that communication with clinicians may need to be improved to use drugs for dementia more cost-effectively.

Abstract Background There is ongoing debate about the harms and benefits of a national prostate cancer screening programme. Several model-based cost-effectiveness analyses have been developed to determine whether the benefits of prostate cancer screening outweigh the costs and harms caused by over-detection and over-treatment, and the different approaches may impact results. Methods To identify models of prostate cancer used to assess the cost-effectiveness of prostate cancer screening strategies, a systematic review of articles published since 2006 was conducted using the NHS Economic Evaluation Database, Medline, EMBASE and HTA databases. The NICE website, UK National Screening website, reference lists from relevant studies were also searched and experts contacted. Key model features, inputs, and cost-effectiveness recommendations were extracted. Results Ten studies were included. Four of the studies identified some screening strategies to be potentially cost-effective at a PSA threshold of 3.0 ng/ml, including single screen at 55 years, annual or two yearly screens starting at 55 years old, and delayed radical treatment. Prostate cancer screening was modelled using both individual and cohort level models. Model pathways to reflect cancer progression varied widely, Gleason grade was not always considered and clinical verification was rarely outlined. Where quality of life was considered, the methods used did not follow recommended practice and key issues of overdiagnosis and overtreatment were not addressed by all studies. Conclusion The cost-effectiveness of prostate cancer screening is unclear. There was no consensus on the optimal model type or approach to model prostate cancer progression. Due to limited data availability, individual patient-level modelling is unlikely to increase the accuracy of cost-effectiveness results compared with cohort-level modelling, but is more suitable when assessing adaptive screening strategies. Modelling prostate cancer is challenging and the justification for the data used and the approach to modelling natural disease progression was lacking. Country-specific data are required and recommended methods used to incorporate quality of life. Influence of data inputs on cost-effectiveness results need to be comprehensively assessed and the model structure and assumptions verified by clinical experts.

Excess body weight is thought to increase the risk of aggressive prostate cancer (PCa), although the biological mechanism is currently unclear. Body fatness is positively associated with a diminished cellular response to insulin and biomarkers of insulin signalling have been positively associated with PCa risk. We carried out a two-pronged systematic review of (a) the effect of reducing body fatness on insulin biomarker levels and (b) the effect of insulin biomarkers on PCa risk, to determine whether a reduction in body fatness could reduce PCa risk via effects on the insulin signalling pathway. We identified seven eligible randomised controlled trials of interventions designed to reduce body fatness which measured insulin biomarkers as an outcome, and six eligible prospective observational studies of insulin biomarkers and PCa risk. We found some evidence that a reduction in body fatness improved insulin sensitivity although our confidence in this evidence was low based on GRADE (Grading of Recommendations, Assessment, Development and Evaluations). We were unable to reach any conclusions on the effect of insulin sensitivity on PCa risk from the few studies included in our systematic review. A reduction in body fatness may reduce PCa risk via insulin signalling, but more high-quality evidence is needed before any conclusions can be reached regarding PCa.

Abstract Background The experience and acceptability of lifestyle interventions for men with localised prostate cancer are not well understood, yet lifestyle interventions are increasingly promoted for cancer survivors. We explored the opinions, experiences and perceived acceptability of taking part in nutritional and physical activity interventions amongst men with prostate cancer and their partners; with the ultimate plan to use such information to inform the development of nutritional and physical activity interventions for men with prostate cancer. Methods Semi-structured interviews with 16 men, and seven partners, undergoing curative surgery or radiotherapy for prostate cancer. Interviews explored experiences of lifestyle interventions, acceptable changes participants would make and perceived barriers and facilitators to change. Interviews were thematically analysed using the framework approach. Results Men were frequently open to lifestyle modification and family support was considered vital to facilitate change. Health beneficial, clinician endorsed, understandable, enjoyable interventions were perceived as attractive. Barriers included ‘modern’ digital technology, poor weather, competing commitments or physical limitations, most notably incontinence following radical prostatectomy. Men were keen to participate in research, with few negative aspects identified. Conclusions Men are willing to change behaviour but this needs to be supported by clinicians and health professionals facilitating lifestyle change. An ‘intention-behaviour gap’, when an intended behaviour does not materialise, may exist. Digital technology for data collection and lifestyle measurement may not be suitable for all, and post-surgery urinary incontinence is a barrier to physical activity. These novel findings should be incorporated into lifestyle intervention development, and implemented clinically.

Abstract Background Head and neck cancers include malignancies of the mouth, larynx and oropharynx. Tobacco use and alcohol consumption are associated with increased risks of developing and dying from head and neck cancer. The aim of this review is to examine the effectiveness of smoking and alcohol cessation interventions on disease-related outcomes, quality of life and behavioural change in adults with head and neck cancer and oral dysplasia. Methods The Cochrane library, CINAHL, Embase, MEDLINE, PsycINFO and Web of Science databases will be searched for randomised controlled trials investigating the effects of smoking or alcohol interventions on patients with either head and neck cancer or oral dysplasia. The primary outcomes are disease-free survival and, for participants with oral dysplasia, malignant transformation to cancer. Secondary outcomes are disease recurrence and progression, quality of life and behavioural change. The quality of included studies will be assessed using the ‘Cochrane Collaborations tool for assessing risk of bias’. A qualitative synthesis of the results will be reported, and a meta-analysis of the outcome data conducted, where appropriate. Discussion This systematic review will identify the extent of the current research on smoking and alcohol cessation interventions in patients with head and neck cancer and oral epithelial dysplasia. The findings have the potential to inform which interventions have been successful and how future behavioural change interventions should be conducted within these populations. Systematic review registration PROSPERO CRD42016038237

Abstract Background A research register (Reach West) has been established to facilitate recruitment of people and patients to health-related research. We conducted a prospective feasibility study to investigate the practicality of recruiting through outpatient clinics. Methods Patients over 18 years of age attending dental, eye or oncology outpatient clinics in an acute hospital in the West of England were provided with the opportunity to participate in Reach West. In Phase I, recruitment packs were handed to clinic attendees who could place completed consent forms in secure drop-box or return them later on-line or by post. In Phase II, recruitment packs were posted directly to patients with consent forms to be returned by post or on-line. Response rates by age, sex, postcode (for level of deprivation), and clinic type were recorded for those agreeing to participate on paper or on-line. Results In Phase I, 2,314 of 4,500 (51.4%) of recruitment packs were handed out to clinic attendees, and 114 (5%) consented to join Reach West. In Phase II, 7,173 of 9000 packs were posted (79.7%), and 387 (5.4%) consented to participate. The overall consent rate was 6% (580), with the majority doing so on paper (87%) rather than on-line. The sample was balanced by sex, but mostly comprised people over 50 years located in less deprived postcodes. Non-staff costs for postal recruitment were lower than hand-outs in clinic (£6.84 compared with £8.05 per participant). Conclusions Recruiting participants to the Reach West register was feasible among those with oncology, dental or eye outpatient appointments by post or with packs given out in the clinic. Response rates were similar to those achieved for other registers. Recruitment of participants can be achieved through outpatient clinics but other strategies will also be required to attract large numbers of participants and more diverse populations.