Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk.

Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200,139 single nucleotide polymorphisms (SNPs) of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer genome-wide association studies. Discovery data included 18,082 cases and 13,780 controls of European ancestry. Replication data included 1,914 cases and 3,065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH [rs34577742 C > T, odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.89-0.93, P = 7.64 × 10-9] and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27 × 10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76 × 10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25 × 10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94 × 10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25 × 10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64 × 10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81 × 10-2). Subsequent transcriptome-wide association study using expression weights from a lung expression quantitative trait loci study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44 × 10-4) and SFTA2 (PTWAS = 2.32 × 10-6).

Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk.

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.

The impact of circulating protein levels identified by affinity proteomics on short-term, overall breast cancer risk.

OBJECTIVE: Current breast cancer risk prediction scores and algorithms can potentially be further improved by including molecular markers. To this end, we studied the association of circulating plasma proteins using Proximity Extension Assay (PEA) with incident breast cancer risk. SUBJECTS: In this study, we included 1577 women participating in the prospective KARMA mammographic screening cohort. RESULTS: In a targeted panel of 164 proteins, we found 8 candidates nominally significantly associated with short-term breast cancer risk (P < 0.05). Similarly, in an exploratory panel consisting of 2204 proteins, 115 were found nominally significantly associated (P < 0.05). However, none of the identified protein levels remained significant after adjustment for multiple testing. This lack of statistically significant findings was not due to limited power, but attributable to the small effect sizes observed even for nominally significant proteins. Similarly, adding plasma protein levels to established risk factors did not improve breast cancer risk prediction accuracy. CONCLUSIONS: Our results indicate that the levels of the studied plasma proteins captured by the PEA method are unlikely to offer additional benefits for risk prediction of short-term overall breast cancer risk but could provide interesting insights into the biological basis of breast cancer in the future.

Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

BACKGROUND: The association of fitness with cancer risk is not clear. METHODS: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method. RESULTS: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min-1⋅kg-1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min-1⋅kg-1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. DISCUSSION: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

Implementation considerations for risk-tailored cancer screening in the population: A scoping review.

BACKGROUND: Risk-tailored screening has emerged as a promising approach to optimise the balance of benefits and harms of existing population cancer screening programs. It tailors screening (e.g., eligibility, frequency, interval, test type) to individual risk rather than the current one-size-fits-all approach of most organised population screening programs. However, the implementation of risk-tailored cancer screening in the population is challenging as it requires a change of practice at multiple levels i.e., individual, provider, health system levels. This scoping review aims to synthesise current implementation considerations for risk-tailored cancer screening in the population, identifying barriers, facilitators, and associated implementation outcomes. METHODS: Relevant studies were identified via database searches up to February 2023. Results were synthesised using Tierney et al. (2020) guidance for evidence synthesis of implementation outcomes and a multilevel framework. RESULTS: Of 4138 titles identified, 74 studies met the inclusion criteria. Most studies in this review focused on the implementation outcomes of acceptability, feasibility, and appropriateness, reflecting the pre-implementation stage of most research to date. Only six studies included an implementation framework. The review identified consistent evidence that risk-tailored screening is largely acceptable across population groups, however reluctance to accept a reduction in screening frequency for low-risk informed by cultural norms, presents a major barrier. Limited studies were identified for cancer types other than breast cancer. CONCLUSIONS: Implementation strategies will need to address alternate models of delivery, education of health professionals, communication with the public, screening options for people at low risk of cancer, and inequity in outcomes across cancer types.

Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.

Prediction of acute myeloid leukaemia risk in healthy individuals.

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

Cancer Stage Compared With Mortality as End Points in Randomized Clinical Trials of Cancer Screening: A Systematic Review and Meta-Analysis.

Importance: Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential alternative end point that may accelerate completion of randomized clinical trials of cancer screening. Objective: To compare cancer-specific mortality with stage III-IV cancer as end points in randomized clinical trials of cancer screening. Design, Setting, and Participants: This meta-analysis included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through February 19, 2024. Data extracted included numbers of participants, cancer diagnoses, and cancer deaths in the intervention and comparison groups. For each clinical trial, the effect of screening was calculated as the percentage reduction between the intervention and comparison groups in the incidence of participants with cancer-specific mortality and stage III-IV cancer. Exposures: Randomization to a cancer screening test or to a comparison group in a clinical trial of cancer screening. Main Outcomes and Measures: End points of cancer-specific mortality and incidence of stage III-IV cancer were compared using Pearson correlation coefficients with 95% CIs, linear regression, and fixed-effects meta-analysis. Results: The included randomized clinical trials tested benefits of screening for breast (n = 6), colorectal (n = 11), lung (n = 12), ovarian (n = 4), prostate (n = 4), and other cancers (n = 4). Correlation between reductions in cancer-specific mortality and stage III-IV cancer varied by cancer type (I2 = 65%; P = .02). Correlation was highest for trials that screened for ovarian (Pearson ρ = 0.99 [95% CI, 0.51-1.00]) and lung (Pearson ρ = 0.92 [95% CI, 0.72-0.98]) cancers, moderate for breast cancer (Pearson ρ = 0.70 [95% CI, -0.26 to 0.96]), and weak for colorectal (Pearson ρ = 0.39 [95% CI, -0.27 to 0.80]) and prostate (Pearson ρ = -0.69 [95% CI, -0.99 to 0.81]) cancers. Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and -3.58 for prostate cancer, suggesting that a given magnitude of reduction in incidence of stage III-IV cancer produced different magnitudes of change in incidence of cancer-specific mortality (P for heterogeneity = .004). Conclusions and Relevance: In randomized clinical trials of cancer screening, incidence of late-stage cancer may be a suitable alternative end point to cancer-specific mortality for some cancer types, but is not suitable for others. These results have implications for clinical trials of multicancer screening tests.

Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers: A retrospective nested case-control study in two prospective cohorts.

The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI: 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6-14) and overall specificity was 92% (95% CI: 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts.

Prevalence of oral and blood oncogenic human papillomavirus biomarkers among an enriched screening population: Baseline results of the MOUTH study.

BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal cancer screening is being explored in research studies, but strategies to identify an appropriate population are not established. The authors evaluated whether a screening population could be enriched for participants with oncogenic HPV biomarkers using risk factors for oral HPV. METHODS: Participants were enrolled at Johns Hopkins Hospitals and Mount Sinai Icahn School of Medicine. Eligible participants were either men aged 30 years or older who had two or more lifetime oral sex partners and a personal history of anogenital dysplasia/cancer or partners of patients who had HPV-related cancer. Oral rinse and serum samples were tested for oncogenic HPV DNA, RNA, and E6 or E7 antibodies, respectively. Participants with any biomarker were considered at-risk. RESULTS: Of 1108 individuals, 7.3% had any oncogenic oral HPV DNA, and 22.9% had serum antibodies for oncogenic HPV E6 or E7. Seventeen participants (1.5%) had both oral and blood biomarkers. HPV type 16 (HPV16) biomarkers were rarer, detected in 3.7% of participants, including 20 with oral HPV16 DNA and 22 with HPV16 E6 serum antibodies (n = 1 had both). In adjusted analysis, living with HIV (adjusted odds ratio, 2.65; 95% CI, 1.60-4.40) and older age (66-86 vs. 24-45 years; adjusted odds ratio, 1.70; 95% CI, 1.07-2.70) were significant predictors of being at risk. Compared with the general population, the prevalence of oral HPV16 (1.8% vs. 0.9%), any oncogenic oral HPV DNA (7.3% vs. 3.5%), and HPV16 E6 antibodies (2.2% vs. 0.3%) was significantly elevated. CONCLUSIONS: Enrichment by the eligibility criteria successfully identified a population with higher biomarker prevalence, including HPV16 biomarkers, that may be considered for screening trials. Most in this group are still expected to have a low risk of oropharyngeal cancer.

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

The influence of postscreening follow-up time and participant characteristics on estimates of overdiagnosis from lung cancer screening trials.

We aimed to explore the underlying reasons that estimates of overdiagnosis vary across and within low-dose computed tomography (LDCT) lung cancer screening trials. We conducted a systematic review to identify estimates of overdiagnosis from randomised controlled trials of LDCT screening. We then analysed the association of Ps (the excess incidence of lung cancer as a proportion of screen-detected cases) with postscreening follow-up time using a linear random effects meta-regression model. Separately, we analysed annual Ps estimates from the US National Lung Screening Trial (NLST) and German Lung Cancer Screening Intervention Trial (LUSI) using exponential decay models with asymptotes. We conducted stratified analyses to investigate participant characteristics associated with Ps using the extended follow-up data from NLST. Among 12 overdiagnosis estimates from 8 trials, the postscreening follow-up ranged from 3.8 to 9.3 years, and Ps ranged from -27.0% (ITALUNG, 8.3 years follow-up) to 67.2% (DLCST, 5.0 years follow-up). Across trials, 39.1% of the variation in Ps was explained by postscreening follow-up time. The annual changes in Ps were -3.5% and -3.9% in the NLST and LUSI trials, respectively. Ps was predicted to plateau at 2.2% for NLST and 9.2% for LUSI with hypothetical infinite follow-up. In NLST, Ps increased with age from -14.9% (55-59 years) to 21.7% (70-74 years), and time trends in Ps varied by histological type. The findings suggest that differences in postscreening follow-up time partially explain variation in overdiagnosis estimates across lung cancer screening trials. Estimates of overdiagnosis should be interpreted in the context of postscreening follow-up and population characteristics.

Biomarkers of the transsulfuration pathway and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Previous studies have suggested that components of one-carbon metabolism, particularly circulating vitamin B6, have an etiological role in renal cell carcinoma (RCC). Vitamin B6 is a cofactor in the transsulfuration pathway. We sought to holistically investigate the role of the transsulfuration pathway in RCC risk. We conducted a nested case-control study (455 RCC cases and 455 matched controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Plasma samples from the baseline visit were analyzed for metabolites of the transsulfuration pathway, including pyridoxal 5'-phosphate (PLP, the biologically active form of vitamin B6), homocysteine, serine, cystathionine, and cysteine, in addition to folate. Bayesian conditional logistic regression was used to estimate associations of metabolites with RCC risk as well as interactions with established RCC risk factors. Circulating PLP and cysteine were inversely associated with RCC risk, and these associations were not attenuated after adjustment for other transsulfuration metabolites (odds ratio (OR) and 90% credible interval (CrI) per 1 SD increase in log concentration: 0.76 [0.66, 0.87]; 0.81 [0.66, 0.96], respectively). A comparison of joint metabolite profiles suggested substantially greater RCC risk for the profile representative of low overall transsulfuration function compared to high function (OR 2.70 [90% CrI 1.26, 5.70]). We found some statistical evidence of interactions of cysteine with body mass index, and PLP and homocysteine with smoking status, on their associations with RCC risk. In conclusion, we found evidence suggesting that the transsulfuration pathway may play a role in metabolic dysregulation leading to RCC development.

Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis.

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.

Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. METHODS: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. RESULTS: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. CONCLUSIONS: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.

Connecting Through Dance: Understanding Conscious Clubbing Event Experiences.

Individuals abstaining from alcohol consumption frequently find themselves in contexts encouraging consumption, with limited alternative social interaction opportunities. Conscious clubbing events exclude alcohol and drugs, possibly providing valuable social connections, but little is known about event benefits. Twelve conscious clubbing event attendees and facilitators aged 25-55 from across Europe participated in semi-structured photo-elicitation interviews, which were analysed using thematic analysis. Findings suggested that conscious clubbing appears to enhance health, healing and growth, aiding recovery from substance dependency and trauma. Positioned as a modern ritual, symbolic and ritualistic preparations and experiences promoted storytelling and self-discovery. Connecting through synchronised but unchoreographed movement, participants engaged in powerful journeys and transformative experiences detached from life constraints. Inclusive digital and face-to-face conscious clubbing communities provided a sense of meaning and belonging away from substance use pressures and harms, particularly for those marginalised within society. Findings provide important and in-depth insights, including novel harm prevention implications. Future work should consider participatory barriers, event sustainability and misconceptions to increase event availability and participation.

Circulating adipokine concentrations and risk of five obesity-related cancers: A Mendelian randomization study.

Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10-8 ). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 µg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers.

Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.