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Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Abstract Background Radon is a radioactive gas and a major risk factor for lung cancer (LC). Methods We investigated the dose–response relationship between radon and LC risk in the International Lung Cancer Consortium with 8927 cases and 5562 controls from Europe, North America, and Israel, conducted between 1992 and 2016. Spatial indoor radon exposure in the residential area (sIR) obtained from national surveys was linked to the participants' residential geolocation. Parametric linear and spline functions were fitted within a logistic regression framework. Results We observed a non‐linear spatial‐dose response relationship for sIR

Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value

Abstract Background Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Methods Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Results Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

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.

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).

Summary: Background: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. Methods: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. Findings: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value

This study analyzed the overall quality of the diet using predefined indices, including the Healthy Eating Index-2015 (HEI-2015), the Alternative Healthy Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED) score, the Dietary Approaches to Stop Hypertension (DASH) score, and the Dietary Inflammatory Index (DII®), to explore their association with the risk of bladder cancer in the Multiethnic Cohort Study. Data were taken from 186,979 African American, Japanese American, Latino, Native Hawaiian, and non-Hispanic White participants aged 45–75 years, with 1152 incident cases of invasive bladder cancer during a mean follow-up period of 19.2 ± 6.6 years. Cox models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) with comprehensive adjustment for smoking. Comparing the highest vs. lowest diet quality score quintile, HRs (95% CIs) in men was 1.08 (0.86–1.36) for HEI-2015, 1.05 (0.84–1.30) for AHEI-2010, 1.01 (0.80–1.27) for aMED, 1.13 (0.90–1.41) for DASH, and 0.96 (0.76–1.21) for DII®, whereas the corresponding HRs for women were 0.75 (0.53–1.07), 0.64 (0.45–0.92), 0.60 (0.40–0.88), 0.66 (0.46–0.95), and 0.63 (0.43–0.90) with all p values for trend

Abstract Background There are established links between the accumulation of body fat as visceral adipose tissue (VAT) and the risk of developing obesity‐associated metabolic disease. Previous studies have suggested that levels of intake of specific foods and nutrients are associated with VAT accumulation after accounting for total energy intake. Objective This study assessed associations between a priori selected dietary factors on VAT quantified using abdominal magnetic resonance imaging. Methods The cross‐sectional Multiethnic Cohort Adiposity Phenotype Study included n = 395 White, n = 274 Black, n = 269 Native Hawaiian, n = 425 Japanese American and n = 358 Latino participants (mean age = 69 years ± 3 SD). Participants were enrolled stratified on sex, race, ethnicity and body mass index. General linear models were used to estimate the mean VAT area (cm2) for participants categorized into quartiles based on their dietary intake of selected foods/nutrients adjusting for age, sex, racial and ethnic groups, the total percentage fat from whole‐body dual energy X‐ray absorptiometry and total energy. Results There were significant inverse associations with VAT for dietary intake of total vegetables, total fruits (including juice), cereals, whole grains, calcium, copper and dietary fiber (p‐trend ≤0.04). Positive trends were observed for VAT for participants who reported higher intake of potatoes, total fat and saturated fatty acids (SFA) (p‐trend ≤0.02). Foods/nutrients that met the multiple testing significance threshold were total fruits, whole grains, copper, dietary fiber and SFA intake. Conclusions These results highlight foods and nutrients including SFA, total fruit, whole grains, fiber and copper as potential candidates for future research to inform dietary guidelines for the prevention of chronic disease among older adults.

BackgroundWe previously developed a prediction score for MRI-quantified abdominal visceral adipose tissue (VAT) based on concurrent measurements of height, body mass index (BMI), and nine blood biomarkers, for optimal performance in five racial/ethnic groups. Here we evaluated the VAT score for prediction of future VAT and examined if enhancement with additional biomarkers, lifestyle behavior information, and medical history improves the prediction.MethodsWe examined 500 participants from the Multiethnic Cohort (MEC) with detailed data (age 50-66) collected 10 years prior to their MRI assessment of VAT. We generated three forecasted VAT prediction models: first by applying the original VAT equation to the past data on the predictors ("original"), second by refitting the past data on anthropometry and biomarkers ("refit"), and third by building a new prediction model based on the past data enhanced with lifestyle and medical history ("enhanced"). We compared the forecasted prediction scores to future VAT using the coefficient of determination (R2). In independent nested case-control data in MEC, we applied the concurrent and forecasted VAT models to assess association of the scores with subsequent incident breast cancer (950 pairs) and colorectal cancer (831 pairs).ResultsCompared to the VAT prediction by the concurrent VAT score (R2 = 0.70 in men, 0.68 in women), the forecasted original VAT score (R2 = 0.54, 0.48) performed better than past anthropometry alone (R2 = 0.47, 0.40) or two published scores (VAI, METS-VF). The forecasted refit (R2 = 0.61, 0.51) and enhanced (R2 = 0.62, 0.55) VAT scores each showed slight improvements. Similar to the concurrent VAT score, the forecasted VAT scores were associated with breast cancer, but not colorectal cancer. Both the refit score (adjusted OR for tertile 3 vs. 1 = 1.27; 95% CI: 1.00-1.62) and enhanced score (1.27; 0.99-1.62) were associated with breast cancer independently of BMI.ConclusionsPredicted VAT from midlife data can be used as a surrogate to assess the effect of VAT on incident diseases associated with obesity, as illustrated for postmenopausal breast cancer.

Obesity in the United States and Western countries represents a major health challenge associated with an increased risk of metabolic diseases, including cardiovascular disease, hypertension, diabetes, and certain cancers. Our past work revealed a more pronounced obesity–cancer link in certain ethnic groups, motivating us to develop a tailored dietary intervention called the Healthy Diet and Lifestyle 2 (HDLS2). The study protocol is described herein for this randomized six-month trial examining the effects of intermittent energy restriction (5:2 Diet) plus the Mediterranean dietary pattern (IER + MED) on visceral adipose tissue (VAT), liver fat, and metabolic biomarkers, compared to a standard MED with daily energy restriction (DER + MED), in a diverse participant group. Using MRI and DXA scans for body composition analysis, as well as metabolic profiling, this research aims to contribute to nutritional guidelines and strategies for visceral obesity reduction. The potential benefits of IER + MED, particularly regarding VAT reduction and metabolic health improvement, could be pivotal in mitigating the obesity epidemic and its metabolic sequelae. The ongoing study will provide essential insights into the efficacy of these energy restriction approaches across varied racial/ethnic backgrounds, addressing an urgent need in nutrition and metabolic health research. Registered Trial, National Institutes of Health, ClinicalTrials.gov (NCT05132686).