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Background: Associations of waist circumferences (WC) and body mass index (BMI) measured once or over time, with cancer incidence were studied. WC is associated with some cancers independent of BMI. Analyses of cumulative central adiposity and cancer are lacking. We investigated associations between waist circumference-years, incorporating exposure time to WC ≥ 102 cm in men or ≥88 cm in women, and cancer, and compared this with single WC or BMI., Methods: Serial WC measurements taken over 9 years in the prospective Atherosclerosis Risk in Communities Study (ARIC) predicted yearly WC. Cox proportional hazards regression estimated hazard ratios (HRs) of cancer incidence for waist circumference-years, WC or BMI, measured in Visit 4. Harrell's C-statistic quantified metric predictive performances., Results: 10,172 participants were followed up from Visit 4 for cancer over a median 13.7 for men and 15.8 years for women. For obesity-related cancers, HRs per standard deviation waist circumference-years were 1.14 (95%CI:1.04,1.25) and 1.19 (95%CI:1.12,1.27), respectively. Differences in metric predictive performances were marginal., Discussion: This is the first study to identify positive associations between waist circumference-years and cancer. Waist circumference-years did not provide additional information on cancer risk beyond that of WC and BMI. BMI is routinely measured in clinic so it may be preferred over WC., (© 2024. The Author(s).)

Background: Periodontal disease and DNA methylation markers have separately been associated with lung cancer risk. Examining methylation levels at genomic regions previously linked to periodontal disease may provide insights on the link between periodontal disease and lung cancer., Methods: In a nested case-control study drawn from the CLUE II cohort, we measured DNA methylation levels in 208 lung cancer cases and 208 controls. We examined the association between 37 DNA-methylated 5'-C-phosphate-G-3' (CpG) sites at three genomic regions, homeobox 4 (HOXA4), zinc finger protein (ZFP57), and a long noncoding RNA gene located in Chr10 (ENSG00000231601), and lung cancer risk., Results: Statistically significant associations with lung cancer risk were observed for all 14 CpG sites from HOXA4 (OR ranging 1.41-1.62 for 1 SD increase in the DNA methylation level, especially within 15 years) and 1 CpG site on gene ENSG00000231601 (OR = 1.34 for 1 SD increase in the DNA methylation level). Although CpG sites on gene ZFP57 were not associated with lung cancer risk overall, statistically significant inverse associations were noted for six CpG sites when restricting follow-up to 15 years (OR = 0.73-0.77 for 1 SD increase in the DNA methylation level)., Conclusions: Key methylation levels associated with periodontal disease are also associated with lung cancer risk. For both HOXA4 and ZFP57, the associations were stronger within 15 years of follow-up, which suggest that, if causal, the impact of methylation is acting late in the natural history of lung cancer., Impact: Identifying biological pathways that link periodontal disease and lung cancer could provide new opportunities for lung cancer detection and prevention., (©2024 American Association for Cancer Research.)

Significance: This study describes associations between immune cell types and cancer risk in a Black population; elevated regulatory T-cell proportions that were associated with increased overall cancer and lung cancer risk, and elevated memory B-cell proportions that were associated with increased prostate and all cancer risk., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Biological age may be estimated by proteomic aging clocks (PACs). Previous published PACs were constructed either in smaller studies or mainly in white individuals, and they used proteomic measures from only one-time point. In this study, we created de novo PACs and compared their performance to published PACs at 2 different time points in the Atherosclerosis Risk in Communities (ARIC) study of white and black participants (around 75% white and 25% black)., Medthods and Findings: A total of 4,712 plasma proteins were measured using SomaScan in blood samples collected in 1990 to 1992 from 11,761 midlife participants (aged 46 to 70 years) and in 2011 to 2013 from 5,183 late-life participants (aged 66 to 90 years). The de novo ARIC PACs were constructed by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and validated in the remaining one-third of healthy participants at the corresponding time point. We also computed 3 published PACs. We estimated age acceleration for each PAC as residuals after regressing each PAC on chronological age. We also calculated the change in age acceleration from midlife to late life. We examined the associations of age acceleration and change in age acceleration with mortality through 2019 from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in participants (irrespective of health) after excluding the training set. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. We externally validated the midlife PAC using the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 1 data. The ARIC PACs had a slightly stronger correlation with chronological age than published PACs in healthy participants at each time point. Associations with mortality were similar for the ARIC PACs and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per 1 standard deviation were 1.65 and 1.38 (both p < 0.001) for all-cause mortality, 1.37 and 1.20 (both p < 0.001) for CVD mortality, 1.21 (p = 0.028) and 1.04 (p = 0.280) for cancer mortality, and 1.68 and 1.36 (both p < 0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to the HRs for late-life age acceleration. The association between the change in age acceleration and cancer mortality was not significant. The external validation of the midlife PAC in MESA showed significant associations with mortality, as observed for midlife participants in ARIC. The main limitation is that our PACs were constructed in midlife and late-life participants. It is unknown whether these PACs could be applied to young individuals., Conclusions: In this longitudinal study, we found that the ARIC PACs and published PACs were similarly associated with an increased risk of mortality. These findings suggested that PACs show promise as biomarkers of biological age. PACs may be serve as tools to predict mortality and evaluate the effect of anti-aging lifestyle and therapeutic interventions., Competing Interests: B.L. is a full-time employee of the biopharmaceutical company Alkahest, Inc. P.L.L’s institute receives grants from NIH., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure., Methods: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk., Results: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility., Conclusions: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention., Competing Interests: Conflict of Interest: SB Gruber: Brogent International LLC, co-founder, not related to submitted work. All other authors do not have any conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Several studies reported an increased cancer risk related to lower-extremity peripheral artery disease (PAD) but had important caveats: not accounting for key confounders like smoking, follow-up <10 years, or no race-specific results. To assess the long-term independent association of PAD with cancer incidence in a bi-racial community-based cohort., Methods: We categorized 13,106 ARIC participants without cancer at baseline (mean age 54.0 [SD 5.7] years, 45.7 % male, and 26.1 % Black) into symptomatic PAD (clinical history or intermittent claudication), asymptomatic PAD (ankle-brachial index [ABI] ≤0.9), and five ABI categories (0.1-interval between 0.9 and 1.3 and > 1.3). We used cancer registries and medical records to ascertain cancer cases and ran multivariable Cox models., Results: During the median follow-up of 25.3 years, there were 4143 incident cancer cases. 25-year cumulative incidence was 37.2 % in symptomatic PAD, 32.3 % in asymptomatic PAD, and 28.0-31.0 % in the other categories. Symptomatic and asymptomatic PAD remained significantly associated with cancer incidence after adjusting for potential confounders, including smoking and diabetes (hazard ratio [HR] 1.42 [1.05-1.92] and 1.24 [1.05-1.46], respectively). When stratified by smoking status, we observed a robust association of PAD (symptomatic and asymptomatic combined) vs. no PAD with cancer risk in ever smokers (HR 1.42 [1.21-1.67]) but not in never smokers. The results were most evident for lung cancer (HR 2.16 (95 %CI 1.65-2.83) for PAD vs. no PAD within ever smokers)., Conclusions: Symptomatic and asymptomatic PAD conferred cancer risk, particularly among ever smokers and for lung cancer. Patients with PAD should receive evidence-based cancer prevention and screening., Competing Interests: Declaration of competing interest Dr. Matsushita received personal fees from Fukuda Denshi, Kowa Company, and RhythmX AI outside of the submitted work. The other authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cardiovascular disease (CVD) and cancer frequently co-occur due to shared risk factors such as obesity, which is linked to CVD and 14 cancer types. This study explores whether CVD pathophysiologies, combined with obesity, increase cancer risk, impacting clinical management., Methods and Results: Data from the ARIC (Atherosclerosis Risk in Communities) study, spanning 28 years, were analyzed. The cohort included 5127 participants with incident CVD (myocardial infarction, stroke, heart failure, coronary heart disease), of whom 1511 developed a first primary cancer. Follow-up began at CVD diagnosis after Visit 1. Obesity was assessed using body mass index, waist circumference, and waist-to-hip ratio. Incidence rate differences between obesity groups were adjusted for age, sex, and center, whereas the obesity-cancer association was estimated using Fine-Gray regression adjusted for shared risk factors including smoking. Cancer incidence in obese individuals with CVD (body mass index: rate differences=226.6/100 000 person-years) was higher than in those with normal weight. Although obesity was not linked to overall cancer after adjusting for shared risk factors, it was nominally associated with obesity-related cancers. Specifically, women with CVD and obesity had increased obesity-related cancer risk (body mass index: hazard ratio, 1.67 [95% CI, 1.17-2.31]). No significant associations were found in men, even after excluding prostate cancer., Conclusions: This study suggests that obesity is linked to higher obesity-related cancer risk in women with incident CVD, independent of shared risk factors. Further research is needed to eliminate residual confounding, understand sex differences, and explore how CVD pathophysiologies and obesity together influence cancer risk.

Background: Multiple novel protein biomarkers have been shown to be associated with prostate cancer risk using genetic instruments. This study aimed to externally validate the associations of 30 genetically predicted candidate proteins with prostate cancer risk using aptamer-based levels in US Black and White men in the Atherosclerosis Risk in Communities (ARIC) study. Plasma protein levels were previously measured by SomaScan® using the blood collected in 1990-1992., Methods: Among 4864 eligible participants, we ascertained 667 first primary prostate cancer cases through 2015. Hazard ratios (HRs) of prostate cancer and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression for tertiles of each protein. We adjusted for age, race, and other risk factors., Results: Of the 30 proteins and considering a nominal p trend < 0.05, two were positively associated with prostate cancer risk-RF1ML (tertile 3 vs. 1: HR = 1.23; 95% CI 1.02-1.48; p trend = 0.037) and TPST1 (1.28, 95% CI 1.06-1.55; p trend = 0.0087); two were inversely associated-ATF6A (HR = 0.80, 95% CI 0.65-0.98; p trend = 0.028) and SPINT2 (HR = 0.74, 95% CI 0.61-0.90; p trend = 0.0025). One protein, KDEL2, which was nonlinearly associated (test-for-linearity: p < 0.01) showed a statistically significant lower risk in the second tertile (HR = 0.79, 95% CI 0.65-0.95). Of these five, four proteins-ATF6A, KDEL2, RF1ML, and TPST1-were consistent in the direction of association with the discovery studies., Conclusion: This study validated some pre-diagnostic protein biomarkers of the risk of prostate cancer., (© 2024 Wiley Periodicals LLC.)

Background: We constructed a new proteomic aging clock (PAC) and computed the published Lehallier's PAC to estimate biological age. We tested PACs' associations with mortality in longer-term cancer survivors and cancer-free participants., Methods: ARIC measured 4,712 proteins using SomaScan in plasma samples collected at multiple visits, including Visit 5 (2011-13), from 806 cancer survivors and 3,699 cancer-free participants (aged 66-90). In the training set (N=2,466 randomly selected cancer-free participants), we developed the new PAC using elastic net regression and computed Lehallier's PAC. Age acceleration was calculated as residuals after regressing each PAC on chronological age after excluding the training set. We used multivariable-adjusted Cox proportional hazards regression to examine the associations of age acceleration with all-cause, cardiovascular disease (CVD), and cancer mortality., Results: Both PACs were correlated with chronological age [r=0.70-0.75]. Age acceleration for these two PACs was similarly associated with all-cause mortality in cancer survivors [hazard ratios (HRs) per 1 SD=1.40-1.42, p<0.01]. The associations with all-cause mortality were similar in cancer survivors and cancer-free participants for both PACs [p-interactions=0.20-0.62]. There were also associations with all-cause mortality in breast cancer survivors for both PACs [HRs=1.54-1.72, p<0.01] and colorectal cancer survivors for the new PAC [HR=1.96, p=0.03]. Additionally, the new PAC was associated with cancer mortality in all cancer survivors. Finally, HRs=1.42-1.61 [p<0.01] for CVD mortality in cancer-free participants for two PACs but the association was insignificant in cancer survivors perhaps due to a limited number of outcomes., Conclusion: PACs hold promise as potential biomarkers for premature mortality in cancer survivors.

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 <5 × 10 -8 . Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10 -3 ) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10 -7 ). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10 -8 ) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029)., Interpretation: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings., Funding: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments., Competing Interests: Declaration of interests ESK is a co-investigator in a grant from National Institutes of Health (R01CA196569). JW is Stock shareholder of Gilead Sciences Inc. AK has received consulting fees for Illumina Inc., has participated on data safety monitoring boards or advisory boards of TensorBio, PatchBio, Serimmune, and OpenTargets, and has stock or stock options of Illumina, Freenome, Deep Genomics, Immunai, TensorBio, PatchBio, and Serimmune. MCS was a co-investigator in a grant from National Institutes of Health (R01CA201407). VM has received grant support from Instituto de Salud Carlos III and Fundacion Cientifica Asociación Española Contra el Cáncer. SBG is a co-founder of Brogent international LLC. JPL has received additional grant support (5P01CA196569, 6R01CA201407). The remaining authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk., Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated., Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10 -8 ). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10 -14 ); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10 -3 ), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk., Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use., (© 2024. The Author(s).)

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Background: Telomeres are located at chromosomal termini and function to maintain genomic integrity. Telomere dysfunction is a well-recognized contributor to aging and age-related diseases, such as prostate cancer. Since telomere length is highly heritable, we postulate that stromal cell telomere length in the tissue of a particular solid organ may generally reflect constitutive stromal cell telomere length in other solid organs throughout the body. Even with telomere loss occurring with each round of cell replication, in general, telomere length in prostate stromal cells in mid-life would still be correlated with the telomere length in stromal cells in other organs. Thus, we hypothesize that prostate stromal cell telomere length and/or telomere length variability is a potential indicator of the likelihood of developing future solid cancers, beyond prostate cancer, and especially lethal cancer., Methods: To explore this hypothesis, we conducted a cohort study analysis of 1,175 men who were surgically treated for prostate cancer and were followed for death, including from causes other than their prostate cancer., Results: In this cohort study with a median follow-up of 19 years, we observed that longer prostate stromal cell telomere length measured in tissue microarray spots containing prostate cancer was associated with an increased risk of death from other solid cancers. Variability in telomere length among these prostate stromal cells was possibly positively associated with risk of death from other solid cancers., Conclusion: Studying the link between stromal cell telomere length and cancer mortality may be important for guiding the development of cancer interception and prevention strategies., Competing Interests: AD is a paid consultant or advisor to Merck and Cepheid and has received research funding from Janssen and Myriad for unrelated work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mori, Platz, Lu, Brame, Han, Joshu, De Marzo, Meeker and Heaphy.)

Background: Previous studies have observed inconsistent associations between birth weight and aggressive prostate cancer risk. This study aimed to prospectively analyse this association in the Health Professionals Follow-up Study (HPFS)., Methods: Birth weight was self-reported in 1994, and prostate cancer diagnoses were assessed biennially through January 2017 and confirmed by medical record review. Multivariable Cox proportional hazards regression was used to evaluate the association between birth weight and prostate cancer risk and mortality., Results: Among 19,889 eligible men, 2520 were diagnosed with prostate cancer, including 643 with higher-grade/advanced stage, 296 with lethal, and 248 with fatal disease. Overall, no association was observed for increasing birth weight with risk of overall prostate cancer, lower-grade, and organ-confined disease. However, a borderline statistically significant positive trend was observed for increasing birth weight with risk of higher-grade and/or advanced-stage prostate cancer (adjusted hazard ratio [HR adj ] per pound: 1.05; 95% confidence interval [CI]: 0.99-1.11; P-trend = 0.08), but no associations were observed with risk of lethal or fatal disease (HR adj : 0.99, 95% CI: 0.91-1.08; P-trend = 0.83; and HR adj : 0.99, 95% CI: 0.90-1.08; P-trend = 0.82, respectively)., Conclusion: No consistent associations were observed between birth weight and prostate cancer risk or mortality in this 22-year prospective cohort study., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The stromal component of the tumour microenvironment in primary and metastatic prostate cancer can influence and promote disease progression. Within the prostatic stroma, fibroblasts are one of the most prevalent cell types associated with precancerous and cancerous lesions; they have a vital role in the structural composition, organization and integrity of the extracellular matrix. Fibroblasts within the tumour microenvironment can undergo cellular senescence, which is a stable arrest of cell growth and a phenomenon that is emerging as a recognized hallmark of cancer. Supporting the idea that cellular senescence has a pro-tumorigenic role, a subset of senescent cells exhibits a senescence-associated secretory phenotype (SASP), which, along with increased inflammation, can promote prostate cancer cell growth and survival. These cellular characteristics make targeting senescent cells and/or modulating SASP attractive as a potential preventive or therapeutic option for prostate cancer., (© 2023. Springer Nature Limited.)

Excess body mass index (BMI) is associated with a higher risk of at least 13 cancers, but it is usually measured at a single time point. We tested whether the overweight-years metric, which incorporates exposure time to BMI ≥25 kg/m 2 , is associated with cancer risk and compared this with a single BMI measure. We used adulthood BMI readings in the Atherosclerosis Risk in Communities (ARIC) study to derive the overweight-years metric. We calculated associations between the metric and BMI and the risk of cancers using Cox proportional hazards models. Models that either included the metric or BMI were compared using Harrell's C-statistic. We included 13,463 participants, with 3,876 first primary cancers over a mean of 19 years (SD 7) of cancer follow-up. Hazard ratios for obesity-related cancers per standard deviation overweight-years were 1.15 (95% CI: 1.05-1.25) in men and 1.14 (95% CI: 1.08-1.20) in women. The difference in the C-statistic between models that incorporated BMI, or the overweight-years metric was non-significant in men and women. Overweight-years was associated with the risk of obesity-related cancers but did not outperform a single BMI measure in association performance characteristics., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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., (© 2024. The Author(s).)

Background: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited., Objective: The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC., Design: The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study., Participants/setting: There were 842 149 men followed for up to 9 to 22 years between 1985 and 2009 across studies., Main Outcome Measures: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score ≥8 or poorly differentiated/undifferentiated) and PC mortality., Statistical Analysis Performed: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models., Results: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n = 4863), advanced restricted (n = 2978), or high-grade PC (n = 9673) or PC mortality (n = 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P ≤ .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend = .002) for localized PC (n = 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend = .04) for low/intermediate grade PC (n = 34 366)., Conclusions: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality., (Copyright © 2024. Published by Elsevier Inc.)

Background: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations., Methods: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan., Results: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively., Conclusions: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer., Impact: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups., (©2023 American Association for Cancer Research.)

Background: Cancer survivors may have elevated atherosclerotic cardiovascular disease (ASCVD) risk. Therefore, we tested how accurately the American College of Cardiology/American Heart Association 2013 pooled cohort equations (PCEs) predict 10-year ASCVD risk in cancer survivors., Objectives: To estimate the calibration and discrimination of the PCEs in cancer survivors compared to non-cancer participants in the Atherosclerosis Risk in Communities (ARIC) study., Methods: We evaluated the PCEs' performance among 1244 cancer survivors and 3849 cancer-free participants who were free of ASCVD at the start of follow-up. Each cancer survivor was incidence-density matched with up to five controls by age, race, sex, and study center. Follow-up began at the first study visit at least 1 year after the diagnosis date of the cancer survivor and finished at the ASCVD event, death, or end of follow-up. Calibration and discrimination were assessed and compared between cancer survivors and cancer-free participants., Results: Cancer survivors had higher PCE-predicted risk, at 26.1%, compared with 23.1% for cancer-free participants. There were 110 ASCVD events in cancer survivors and 332 ASCVD events in cancer-free participants. The PCEs overestimated ASCVD risk in cancer survivors and cancer-free participants by 45.6% and 47.4%, respectively, with poor discrimination in both groups (C-statistic for cancer survivors = 0.623; for cancer-free participants, C = 0.671)., Conclusions: The PCEs overestimated ASCVD risk in all participants. The performance of the PCEs was similar in cancer survivors and cancer-free participants., Implications for Cancer Survivors: Our findings suggest that ASCVD risk prediction tools tailored to survivors of adult cancers may not be needed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Clonal hematopoiesis (CH) with acquired pathogenic variants in myeloid leukemia driver genes is common in older adults but of unknown prognostic value., Objective: To investigate the prevalence of CH and the utility of the CH risk score (CHRS) in estimating all-cause and disease-specific mortality in older adults with CH., Design, Setting, and Participants: This population-based prospective cohort study involved community-dwelling older adults (aged 67-90 years) without hematologic malignant neoplasms (HMs) who were participants in the Atherosclerosis Risk in Communities Visit 5 at 4 US centers: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Samples were collected from 2011 to 2013, sequencing was performed in 2022, and data analysis was completed in 2023., Exposure: The exposure was a diagnosis of CH. CHRS scores (calculated using 8 demographic, complete blood cell count, and molecular factors) were used to categorize individuals with CH into low-risk (CHRS ≤9.5), intermediate-risk (CHRS >9.5 to <12.5), and high-risk (CHRS ≥12.5) groups., Main Outcomes and Measures: The primary outcome was all-cause mortality, and secondary outcomes were HM mortality, cardiovascular disease mortality, and death from other causes., Results: Among 3871 participants without a history of HM (mean [SD] age, 75.7 [5.2] years; 2264 [58.5%] female individuals; 895 [23.1%] Black individuals; 2976 White individuals [76.9%]), 938 (24.2%) had CH. According to the CHRS, 562 (59.9%) were low risk, 318 (33.9%) were intermediate risk, and 58 (6.2%) were high risk. During a median (IQR) follow-up of 7.13 (5.63-7.78) years, 570 participants without CH (19.4%) and 254 participants with CH (27.1%) died. Mortality by CHRS risk group was 128 deaths (22.8%) for low risk, 93 (29.2%) for intermediate risk, and 33 (56.9%) for high risk. By use of multivariable competing risk regression, subdistribution hazard ratios (sHRs) for all-cause mortality were 1.08 (95% CI, 0.89-1.31; P = .42) for low-risk CH, 1.12 (95% CI, 0.89-1.41; P = .31) for intermediate-risk CH, and 2.52 (95% CI, 1.72-3.70; P < .001) for high-risk CH compared with no CH. Among individuals in the high-risk CH group, the sHR of death from HM (6 deaths [10.3%]) was 25.58 (95% CI, 7.55-86.71; P < .001) and that of cardiovascular death (12 deaths [20.7%]) was 2.91 (95% CI, 1.55-5.47; P < .001)., Conclusions and Relevance: In this cohort study, the CHRS was associated with all-cause, HM-related, and cardiovascular disease mortality in older adults with CH and may be useful in shared decision-making to guide clinical management and identify appropriate candidates for clinical trials.

Black men are disproportionately burdened by hypertension and prostate cancer (PCa), and some cohorts suggest hypertension is associated with increased PCa risk. We investigated the association of hypertension and antihypertensive use with total (N = 889; 290 Black, 599 White) and fatal (N = 127; 42 Black, 85 White) PCa risk in 6658 (1578 Black, 5080 White) men in the Atherosclerosis Risk in Communities study. In adjusted Cox models, time-updated untreated stage 1 hypertension (systolic/diastolic blood pressure 130-139/80-89 mmHg) was associated with a higher risk of fatal PCa compared to untreated normal blood pressure (hazard ratio (HR) = 1.95; 95% confidence interval (CI) = 1.03-3.70). Compared to untreated normal/elevated blood pressure (combined given few events in those with untreated normal blood pressure), the association was significant in Black (HR = 3.35; 95% CI = 1.27-8.83), but not White (HR = 1.21; 95% CI = 0.58-2.55) men. Ever antihypertensive use was associated with a lower risk of fatal PCa compared to never use (HR = 0.52; 95% CI = 0.31-0.87), including short-term (< 10 years) and long-term ( 3 10 years) use (p-trend = 0.02) with similar inverse associations in Black and White men. Hypertension and antihypertensive use were not significantly associated with total PCa. The positive association of untreated stage 1 hypertension and fatal PCa warrants additional confirmation, especially in Black men, and characterization of the underlying mechanism., (© 2023. W. Montague Cobb-NMA Health Institute.)

Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC., Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk., Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO)., Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10 -8 ) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10 -8 ). No interactions were observed for dietary and total folate., Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice., (© 2023. Springer Nature Limited.)

Our previous publication found an increased risk of higher-grade (Gleason sum ≥7) prostate cancer for men with high total cholesterol concentration (≥200 mg/dl) in the Health Professionals Follow-up Study (HPFS). With additional 568 prostate cancer cases, we are now able to investigate this association in more detail. For the nested case-control study, we included 1260 men newly diagnosed with prostate cancer between 1993 and 2004, and 1328 controls. For the meta-analyses, 23 articles studied the relationship between total cholesterol level and prostate cancer incidence were included. Logistic regression models and dose-response meta-analysis were performed. An increased risk of higher-grade (Gleason sum ≥4 + 3) prostate cancer for high vs low quartile of total cholesterol level was observed in the HPFS (OR multivariable  = 1.56; 95% CI = 1.01-2.40). This finding was compatible with the association noted in the meta-analysis of highest vs lowest group of total cholesterol level, which suggested a moderately increased risk of higher-grade prostate cancer (Pooled RR =1.21; 95%CI: 1.11-1.32). Moreover, the dose-response meta-analysis indicated that an increased risk of higher-grade prostate cancer occurred primarily at total cholesterol levels ≥200 mg/dl, where the RR was 1.04 (95%CI: 1.01-1.08) per 20 mg/dl increase in total cholesterol level. However, total cholesterol concentration was not associated with the risk of prostate cancer overall either in the HPFS or in the meta-analysis. Our primary finding, as well as the result of the meta-analysis suggested a modest increased risk of higher-grade prostate cancer, at total cholesterol concentrations exceeding 200 mg/dl., (© 2023 UICC.)

Objective: To inform guidance for cancer detection in patients with idiopathic inflammatory myopathy (IIM), we evaluated the diagnostic yield of computed tomography (CT) imaging for cancer screening/surveillance within distinct IIM subtypes and myositis-specific autoantibody strata., Methods: We conducted a single-center, retrospective cohort study in IIM patients. Overall diagnostic yield (number of cancers diagnosed/number of tests performed), percentage of false positives (number of biopsies performed not leading to cancer diagnosis/number of tests performed), and test characteristics were determined on CT of the chest and abdomen/pelvis., Results: Within the first 3 years since IIM symptom onset, a total of 9 of 1,011 (0.9%) chest CT scans and 12 of 657 (1.8%) abdomen/pelvis CT scans detected cancer. Diagnostic yields for both CT of the chest and CT of the abdomen/pelvis were highest in dermatomyositis, specifically anti-transcription intermediary factor 1γ (2.9% and 2.4% for CT of the chest and abdomen/pelvis, respectively). The highest percentage of false positives was in patients with antisynthetase syndrome (ASyS) (4.4%) and immune-mediated necrotizing myopathy (4.4%) on CT of the chest, and ASyS (3.8%) on CT of the abdomen/pelvis. Patients ages <40 years old at IIM onset had both low diagnostic yields (0% and 0.5%) and high false-positive rates (1.9% and 4.4%) for CT of the chest and abdomen/pelvis, respectively., Conclusion: In a tertiary referral cohort of IIM patients, CT imaging has a wide range of diagnostic yield and frequency of false positives for contemporaneous cancer. These findings suggest that cancer detection strategies targeted according to IIM subtype, autoantibody positivity, and age may maximize cancer detection while minimizing the harms and costs of over-screening., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Genetically predicted proteins have been associated with pancreatic cancer risk previously. We aimed to externally validate the associations of 53 candidate proteins with pancreatic cancer risk using directly measured, prediagnostic levels. We conducted a prospective cohort study of 10 355 US Black and White men and women in the Atherosclerosis Risk in Communities (ARIC) study. Aptamer-based plasma proteomic profiling was previously performed using blood collected in 1993 to 1995, from which the proteins were selected. By 2015 (median: 20 years), 93 incident pancreatic cancer cases were ascertained. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for protein tertiles, and adjust for age, race, and known risk factors. Of the 53 proteins, three were statistically significantly, positively associated with risk-GLCE (tertile 3 vs 1: HR = 1.88, 95% CI: 1.12-3.13; P-trend = 0.01), GOLM1 (aptamer 1: HR = 1.98, 95% CI: 1.16-3.37; P-trend = 0.01; aptamer 2: HR = 1.86, 95% CI: 1.07-3.24; P-trend = 0.05), and QSOX2 (HR = 1.96, 95% CI: 1.09-3.58; P-trend = 0.05); two were inversely associated-F177A (HR = 0.59, 95% CI: 0.35-1.00; P-trend = 0.05) and LIFsR (HR = 0.55, 95% CI: 0.32-0.93; P-trend = 0.03); and one showed a statistically significant lower risk in the middle tertile-endoglin (HR = 0.50, 95% CI: 0.29-0.86); by chance, we expected significant associations for 2.65 proteins. FAM3D, IP10, sTie-1 (positive); SEM6A and JAG1 (inverse) were suggestively associated with risk. Of these 11, 10 proteins-endoglin, FAM3D, F177A, GLCE, GOLM1, JAG1, LIFsR, QSOX2, SEM6A and sTie-1-were consistent in direction of association with the discovery studies. This prospective study validated or supports 10 proteins as associated with pancreatic cancer risk., (© 2023 UICC.)

Aim: To investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood., Materials and Methods: We included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at Visit 4 and had available data on DNA methylation from Visit 2 or 3. DNA methylation levels were compared by periodontal disease severity and edentulism through discovery analyses and subsequent testing of individual CpGs., Results: Our discovery analysis replicated findings from a previous study reporting a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared with no/mild periodontal disease in European American participants. Higher methylation levels in a separate region in an unknown gene (located in Chr10: 743,992-744,958) was associated with significantly higher odds of edentulism compared with no/mild periodontal disease in African American participants. In subsequent CpG testing, four CpGs in a region previously associated with periodontitis located within HOXA4 were significantly hypermethylated in severe periodontal disease compared with no/mild periodontal disease in African American participants (odds ratio per 1 SD increase in methylation level: cg11015251: 1.28 (1.02, 1.61); cg14359292: 1.24 (1.01, 1.54); cg07317062: 1.30 (1.05, 1.61); cg08657492: 1.25 (1.01, 1.55))., Conclusions: Our study highlights epigenetic variations in ZPF57 and HOXA4 that are significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Subclinical liver impairment due to fibrosis could influence the development and detectability of prostate cancer. To investigate the association between liver fibrosis and prostate cancer incidence and mortality, we included 5,284 men (mean age: 57.6 years, 20.1% Black) without cancer or liver disease at Visit 2 in the Atherosclerosis Risk in Communities study. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index, fibrosis 4 index (FIB-4), and nonalcoholic fatty liver disease fibrosis score (NFS). Over 25 years, 215 Black and 511 White men were diagnosed with prostate cancer, and 26 Black and 51 White men died from the disease. We estimated HRs for total and fatal prostate cancer using Cox regression. FIB-4 [quintile 5 vs. 1: HR = 0.47, 95% confidence interval (CI): 0.29-0.77, Ptrend = 0.004] and NFS (HR = 0.56, 95% CI: 0.33-0.97, Ptrend = 0.03) were inversely associated with prostate cancer risk in Black men. Compared with no abnormal score, men with ≥1 abnormal score had a lower prostate cancer risk if they were Black (HR = 0.46, 95% CI: 0.24-0.89), but not White (HR = 1.04, 95% CI: 0.69-1.58). Liver fibrosis scores did not appear to be associated with fatal prostate cancer in Black or White men. Among men without a clinical diagnosis of liver disease, higher liver fibrosis scores were associated with lower incidence of prostate cancer in Black men, but not in White men, and not with fatal prostate cancer in either race. Further research is needed to understand the influence of subclinical liver disease on prostate cancer development versus detectability and the racial differences observed., Prevention Relevance: Investigating the link between liver fibrosis and prostate cancer risk and mortality, our study reveals the potential influence of liver health on prostate cancer development and on detection using PSA test, urging further research to understand the differential findings by race and to optimize prevention and intervention strategies., (©2023 American Association for Cancer Research.)

Background: Cholesterol reduction is considered a mechanism through which cholesterol-lowering drugs including statins are associated with a reduced aggressive prostate cancer risk. While prior cohort studies found positive associations between total cholesterol and more advanced stage and grade in White men, whether associations for total cholesterol, low (LDL)- and high (HDL)-density lipoprotein cholesterol, apolipoprotein B (LDL particle) and A1 (HDL particle), and triglycerides are similar for fatal prostate cancer and in Black men, who experience a disproportionate burden of total and fatal prostate cancer, is unknown., Methods: We conducted a prospective study of 1553 Black and 5071 White cancer-free men attending visit 1 (1987-1989) of the Atherosclerosis Risk in Communities Study. A total of 885 incident prostate cancer cases were ascertained through 2015, and 128 prostate cancer deaths through 2018. We estimated multivariable-adjusted hazard ratios (HRs) of total and fatal prostate cancer per 1-standard deviation increments and for tertiles (T1-T3) of time-updated lipid biomarkers overall and in Black and White men., Results: Greater total cholesterol concentration (HR per-1 SD = 1.25; 95% CI = 1.00-1.58) and LDL cholesterol (HR per-1 SD = 1.26; 95% CI = 0.99-1.60) were associated with higher fatal prostate cancer risk in White men only. Apolipoprotein B was nonlinearly associated with fatal prostate cancer overall (T2 vs. T1: HR = 1.66; 95% CI = 1.05-2.64) and in Black men (HR = 3.59; 95% CI = 1.53-8.40) but not White men (HR = 1.13; 95% CI = 0.65-1.97). Tests for interaction by race were not statistically significant., Conclusions: These findings may improve the understanding of lipid metabolism in prostate carcinogenesis by disease aggressiveness, and by race while emphasizing the importance of cholesterol control., (© 2023 Wiley Periodicals LLC.)

Background: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis., Methods: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test)., Results: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - OR AA : 1.62, 95% CI: 1.34-1.96; OR AG : 1.41, 95% CI: 1.30-1.54; OR GG : 1.22, 95% CI: 1.13-1.31; p-value 3-d.f. : 5.46 × 10 -11 ) and 13q14.13 (rs9526201, LRCH1 - OR GG : 2.11, 95% CI: 1.56-2.83; OR GA : 1.52, 95% CI: 1.38-1.68; OR AA : 1.13, 95% CI: 1.06-1.21; p-value 2-d.f. : 7.84 × 10 -09 )., Discussion: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship., (© 2023. The Author(s).)

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer., Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies., (©2023 The Authors; Published by the American Association for Cancer Research.)

Periodontitis has been associated with an increased risk for gastrointestinal cancers. The objective of our study was to investigate the association of antibodies to oral bacteria and the risk of colon cancer in a cohort setting. Using the CLUE I cohort, a prospective cohort initiated in 1974 in Washington County, Maryland, we conducted a nested case-control study to examine the association of levels of IgG antibodies to 11 oral bacterial species (13 total strains) with risk of colon cancer diagnosed a median of 16 years later (range: 1-26 years). Antibody response was measured using checkerboard immunoblotting assays. We included 200 colon cancer cases and 200 controls matched on age, sex, cigarette smoking status, time of blood draw and pipe or cigar smoking status. Controls were selected using incidence density sampling. Conditional logistic regression models were used to assess the association between antibody levels and colon cancer risk. In the overall analysis, we observed significant inverse associations for 6 of the 13 antibodies measured (P-trends <.05) and one positive association for antibody levels to Aggregatibacter actinomycetemcomitans (ATCC 29523; P-trend = .04). While we cannot rule out a role for periodontal disease in colon cancer risk, findings from our study suggest that a strong adaptive immune response may be associated with a lower risk of colon cancer. More studies will need to examine whether the positive associations we observed with antibodies to A. actinomycetemcomitans reflect a true causal association for this bacterium., (© 2023 UICC.)

Background: The MHC class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer, but have not been examined in colorectal cancer development., Methods: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities Study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies. SNPs were genotyped by the Affymetrix Genome-Wide Human SNP Array. We applied linear and Cox proportional hazards regressions to examine the associations of preselected SNPs with sMICA and sMICB levels and colorectal cancer risk (236 colorectal cancers, 8,609 participants) and of sMICA and sMICB levels with colorectal cancer risk (312 colorectal cancers, 10,834 participants). In genetic analyses, estimates adjusted for ancestry markers were meta-analyzed., Results: Rs1051792-A, rs1063635-A, rs2516448-C, rs3763288-A, rs2596542-T, and rs2395029-G were significantly associated with decreased sMICA levels. Rs2395029-G, in the vicinity of MICA and MICB, was also associated with increased sMICB levels. Rs2596542-T was significantly associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males (HR = 0.68; 95% confidence interval, 0.49-0.96) but not in females (Pinteraction = 0.08)., Conclusions: Rs2596542-T associated with lower sMICA levels was associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males., Impact: These findings support an importance of immunosurveillance in colorectal cancer., (©2023 American Association for Cancer Research.)

Background: Oral health is a key indicator of overall health, well-being, and quality of life. Several studies have provided new evidence about the role of oral diseases, specifically periodontitis, in generating risk for various forms of cancers, including lung, colorectal, and pancreatic cancers., Methods: Incident lung cancer cases (n = 192) and matched controls (n = 192) were selected from participants of the CLUE I and CLUE II cohorts. Archived serum samples collected from participants in 1974 (in CLUE I) were analyzed using immunoblotting for immunoglobulin G (IgG) antibody levels to 13 bacteria of the periodontium. Associations between antibody levels and lung cancer were estimated using conditional logistic regression., Results: Most of the periodontal bacterial antibodies measured were inversely associated with lung cancer risk; of these, 3 were statistically significant (Prevotellaintermedia, Actinomyces naeslundii, and Veillonella parvula). A statistically significant positive association was observed for one of the Porphyromonas gingivalis strains after adjusting for P. intermedia. The sum of the logarithm of antibodies against the 13 measured bacteria was inversely associated with risk of lung cancer when the analysis was restricted to a longer follow-up (31-44 years after blood collection, highest vs lowest quartile: odds ratio = 0.26, 95% confidence interval = 0.08 to 0.84)., Conclusions: Findings from this study highlight the complexity of using serum IgG antibodies to periodontal bacteria to identify associations between oral pathogens and risk of lung cancer. The inverse associations observed for antibodies to periodontal bacteria suggest that these may represent markers of immunity that provide some advantage in reducing the development of lung cancer., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Evidence suggests that periodontal disease is associated with increased lung cancer risk, but whether periodontal pathogens are explanatory is unknown. We prospectively studied associations of prediagnostic circulating antibodies with oral bacteria and of periodontal bacteria in subgingival plaque with lung cancer., Methods: We included 4,263 cancer-free participants in the Atherosclerosis Risk in Communities study with previously measured serum IgG antibodies to 18 oral bacteria. In 1,287 participants for whom subgingival plaque was collected, counts for 8 periodontal bacteria were previously measured. Incident lung cancers (N = 118) were ascertained through 2015 (median follow-up = 17.5 years). We used Cox regression to estimate multivariable-adjusted associations, including for sums of antibodies to orange (C. rectus, F. nucleatum, P. intermedia, P. micra, and P. nigrescens) and red (P. gingivalis, T. forsythensis, and T. denticola) complex bacteria., Results: Orange complex bacteria antibodies were positively associated with lung cancer [per IQR hazard ratios (HR) = 1.15; 95% confidence intervals (CI), 1.02-1.29], which was stronger in men (HR = 1.27, 95% CI 1.08-1.49), and explained by P. intermedia and P. nigrescens (HR = 1.15; 95% CI, 1.04-1.26). Suggestive positive associations with lung cancer (N = 40) were observed for F. nucleatum, A. actinomycetemcomitans, and P. gingivalis counts. Significant positive associations were found for the count to antibody ratio for P. intermedia and P. gingivalis., Conclusions: We identified positive associations with lung cancer for oral bacteria, especially orange complex that are moderately pathogenic for periodontal disease., Impact: This prospective study supports the need for more research on periodontal bacteria in lung cancer etiology. If associations are supported, this may inform novel lung cancer prevention strategies., (©2022 American Association for Cancer Research.)

Objective: This study investigates cancer risk in idiopathic inflammatory myopathy (IIM) relative to the general population., Methods: We conducted a single-center, retrospective cohort study of IIM patients and malignancy. Myositis-specific and -associated autoantibodies were determined by Euroimmun line blot, enzyme-linked immunosorbent assay, and immunoprecipitation. We calculated standardized prevalence ratios (SPRs) and adjusted for calendar year, age, sex, race, and ethnicity by comparing observed cancers in IIM patients versus expected cancers in the general population using the Surveillance, Epidemiology, and End Results registry., Results: Of 1,172 IIM patients, 203 (17%) patients with a cancer history were studied. Over a median follow-up of 5.2 years, the observed number of IIM patients diagnosed with cancer was increased 1.43-fold (SPR 1.43 [95% confidence interval (95% CI) 1.15-1.77]; P = 0.002). Within 3 years of IIM symptom onset, an increased SPR was observed for anti-transcription intermediary factor 1γ (anti-TIF1γ)-positive patients for ovarian and breast cancer (ovarian SPR 18.39 [95% CI 5.01-47.08], P < 0.001; breast SPR 3.84 [95% CI 1.99-6.71], P < 0.001). As expected, anti-TIF1γ positivity was associated with a significantly elevated SPR; however, only 55% (36 of 66) of all cancers within 3 years of dermatomyositis onset were observed in anti-TIF1γ-positive patients. Other myositis-specific autoantibodies, including anti-Mi-2, anti-small ubiquitin-like modifier activating enzyme (SAE), and anti-nuclear matrix protein 2 (NXP-2), accounted for 26% (17 of 66) of cancers diagnosed within 3 years of dermatomyositis onset. No cancer association, positive or negative, was observed for patients with antisynthetase, anti-melanoma differentiation-associated protein 5 (anti-MDA-5), or anti-hydroxymethylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies., Conclusion: In a tertiary referral center population, anti-TIF1γ was most strongly associated with breast and ovarian cancer. Patients with antisynthetase, anti-MDA-5, or anti-HMGCR antibodies had the same cancer risk as the general population., (© 2022 American College of Rheumatology.)

Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer., Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia., Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33)., Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response., Impact: These findings can guide potential prevention treatments., (©2022 American Association for Cancer Research.)

Background: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance., Methods: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group)., Results: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity., Conclusions: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort., Impact: The proposed model has potential utility in risk-stratified colorectal cancer prevention., (©2023 American Association for Cancer Research.)

Purpose: In Tanzania, high breast cancer mortality can be attributed to delays in diagnosis and treatment initiation. We adapted the cascade analysis method to depict sequential steps along the breast cancer care pathway in a tertiary hospital in Mwanza, to identify where correction of loss to attrition would have the biggest impact on improving outcomes., Methods: This prospective cohort included adult women presenting with breast concerns between February 2020 and January 2022. Five cascade steps beginning with patients' initial clinical breast assessment (CBA) through cancer treatment were identified: (1) CBA, (2) ordering diagnostic test(s), (3) completion of diagnostic test(s), (4) receipt of final diagnosis, and (5) initiating cancer treatment., Results: Overall, 721 eligible women with a median age of 42.8 years (IQR, 32.5-55.0) were included. Median time from presentation to treatment initiation was 35 days (IQR, 20-63). For step 1, 39.1% (n = 282) of patients were diagnosed with a benign concern and removed from the cascade. Completion rates for steps 2-4 were 95.0%, 90.2%, and 91.0, respectively. There were 156 (45.6%) patients diagnosed with breast cancer, and for step 5, 71.2% of patients initiated cancer treatment. In steps 2, 3, 4, and 5, there was a loss of 22, 41, 34, and 45 patients, respectively. If loss was eliminated at steps 2, 3, 4, or 5, an additional 6, 12, 11, or 45 patients, respectively, would have completed the pathway., Conclusion: Initiating cancer treatment was identified as the step with the biggest loss and, if remedied, would have the biggest impact on improving breast cancer outcomes at Bugando Medical Centre. These results will inform future programs focused on reducing overall loss in the system and supporting patients with breast cancer.

Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer., Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium., Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I., Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Epigenetic age, a robust marker of biological aging, has been associated with obesity, low-grade inflammation and metabolic diseases. However, few studies have examined associations between different epigenetic age measures and risk of lung cancer, despite great interest in finding biomarkers to assist in risk stratification for lung cancer screening., Methods: A nested case-control study of lung cancer from the CLUE II cohort study was conducted using incidence density sampling with 1:1 matching of controls to lung cancer cases ( n = 208 matched pairs). Prediagnostic blood samples were collected in 1989 (CLUE II study baseline) and stored at -70°C. DNA was extracted from buffy coat and DNA methylation levels were measured using Illumina MethylationEPIC BeadChip Arrays. Three epigenetic age acceleration (i.e., biological age is greater than chronological age) measurements (Horvath, Hannum and PhenoAge) were examined in relation to lung cancer risk using conditional logistic regression., Results: We did not observe associations between the three epigenetic age acceleration measurements and risk of lung cancer overall; however, inverse associations for the two Hannum age acceleration measures (intrinsic and extrinsic) were observed in men and among younger participants, but not in women or older participants. We did not observe effect modification by time from blood draw to diagnosis., Conclusion: Findings from this study do not support a positive association between three different biological age acceleration measures and risk of lung cancer. Additional studies are needed to address whether epigenetic age is associated with lung cancer in never smokers.