Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

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: To examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC. DESIGN: Pooled analysis of the primary data in 15 cohorts in three continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study. PARTICIPANTS/SETTING: 842,149 men were followed for up to 9-22 years between 1985-2009 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), high grade (Gleason score ≥8 or poorly differentiated/undifferentiated) PC, and PC mortality. STATISTICAL ANALYSIS: 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=4,863), advanced restricted (n=2,978), or high-grade PC (n=9,673) or PC mortality (n=3,097). Dietary fiber intake from grains was inversely associated with advanced PC (MVHR comparing the highest vs. lowest quintile=0.84, 95% confidence interval [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≤0.03), while 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=0.002) for localized (n=35,199) and 1.05 (95%CI 0.99-1.11, , p-value, test for trend=0.04) for low/intermediate grade (n=34,366) PC. 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.

A prospective study of birth weight and prostate cancer risk and mortality in the Health Professionals Follow-up Study.

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 [HRadj] 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 (HRadj: 0.99, 95% CI: 0.91-1.08; P-trend = 0.83; and HRadj: 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.

Clonal Hematopoiesis Risk Score and All-Cause and Cardiovascular Mortality in Older Adults.

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.

Performance of the pooled cohort equations in cancer survivors: the Atherosclerosis Risk in Communities study.

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.

Overweight-years and cancer risk: A prospective study of the association and comparison of predictive performance with body mass index (Atherosclerosis Risk in Communities Study).

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/m2 , 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.

Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk.

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.

Blood Pressure, Hypertension, and Antihypertensive Medication Use and Risk of Total and Fatal Prostate Cancer in Black and White Men in the Atherosclerosis Risk in Communities (ARIC) Study.

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 (310 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.

Prognostic and therapeutic potential of senescent stromal fibroblasts in prostate cancer.

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.

Development and Characterization of Proteomic Aging Clocks in the Atherosclerosis Risk in Communities (ARIC) Study.

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 the Atherosclerosis Risk in Communities (ARIC) study of about 12,000 persons followed for 30 years (around 75% White, 25% Black), we created de novo PACs and compared their performance to published PACs at two different time points. We measured 4,712 plasma proteins by SomaScan in 11,761 midlife participants, aged 46-70 years (1990-92), and 5,183 late-life pariticpants, aged 66-90 years (2011-13). All proteins were log2-transformed to correct for skewness. We created de novo PACs by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and compared their performance to three published PACs. We estimated age acceleration (by regressing each PAC on chronological age) and its change from midlife to late life. We examined their associations with mortality from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in all remaining participants irrespective of health. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. 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 and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per one 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=0.03) and 1.04 (p=0.19) for cancer mortality, and 1.46 and 1.68 (both p<0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to those observed for late-life age acceleration. The association between the change in age acceleration and cancer mortality was insignificant. In this prospective study, the ARIC and published PACs were similarly associated with an increased risk of mortality and advanced testing in relation to various age-related conditions in future studies is suggested.

Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study.

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.

Plasma total cholesterol concentration and risk of higher-grade prostate cancer: A nested case-control study and a dose-response meta-analysis.

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 (ORmultivariable = 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.

External validation of genetically predicted protein biomarkers for pancreatic cancer risk using aptamer-based plasma levels: A prospective analysis in the Atherosclerosis Risk in Communities Study.

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.

Liver Fibrosis Scores and Prostate Cancer Risk and Mortality in the Atherosclerosis Risk in Communities Study.

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.

Total-, LDL-, and HDL-cholesterol, apolipoproteins, and triglycerides with risk of total and fatal prostate cancer in Black and White men in the ARIC study.

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.

Circulating IgG antibodies to periodontal bacteria and lung cancer risk in the CLUE cohorts.

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.

Cascade Analysis for Women Presenting With Breast Concerns to a Zonal Hospital in Mwanza, Tanzania.

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.

Antibodies to oral pathobionts and colon cancer risk in the CLUE I cohort study.

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.

Associations between MICA and MICB Genetic Variants, Protein Levels, and Colorectal Cancer: Atherosclerosis Risk in Communities (ARIC).

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.

Diagnostic Yield of Computed Tomography for Cancer Detection in a Tertiary Referral Population of Idiopathic Inflammatory Myositis Patients.

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.

Epigenetic age and lung cancer risk in the CLUE II prospective cohort study.

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.