Validation of candidate protein biomarkers previously identified by genetic instruments for prostate cancer risk: A prospective cohort analysis of directly measured protein levels in the ARIC study.

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.

Proteomic Aging Clocks and the Risk of Mortality among Longer-Term Cancer Survivors in the Atherosclerosis Risk in Communities (ARIC) Study.

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.

Association between Circulating T Cells and the Gut Microbiome in Healthy Individuals: Findings from a Pilot Study.

Though the microbiome's impact on immune system homeostasis is well documented, the effect of circulating T cells on the gut microbiome remains unexamined. We analyzed data from 50 healthy volunteers in a pilot trial of aspirin, using immunophenotyping and 16S rRNA sequencing to evaluate the effect of baseline T cells on microbiome changes over 6 weeks. We employed an unsupervised sparse canonical correlation analysis (sCCA) and used multivariable linear regression models to evaluate the association between selected T cell subsets and selected bacterial genera after adjusting for covariates. In the cross-sectional analysis, percentages of naïve CD4+ T cells were positively associated with a relative abundance of Intestinimonas, and the percentage of activated CD8+ T cells was inversely associated with Cellulosibacter. In the longitudinal analysis, the baseline percentages of naïve CD4+ T cells and activated CD4+ T cells were inversely associated with a 6-week change in the relative abundance of Clostridium_XlVb and Anaerovorax, respectively. The baseline percentage of terminal effector CD4+ T cells was positively associated with the change in Flavonifractor. Notably, the microbiome taxa associated with T cell subsets exclusively belonged to the Bacillota phylum. These findings can guide future experimental studies focusing on the role of T cells in impacting gut microbiome homeostasis.

Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions.

The population of cancer survivors has markedly increased due to the rapid improvements in cancer treatment. However, cancer survivors experience accelerated aging, which leads to chronic diseases and other age-related conditions, such as frailty. Those conditions may persist years after cancer diagnosis and treatment. Cellular senescence, a hallmark of aging, is one of the mechanisms that contribute to accelerated aging in cancer survivors. Several aging measures, including measures based on clinical markers and biomarkers, have been proposed to estimate the aging process, and some of them have shown associations with mortality and frailty in cancer survivors. Several anti-aging interventions, including lifestyle changes and anti-aging drugs, have been proposed. Future research, particularly in large-scale studies, is needed to determine the efficiency of these aging measures and anti-aging interventions before considering their application in clinics. This review focuses on the mechanisms of cellular senescence and accelerated aging in cancer survivors, assessment of the aging process using clinical markers and biomarkers, and the high prevalence of frailty in that population, as well as possible opportunities for anti-aging interventions. A deeper understanding of aging measures and anti-aging interventions in cancer survivors will contribute to the development of effective strategies to mitigate accelerated aging in cancer survivors and improve their quality of life.

Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort.

Machine learning models are increasingly being used to estimate "brain age" from neuroimaging data. The gap between chronological age and the estimated brain age gap (BAG) is potentially a measure of accelerated and resilient brain aging. Brain age calculated in this fashion has been shown to be associated with mortality, measures of physical function, health, and disease. Here, we estimate the BAG using a voxel-based elastic net regression approach, and then, we investigate its associations with mortality, cognitive status, and measures of health and disease in participants from Atherosclerosis Risk in Communities (ARIC) study who had a brain MRI at visit 5 of the study. Finally, we used the SOMAscan assay containing 4877 proteins to examine the proteomic associations with the MRI-defined BAG. Among N = 1849 participants (age, 76.4 (SD 5.6)), we found that increased values of BAG were strongly associated with increased mortality and increased severity of the cognitive status. Strong associations with mortality persisted when the analyses were performed in cognitively normal participants. In addition, it was strongly associated with BMI, diabetes, measures of physical function, hypertension, prevalent heart disease, and stroke. Finally, we found 33 proteins associated with BAG after a correction for multiple comparisons. The top proteins with positive associations to brain age were growth/differentiation factor 15 (GDF-15), Sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SEVP 1), matrilysin (MMP7), ADAMTS-like protein 2 (ADAMTS), and heat shock 70 kDa protein 1B (HSPA1B) while EGF-receptor (EGFR), mast/stem-cell-growth-factor-receptor (KIT), coagulation-factor-VII, and cGMP-dependent-protein-kinase-1 (PRKG1) were negatively associated to brain age. Several of these proteins were previously associated with dementia in ARIC. These results suggest that circulating proteins implicated in biological aging, cellular senescence, angiogenesis, and coagulation are associated with a neuroimaging measure of brain aging.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.

Effect of ginger supplementation on the fecal microbiome in subjects with prior colorectal adenoma.

Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal microbiome in the direction consistent with its CRC-inhibitory effect. Sixty-eight adults were randomized to take either ginger or placebo daily for 6 weeks, with a 6-week washout and longitudinal stool collection throughout. We performed 16S rRNA sequencing and evaluated changes in overall microbial diversity and the relative abundances of pre-specified CRC-associated taxa using mixed-effects logistic regression. Ginger supplementation showed no significant effect on microbial community structure through alpha or beta diversity. Of 10 pre-specified CRC-associated taxa, there were significant decreases in the relative abundances of the genera Akkermansia (p < 0.001), Bacteroides (p = 0.018), and Ruminococcus (p = 0.013) after 6-week treatment with ginger compared to placebo. Ginger supplementation led to decreased abundances of Akkermansia and Bacteroides, which suggests that ginger may have an inhibitory effect on CRC-associated taxa. Overall, ginger supplementation appears to have a limited effect on gut microbiome in patients with colorectal adenomas.

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.

Association of hormonal and reproductive factors with differentiated thyroid cancer risk in women: a pooled prospective cohort analysis.

BACKGROUND: The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results. METHODS: Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10-11 years; HR, 1.28; 95% CI, 1.00-1.64), younger (<40; HR, 1.31; 95% CI, 1.05-1.62) and older (≥55; HR, 1.33; 95% CI, 1.05-1.68) ages at menopause (vs 40-44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02-1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13-1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00-1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76-0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70-0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles. CONCLUSIONS: Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight.

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.

Immune cells are associated with mortality: the Health and Retirement Study.

Introduction: Age-related immunosenescence is characterized by changes in immune cell subsets and is associated with mortality. However, since immunosenescence is associated with other concurrent age-related changes such as inflammation and multi-organ dysfunction, it is unclear whether the association between age-related immunosenescence and mortality is independent of other concurrent age-related changes. To address these limitations, we evaluated the independent association between immune cell subsets and mortality after adjustment for age-related inflammation and biologic age. Methods: Data for this study was obtained from the 2016 interview of the Health and Retirement Study (N=6802). Cox proportional hazards regression models were used to estimate the association between 25 immune cell subsets (11 T-cell subsets, 4 B-cell subsets, 3 monocyte subsets, 3 natural killer cell subsets, 3 dendritic cell subsets, and neutrophils) and 4-year mortality adjusting for covariates such as the Klemera-Doubal algorithm biological age, chronological age, gender, race/ethnicity, BMI, smoking status, comorbidity index, CMV seropositivity, and inflammatory latent variable comprising C-reactive protein, and 4 cytokines (interleukin-10, interleukin-1 receptor antagonist, interleukin-6, and soluble tumor necrosis factor). Results: Four hundred and seventy-six participants died during the study period with an overall median follow up time of 2.5 years. After controlling for covariates and adjustment for sample-weights, total T cells [HR: 0.86, p=0.004], NK CD56LO cells [HR: 0.88, p=0.005], and neutrophils [HR: 1.22, p=0.004] were significantly associated with mortality. Conclusions: These findings support the idea that an aging immune system is associated with short-term mortality independent of age-related inflammation or other age-related measures of physiological dysfunction. If replicated in other external cohorts, these findings could identify novel targets for both monitoring and intervention to reduce the age-related mortality.

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.

Age-related Differences in T-cell Subsets and Markers of Subclinical Inflammation in Aging Are Independently Associated With Type 2 Diabetes in the Health and Retirement Study.

OBJECTIVES: Age-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T-cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS). METHODS: We measured 11 T-cell subsets, 5 pro-inflammatory markers, and 2 anti-inflammatory markers from the 2016 wave of the HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS, based on levels of blood glucose/glycated hemoglobin in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations. RESULTS: Among 8,540 participants (56 to 107 years of age), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index, and cytomegalovirus seropositivity, individuals with type 2 diabetes had lower naive T cells and higher memory and terminal effector T cells as compared with normoglycemic individuals. Among 3,230 normoglycemic participants in the 2016 survey, the incidence of diabetes was 1.8% over 4 years of follow-up. The baseline percentage of CD4+ effector memory T cells was associated with a lower risk of incident diabetes (hazard ratio [HR]=0.63, 95% confidence interval [CI] 0.49 to 0.80, p=0.0003) after adjustment for covariates. Baseline level of interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52, 95% CI 1.18 to 1.97, p=0.002). The associations between age-related changes in CD4+ effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, although adjusting for CD4+ effector memory T cells nullified the association between IL-6 and incident diabetes. CONCLUSIONS: This study showed that the baseline percentage of CD4+ effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, but CD4+ effector memory T-cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T-cell immunity affects diabetes 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.

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.

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.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). METHODS: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. RESULTS: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. CONCLUSIONS: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

Calcium Intake and Lung Cancer Risk: A Pooled Analysis of 12 Prospective Cohort Studies.

BACKGROUND: Previous studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to the differences in intake amounts and contributing sources of calcium and smoking prevalence. OBJECTIVES: We investigated the associations of lung cancer risk with intake of calcium from foods and/or supplements and major calcium-rich foods in 12 studies. METHODS: Data from 12 prospective cohort studies conducted in the United States, Europe, and Asia were pooled and harmonized. We applied the DRI to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intake. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall HR (95% CI). RESULTS: Among 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 y. Overall, the dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98-1.18) for higher (>1.5 RDA) and 1.01 (0.95-1.07) for lower intake (<0.5 RDA) comparing with recommended intake (EAR to RDA). Milk and soy food intake were positively or inversely associated with lung cancer risk [HR (95% CI) = 1.07 (1.02-1.12) and 0.92 (0.84-1.00)], respectively. The positive association with milk intake was significant only in European and North American studies (P-interaction for region = 0.04). No significant association was observed for calcium supplements. CONCLUSIONS: In this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.

Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology. MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade. CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

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.