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Diabetes is a major predictor of death from heart disease and stroke; its impact on nonvascular mortality, including specific cancers, is less understood. We examined the association of diabetes with cause-specific mortality, including deaths from specific cancers. A prospective cohort of 1,053,831 U.S. adults, without cancer at baseline, enrolled in the Cancer Prevention Study-II in 1982 and was followed for mortality until December 2008. At baseline, participants completed a self-administered questionnaire that included information on diabetes, smoking, physical activity, height, and weight. Multivariable-adjusted relative risks (RRs) (95% CI) were estimated using Cox proportional hazards regression. During 26 years of follow-up, 243,051 men and 222,109 women died. In multivariable models that controlled for age, BMI, and other variables, diabetes was associated with higher risk of all-cause mortality (women RR 1.90 [95% CI 1.87-1.93]; men 1.73 [1.70-1.75]). Among women, diabetes was associated with higher risk of death from cancers of the liver (1.40 [1.05-1.86]), pancreas (1.31 [1.14-1.51]), endometrium (1.33 [1.08-1.65]), colon (1.18 [1.04-1.33]), and breast (1.16 [1.03-1.29]). Among men, diabetes was associated with risk of death from cancers of the breast (4.20 [2.20-8.04]), liver (2.26 [1.89-2.70]), oral cavity and pharynx (1.44 [1.07-1.94]), pancreas (1.40 [1.23-1.59]), bladder (1.22 [1.01-1.47]), colon (1.15 [1.03-1.29]), and (inversely) prostate (0.88 [0.79-0.97]). Diabetes was also associated with higher risks of death involving the circulatory system, respiratory system, digestive system, genitourinary system, and external causes/accidental deaths. Diabetes is associated with higher risk of death for many diseases, including several specific forms of cancer.

ObjectivesAssess differences in movement behaviours within the 24-hour cycle, including light intensity physical activity (LPA), moderate-to-vigorous physical activity (MVPA), sedentary time and sleep, before and during the COVID-19 pandemic and assess these differences stratified by several relevant factors in a subcohort of the Cancer Prevention Study-3.Design and settingUS-based longitudinal cohort study (2018–August 2020).ParticipantsN=1992 participants, of which 1304 (65.5%) are women, and 1512 (75.9%) are non-Latino white, with a mean age 57.0 (9.8) years.MeasuresAge, sex, race/ethnicity, education; self-reported LPA, MVPA, sedentary time and sleep duration collected before and during the pandemic; pandemic-related changes in work, childcare and living arrangement; COVID-19 health history.ResultsCompared to 2018, participants spent an additional 104 min/day sedentary, 61 fewer min/day in LPA and 43 fewer min/day in MVPA during the pandemic. Time spent sleeping was similar at the two time points. Differences in movement behaviours were more pronounced among men, those with a higher level of education, and those who were more active before the pandemic.ConclusionsFrom 2018 to Summer 2020, during the COVID-19 pandemic, US adults have made significant shifts in daily time spent in LPA, MVPA and sedentary. There is an urgent need to promote more physical activity and less sedentary time during this public health crisis to avoid sustaining these patterns long-term.

Purpose: Some recent studies have suggested that higher total cholesterol levels are positively associated with risk of aggressive prostate cancer. However, evidence about this association is limited and few studies examined cholesterol subfractions. We therefore examined associations of total, LDL, and HDL cholesterol concentrations with subsequent risk of aggressive prostate cancer within the Cancer Prevention Study II Nutrition Cohort. Methods: A total of 14,241 men with no history of cancer provided a blood sample between 1998 and 2001. During follow-up through 2007, 236 of these men were diagnosed with aggressive prostate cancer (AJCC stage ≥ III or Gleason score ≥ 7 (4 + 3)). Plasma total, LDL, and HDL cholesterol concentrations were measured in these 236 cases and 236 age and race-matched controls. Multivariable-adjusted odds ratios (OR) and 95 % confidence intervals (CI) were estimated using conditional logistic regression, adjusting for use of cholesterol-lowering drugs, history of heart attack, and physical activity. Results: Neither total, LDL, nor HDL cholesterol concentrations were associated with risk of aggressive prostate cancer. OR's for a 1 standard deviation (SD) difference were 0.93 (95 % CI 0.76-1.14) for total cholesterol (SD = 33.7 mg/dl), 0.94 (95 % CI 0.77-1.15) for LDL cholesterol (SD = 30.3 mg/dl), and 0.97 (95 % CI 0.82-1.16) for HDL cholesterol (SD = 12.5 mg/dl). Results were similar in analyses excluding the first 2 years of follow-up or users of cholesterol-lowering drugs. Conclusions: These results do not support an association between total cholesterol or its subfractions and risk of aggressive prostate cancer.

Research on calcium intake as well as variants in the calcium sensor receptor ( gene and their interaction in relation to CRC survival is still limited. Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary (  = 13.085), supplemental (  = 11,837), total calcium intake (  = 5970) as well as 325 single nucleotide polymorphisms (SNPs) of the gene (  = 15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the gene were assessed. During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the gene. Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the gene.

ObjectiveObesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature.DesignFor the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017.ResultsIn the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24–2.12] and an 81% (HR = 1.81, 95% CI: 1.33–2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR) = 1.49, 95% CI: 1.32–1.70; n = 4 studies; I2 = 0%]. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31–1.78; n = 6 studies). While we noted heterogeneity between studies (I2 = 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case–control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation.ConclusionsThese findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

Purpose Use of glucosamine supplements has been associated with reduced risk of colorectal cancer (CRC) in previous studies; however, information on this association remains limited. Methods We examined the association between glucosamine use and CRC risk among 113,067 men and women in the Cancer Prevention Study II Nutrition Cohort. Glucosamine use was first reported in 2001 and updated every 2 years thereafter. Participants were followed from 2001 through June of 2011, during which time 1440 cases of CRC occurred. Results As has been observed in prior studies, current use of glucosamine, modeled using a time-varying exposure, was associated with lower risk of CRC (HR 0.83; 95% CI 0.71–0.97) compared to never use. However, for reasons that are unclear, this reduction in risk was observed for shorter-duration use (HR 0.68; 95% CI 0.52–0.87 for current users with ≤ 2 years use) rather than longer-duration use (HR 0.90; 95% CI 0.72–1.13 for current users with 3 to < 6 years of use; HR 0.99; 95% CI 0.76–1.29 for current users with ≥ 6 years of use). Conclusions Further research is needed to better understand the association between glucosamine use and risk of CRC, and how this association may vary by duration of use.

A family history of pancreatic cancer is associated with increased risk of pancreatic cancer, but uncertainty remains about the magnitude of this association, whether it varies by age or smoking and whether a family history of other cancers may also be associated with increased risk. We examined family history of 14 cancers and pancreatic cancer mortality among ~ 1.1 million men and women in Cancer Prevention Study-II (CPS-II). CPS-II participants completed a questionnaire at enrollment in 1982. During follow-up through 2006, there were 7,306 pancreatic cancer deaths. A family history of pancreatic cancer in a parent or sibling was associated with pancreatic cancer mortality [multivariable adjusted rate ratio (RR) = 1.66, 95% confidence interval (CI) 1.43-1.94]. This association was stronger among participants aged under 60 (RR = 2.89, 95% CI 1.67-5.02) than among participants aged 60 or older (RR = 1.61, 95% CI 1.37-1.88). Weaker associations were observed for family history of stomach cancer (RR = 1.23, 95% CI 1.11-1.37), liver cancer (RR = 1.25, 95% CI 1.10-1.43), and colorectal cancer (RR = 1.12, 95% CI 1.01-1.23). Results from this large prospective study indicate family history of pancreatic cancer is associated with a moderate increase in risk of pancreatic cancer, and also identify associations with the family history of certain other cancers which may be useful in generating hypotheses about shared risk factors.

Recent studies have demonstrated that for various diseases, incorporating polygenic risk scores (PRSs) for other traits and diseases into the PRS-based risk prediction model may improve predictive performance – known as Multiple Polygenic Score (MPS) approach. We aimed to examine whether the MPS approach improves colorectal cancer (CRC) risk prediction. We included 2,187 non-CRC PRSs from the polygenic Score (PGS) Catalog and used machine learning (ML) models to select the most predictive non-CRC PRSs, utilizing individual-level data from 31,257 CRC cases and 33,408 controls. An independent dataset from the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (4,852 cases and 67,939 controls) was randomly split into subsets for model estimation and validation. The model combined MPS with two existing CRC-PRSs based on known loci and genome-wide genotyping. We then assessed model performance by calculating the area under the receiver operating curve (AUC) in the validation set and performed 1,000 bootstrapped iterations to evaluate AUC improvements. The ML model selected 337 non-CRC PRSs predictive of CRC risk. Adding MPS to the CRC-PRSs significantly improved AUC by 0.017 (95% CI: 0.011–0.022, p  < 0.0001) when combined with known-loci CRC-PRS, 0.005 (95% CI: 0.002–0.007, p  = 0.0005) with genome-wide CRC-PRS, and 0.004 (95% CI: 0.002–0.006, p  = 0.0005) with both the known loci and genome-wide CRC-PRSs. These findings demonstrate MPS’s potential to refine CRC risk prediction models and highlight opportunities for further advancements in risk prediction.

Somatic mutations in KRAS are a common driver of colorectal cancer (CRC) and present at different frequencies by race, sex, tumor site, ethnicity, and genetic similarity. Inherited germline variants may influence tumor somatic mutation frequency by altering mutation or DNA repair processes or altering cellular, immunological and/or microenvironmental responses after a mutation. We hypothesized that the germline genetic background modifies somatic KRAS mutation frequency in CRC. To test this, we performed a genome-wide association study (GWAS) in 7071 individuals with CRC, using KRAS mutation status as the phenotype. Single-nucleotide variants were chosen for validation analyses based on P values from the discovery GWAS, predicted in silico functional effects, and proximity to genes with potential cancer relevance. A validation analysis of 101 SNVs of interest was performed in 2482 individuals. No SNVs were significantly associated with KRAS -mutant CRC ( P value < 0.0005). One variant rs73067863-T showed a non-significant exploratory association with fewer KRAS -mutant tumors in the combined sample ( P value = 9.7 × 10 –7 , OR = 0.75). Follow-up studies are needed to determine if these or other germline variants impact population differences in KRAS mutations in CRC.

Background Identifying significantly mutated genes in tumors aids in understanding disease etiology and survival and may aid in the discovery of new drug targets. We aimed to detect and characterize mutated genes from a large, well-characterized group of colorectal cancers. Methods In tumor and paired normal samples from 6,111 colorectal patients, we sequenced 199 genes identified from whole exome sequencing of over 1,100 tumors. Analyses focused on non-silent mutations. We classified significantly mutated genes after stratification by hypermutation status, and estimated associations of mutated genes/pathways with disease-specific (DS)-survival using Cox regression, adjusting for age, sex, mutation burden, hypermutation status, and study while accounting for multiple comparisons ( n  = 4,874). Results We identified 57 genes that were significantly mutated in colorectal cancer, including 9 that were not previously reported. Among individual genes, only BRAF p.V600E mutations were significantly associated with poorer survival after correction for multiple testing (HR 1.96, P  = 2.07 × 10 − 10 ), with a more pronounced association among those with non-hypermutated tumors (HR 2.24, P  = 1.79 × 10 − 12 ). We also observed statistically significant associations with survival for four mutated pathways: TP53/ATM (HR 1.24, P  = 7.96 × 10 − 4 ), RTK/RAS (HR 1.33, P  = 3.81 × 10 − 6 ), TGF-beta (HR 1.25, P  = 1.85 × 10 − 3 ), and WNT (HR 0.81, P  = 2.52 × 10 − 03 ). Conclusions We identified 9 significantly mutated genes, some of which are known drug targets. Among individual genes, only the BRAF p.V600E mutation was significantly associated with DS-survival, suggesting a limited survival impact from mutations driving colorectal cancer development.