Abstract Background Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). Materials and Method 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. Results 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. Conclusion Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
The role of endogenous androgens and sex hormone-binding globulin (SHBG) in ovarian carcinogenesis is poorly understood. Epithelial invasive ovarian cancer (EOC) is a heterogeneous disease and there are no prospective data on endogenous androgens and EOC risk by tumor characteristics (histology, grade, stage) or the dualistic model of ovarian carcinogenesis (i.e. type I vs. type II, leading to less or more aggressive tumors). We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort evaluating androgens and SHBG and invasive EOC risk by tumor characteristics. Female participants who provided a blood sample and were not using exogenous hormones at blood donation were eligible (n = 183,257). A total of 565 eligible women developed EOC; two controls (n = 1,097) were matched per case. We used multivariable conditional logistic regression models. We observed no association between androgens, SHBG and EOC overall. A doubling of androstenedione reduced risk of serous carcinomas by 21% (odds ratio (OR)log2 = 0.79, 95% confidence interval [CI] = [0.64-0.97]). Moreover, associations differed for low-grade and high-grade carcinomas, with positive associations for low-grade and inverse associations for high-grade carcinomas (e.g. androstenedione: low grade: ORlog2 = 1.99 [0.98-4.06]; high grade: ORlog2 = 0.75 [0.61-0.93], phet ≤ 0.01), similar associations were observed for type I/II tumors. This is the first prospective study to evaluate androgens, SHBG and EOC risk by tumor characteristics and type I/II status. Our findings support a possible role of androgens in ovarian carcinogenesis. Additional studies exploring this association are needed.
Abstract Background and objectives Circulating proteins are integral to many biological processes. We aimed to assess differences in the plasma proteome between people of different dietary groups defined by degree of animal food consumption. Methods The UK Biobank recruited middle-aged adults (mostly 40 to 69 years) throughout the UK between 2006-2010. Relative concentrations of 1463 plasma proteins were quantified using the Olink Proximity Extension Assay on blood samples from 49,326 participants, who were also asked to report their ethnicity and consumption of red and processed meat, poultry, fish, dairy and eggs. We defined six diet groups among the white British participants (23,116 regular meat eaters, 23,323 low meat eaters, 484 poultry eaters, 1074 fish eaters, 722 vegetarians, and 54 vegans), and two diet groups among the British Indians (390 meat eaters and 163 vegetarians). We used multivariable-adjusted linear regressions to assess differences in protein concentrations between diet groups, with correction for multiple testing. Results We observed significant differences in many plasma proteins by diet group (683 proteins in white British participants, 1 in British Indians), in particular many proteins that are majority expressed in the digestive system. Of the biggest differences, compared with regular meat eaters, the non-meat eaters had significantly higher FGF21 (e.g. +0.40 SD in vegetarians), GUCA2A (+0.33), FOLR1 (+0.32), IGFBP2 (+0.31) and DSG2 (+0.30); all groups except the vegans had lower HAVCR1 (−0.38 in vegetarians). The observed differences were generally similar in direction in both ethnicities. Discussion In this first comprehensive assessment of plasma proteins by diet group, we identified many differences in proteins between groups defined by animal food consumption; this variation in protein levels suggests differences in various biological activities, including gastrointestinal tract and kidney function, which may relate to differences in future disease risk.
Fetuin-A, also referred to as α2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case–control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 µg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02–1.24) overall, 1.21 (1.05–1.39) in men, 1.06 (0.93–1.22) in women, 1.13 (1.00–1.27) for colon cancer and 1.12 (0.94–1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case–control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 µg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73–1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development.
Data from prospective epidemiological studies in Asian populations and from experimental studies in animals and cell lines suggest a possible protective association between dietary isoflavones and the development of prostate cancer. We examined the association between circulating concentrations of genistein and prostate cancer risk in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition.Concentrations of the isoflavone genistein were measured in prediagnostic plasma samples for 1,605 prostate cancer cases and 1,697 matched control participants. Relative risks (RRs) for prostate cancer in relation to plasma concentrations of genistein were estimated by conditional logistic regression.Plasma genistein concentrations were not associated with prostate cancer risk; the multivariate relative risk for men in the highest fifth of genistein compared with men in the lowest fifth was 1.00 (95 % confidence interval: 0.79, 1.27; p linear trend = 0.82). There was no evidence of heterogeneity in this association by age at blood collection, country of recruitment, or cancer stage or histological grade.Plasma genistein concentration was not associated with prostate cancer risk in this large cohort of European men.
Abstract We investigated the associations of estimated free and total circulating testosterone and sex hormone‐binding globulin (SHBG) with cancer risk in men and postmenopausal women, using a pan‐cancer approach, including 19 cancers in UK Biobank. Risk was estimated using multivariable‐adjusted Cox regression in up to 182 608 men and 122 112 postmenopausal women who were cancer‐free at baseline. Participants diagnosed with cancer within 2 years of baseline were excluded. Hazard ratios (HRs) and confidence intervals (CIs) were corrected for regression dilution bias using repeat measurements. We accounted for multiple testing using the false discovery rate. In men, higher free testosterone was associated with higher risks of melanoma and prostate cancer (HR per 50 pmol/L increase = 1.35, 95% CI 1.14‐1.61 and 1.10, 1.04‐1.18, respectively). Higher total testosterone was associated with an elevated risk of liver cancer (HR per 5 nmol/L = 2.45, 1.56‐3.84), and higher SHBG was associated with a higher risk of liver cancer (HR per 10 nmol/L = 1.56, 1.31‐1.87) and a lower risk of prostate cancer (0.93, 0.91‐0.96); the associations with liver cancer were partially attenuated after excluding men diagnosed within 4.7 years from baseline. In postmenopausal women, free and total testosterone and SHBG were associated with risks of endometrial (HR per 10 pmol/L = 1.59, 1.32‐1.90; HR per 0.5 nmol/L = 1.34, 1.18‐1.52 and HR per 25 nmol/L = 0.78, 0.67‐0.91, respectively) and breast cancer (1.32, 1.22‐1.43; 1.24, 1.17‐1.31 and 0.88, 0.83‐0.94, respectively). We report a novel association of free testosterone with malignant melanoma in men, and confirm known associations between testosterone and risks for prostate, breast and endometrial cancers. The association with liver cancer in men may be attributable to reverse causation.
The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC. We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status. During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations. WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine. Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine.
Obstet Gynecol Surv 2015;70(8):507–508 The age at natural menopause (ANM) in the Western world ranges from 40 to 60 years, with an average onset of 51 years. The exact mechanisms underlying the timing of ANM are not completely understood.
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