Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

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

Performance of a Shotgun Prediction Model for Colorectal Cancer When Using 16S rRNA Sequencing Data.

Colorectal cancer (CRC), the third most common cancer globally, has shown links to disturbed gut microbiota. While significant efforts have been made to establish a microbial signature indicative of CRC using shotgun metagenomic sequencing, the challenge lies in validating this signature with 16S ribosomal RNA (16S) gene sequencing. The primary obstacle is reconciling the differing outputs of these two methodologies, which often lead to divergent statistical models and conclusions. In this study, we introduce an algorithm designed to bridge this gap by mapping shotgun-derived taxa to their 16S counterparts. This mapping enables us to assess the predictive performance of a shotgun-based microbiome signature using 16S data. Our results demonstrate a reduction in performance when applying the 16S-mapped taxa in the shotgun prediction model, though it retains statistical significance. This suggests that while an exact match between shotgun and 16S data may not yet be feasible, our approach provides a viable method for comparative analysis and validation in the context of CRC-associated microbiome research.

Consumption of aspartame and other artificial sweeteners and risk of cancer in the Spanish multicase-control study (MCC-Spain).

Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase-Control (MCC-Spain) study were recruited (2008-2013). The consumption of AS, from table-top sweeteners and artificially sweetened beverages, was assessed through a self-administered and validated food frequency questionnaire (FFQ). Sex-specific quartiles among controls were determined to compare moderate consumers (

Diabetes mellitus in relation to colorectal tumor molecular subtypes: A pooled analysis of more than 9000 cases.

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference  = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.

Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.

BACKGROUND: Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS: We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), ß-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. CONCLUSIONS: In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.

Polygenic risk score across distinct colorectal cancer screening outcomes: from premalignant polyps to colorectal cancer.

BACKGROUND: Different risk-based colorectal cancer (CRC) screening strategies, such as the use of polygenic risk scores (PRS), have been evaluated to improve effectiveness of these programs. However, few studies have previously assessed its usefulness in a fecal immunochemical test (FIT)-based screening study. METHODS: A PRS of 133 single nucleotide polymorphisms was assessed for 3619 participants: population controls, screening controls, low-risk lesions (LRL), intermediate-risk (IRL), high-risk (HRL), CRC screening program cases, and clinically diagnosed CRC cases. The PRS was compared between the subset of cases (n = 648; IRL+HRL+CRC) and controls (n = 956; controls+LRL) recruited within a FIT-based screening program. Positive predictive values (PPV), negative predictive values (NPV), and the area under the receiver operating characteristic curve (aROC) were estimated using cross-validation. RESULTS: The overall PRS range was 110-156. PRS values increased along the CRC tumorigenesis pathway (Mann-Kendall P value 0.007). Within the screening subset, the PRS ranged 110-151 and was associated with higher risk-lesions and CRC risk (ORD10vsD1 1.92, 95% CI 1.22-3.03). The cross-validated aROC of the PRS for cases and controls was 0.56 (95% CI 0.53-0.59). Discrimination was equal when restricted to positive FIT (aROC 0.56), but lower among negative FIT (aROC 0.55). The overall PPV among positive FIT was 0.48. PPV were dependent on the number of risk alleles for positive FIT (PPVp10-p90 0.48-0.57). CONCLUSIONS: PRS plays an important role along the CRC tumorigenesis pathway; however, in practice, its utility to stratify the general population or as a second test after a FIT positive result is still doubtful. Currently, PRS is not able to safely stratify the general population since the improvement on PPV values is scarce.

Consumption of nuts and seeds and pancreatic ductal adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition.

Four epidemiologic studies have assessed the association between nut intake and pancreatic cancer risk with contradictory results. The present study aims to investigate the relation between nut intake (including seeds) and pancreatic ductal adenocarcinoma (PDAC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to estimate hazards ratio (HR) and 95% confidence intervals (95% CI) for nut intake and PDAC risk. Information on intake of nuts was obtained from the EPIC country-specific dietary questionnaires. After a mean follow-up of 14 years, 476,160 participants were eligible for the present study and included 1,283 PDAC cases. No association was observed between consumption of nuts and PDAC risk (highest intake vs nonconsumers: HR, 0.89; 95% CI, 0.72-1.10; p-trend = 0.70). Furthermore, no evidence for effect-measure modification was observed when different subgroups were analyzed. Overall, in EPIC, the highest intake of nuts was not statistically significantly associated with PDAC risk.

Association study of dietary non-enzymatic antioxidant capacity (NEAC) and colorectal cancer risk in the Spanish Multicase-Control Cancer (MCC-Spain) study.

PURPOSE: Studies attempting to link dietary non-enzymatic antioxidant activity (NEAC) and colorectal cancer (CRC) risk have reported mixed results. We examined this association in the Spanish Multicase-Control Study considering the likely influence of coffee and other dietary factors. METHODS: 1718 CRC cases and 3312 matched-controls provided information about diet through a validated 140-item food frequency questionnaire. Dietary NEAC was estimated for three methods [total radical-trapping antioxidant parameters (TRAP), ferric reducing/antioxidant power (FRAP) and TEAC-ABTS] using published values of NEAC content in food, with and without coffee's NEAC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated through unconditional logistic regression models adjusted for lifestyle and dietary factors. RESULTS: Overall dietary intake of NEAC was significantly lower in cases compared to controls and associated with a significantly reduced CRC risk, in both men (ORQ5vsQ1 = 0.67, 95% CI 0.47-0.96 for FRAP) and women (ORQ5vsQ1 = 0.53, 95% CI 0.32-085 for FRAP), in multivariate models with and without the antioxidant contribution from coffee. The effect was similar for all the NEAC methods evaluated and for both colon and rectum. The association between dietary NEAC and CRC risk became non-significant when adjusting for fiber intake. However, intakes of NEAC and fiber were correlated. CONCLUSION: This study indicates that intake of an antioxidant-rich plant-based diet, both with and without NEAC from coffee, is associated with decreased CRC risk.

Multitrait genome association analysis identifies new susceptibility genes for human anthropometric variation in the GCAT cohort.

BACKGROUND: Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact. In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation. METHODS: We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe. We estimated SNP heritability contribution and single-trait GWAS for all traits from 15 million SNP variants. Then, we applied a multitrait-related approach to study genome-wide association to anthropometric measures in a two-stage meta-analysis with the UK Biobank cohort (n=336 107). RESULTS: Heritability estimates (eg, skin colour, alcohol consumption, smoking habit, body mass index, educational level or height) revealed an important contribution of SNP variants, ranging from 18% to 77%. Single-trait analysis identified 1785 SNPs with genome-wide significance threshold. From these, several previously reported single-trait hits were confirmed in our sample with LINC01432 (p=1.9×10-9) variants associated with male baldness, LDLR variants with hyperlipidaemia (ICD-9:272) (p=9.4×10-10) and variants in IRF4 (p=2.8×10-57), SLC45A2 (p=2.2×10-130), HERC2 (p=2.8×10-176), OCA2 (p=2.4×10-121) and MC1R (p=7.7×10-22) associated with hair, eye and skin colour, freckling, tanning capacity and sun burning sensitivity and the Fitzpatrick phototype score, all highly correlated cross-phenotypes. Multitrait meta-analysis of anthropometric variation validated 27 loci in a two-stage meta-analysis with a large British ancestry cohort, six of which are newly reported here (p value threshold <5×10-9) at ZRANB2-AS2, PIK3R1, EPHA7, MAD1L1, CACUL1 and MAP3K9. CONCLUSION: Considering multiple-related genetic phenotypes improve associated genome signal detection. These results indicate the potential value of data-driven multivariate phenotyping for genetic studies in large population-based cohorts to contribute to knowledge of complex traits.

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations.

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant.

The influence of lifestyle, diet, and reproductive history on age at natural menopause in Spain: Analysis from the EPIC-Spain sub-cohort.

OBJECTIVE: To determinate the role of lifestyle factors, recent diet, menstrual factors, and reproductive history in age at natural menopause in adult Spanish women. METHODS: In total, 12 562 pre-menopausal women were available for analysis from the EPIC-Spain sub-cohort. Women were recruited between 1992 and 1996 in five regions of Spain (Asturias, Granada, Murcia, Navarra, and San Sebastian) and, for these analyses, were followed for 3 years. Questionnaires on diet, lifestyle, anthropometric measurements, and reproductive and exogenous hormones history were collected at baseline. Menopause status was updated at a median of 3 years of follow-up. RESULTS: After a median of 3 years of follow-up 1166 women became postmenopausal. An earlier age at menopause was observed in current smokers (HR: 1.29; 95%CI 1.08-1.55) and in non-users of oral contraceptives (HR: 1.32; 95%CI 1.01-1.57). A later age at menopause was observed in women with irregular menses (HR: 0.71; 95%CI 0.56-0.91) and in women with a higher number of pregnancies (HR: 0.74; 95%CI 0.56-0.94). CONCLUSIONS: Our results confirm that women who smoked had an earlier age at natural menopause, while use of oral contraceptives, higher number of pregnancies, and irregularity of menses were associated with a prolonged reproductive lifespan. No associations were observed for dietary habits assessed after the age of 40 years.

Dietary and lifestyle determinants of acrylamide and glycidamide hemoglobin adducts in non-smoking postmenopausal women from the EPIC cohort.

PURPOSE: Acrylamide was classified as 'probably carcinogenic' to humans in 1994 by the International Agency for Research on Cancer. In 2002, public health concern increased when acrylamide was identified in starchy, plant-based foods, processed at high temperatures. The purpose of this study was to identify which food groups and lifestyle variables were determinants of hemoglobin adduct concentrations of acrylamide (HbAA) and glycidamide (HbGA) in 801 non-smoking postmenopausal women from eight countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Biomarkers of internal exposure were measured in red blood cells (collected at baseline) by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) . In this cross-sectional analysis, four dependent variables were evaluated: HbAA, HbGA, sum of total adducts (HbAA + HbGA), and their ratio (HbGA/HbAA). Simple and multiple regression analyses were used to identify determinants of the four outcome variables. All dependent variables (except HbGA/HbAA) and all independent variables were log-transformed (log2) to improve normality. Median (25th-75th percentile) HbAA and HbGA adduct levels were 41.3 (32.8-53.1) pmol/g Hb and 34.2 (25.4-46.9) pmol/g Hb, respectively. RESULTS: The main food group determinants of HbAA, HbGA, and HbAA + HbGA were biscuits, crackers, and dry cakes. Alcohol intake and body mass index were identified as the principal determinants of HbGA/HbAA. The total percent variation in HbAA, HbGA, HbAA + HbGA, and HbGA/HbAA explained in this study was 30, 26, 29, and 13 %, respectively. CONCLUSIONS: Dietary and lifestyle factors explain a moderate proportion of acrylamide adduct variation in non-smoking postmenopausal women from the EPIC cohort.

Acrylamide and glycidamide hemoglobin adduct levels and endometrial cancer risk: A nested case-control study in nonsmoking postmenopausal women from the EPIC cohort.

Acrylamide, classified in 1994 by IARC as "probably carcinogenic to humans," was discovered in 2002 in some heat-treated, carbohydrate-rich foods. Four prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The purpose of this nested case-control study, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, was to evaluate, for the first time, the association between hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) and the risk of developing EC in non-smoking postmenopausal women. Hemoglobin adducts were measured in red blood cells by HPLC/MS/MS. Four exposure variables were evaluated: HbAA, HbGA, their sum (HbAA+HbGA), and their ratio (HbGA/HbAA). The association between hemoglobin adducts and EC was evaluated using unconditional multivariable logistic regression models, and included 383 EC cases (171 were type-I EC), and 385 controls. Exposure variables were analyzed in quintiles based on control distributions. None of the biomarker variables had an effect on overall EC (HRHbAA;Q5vsQ1 : 0.84, 95%CI: 0.49-1.48; HRHbGA;Q5vsQ1 : 0.94, 95%CI: 0.54-1.63) or type-I EC risk. Additionally, none of the subgroups investigated (BMI < 25 vs. ≥25 kg m(-2) , alcohol drinkers vs. never drinkers, oral contraceptive users vs. non-users) demonstrated effect measure modification. Hemoglobin adducts of acrylamide or glycidamide were not associated with EC or type-I EC risk in 768 nonsmoking postmenopausal women from the EPIC cohort.

Flavonoid and lignan intake and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort.

Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake = 1.03, 95% CI: 0.95-1.11 and 1.02; 95% CI: 0.89-1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake = 0.96, 95% CI: 0.91-1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort.

An epidemiological model for prediction of endometrial cancer risk in Europe.

Endometrial cancer (EC) is the fourth most frequent cancer in women in Europe, and as its incidence is increasing, prevention strategies gain further pertinence. Risk prediction models can be a useful tool for identifying women likely to benefit from targeted prevention measures. On the basis of data from 201,811 women (mostly aged 30-65 years) including 855 incident EC cases from eight countries in the European Prospective Investigation into Cancer and Nutrition cohort, a model to predict EC was developed. A step-wise model selection process was used to select confirmed predictive epidemiologic risk factors. Piece-wise constant hazard rates in 5-year age-intervals were estimated in a cause-specific competing risks model, five-fold-cross-validation was applied for internal validation. Risk factors included in the risk prediction model were body-mass index (BMI), menopausal status, age at menarche and at menopause, oral contraceptive use, overall and by different BMI categories and overall duration of use, parity, age at first full-term pregnancy, duration of menopausal hormone therapy and smoking status (specific for pre, peri- and post-menopausal women). These variables improved the discriminating capacity to predict risk over 5 years from 71% for a model based on age alone to 77% (overall C statistic), and the model was well-calibrated (ratio of expected to observed cases = 0.99). Our model could be used for the identification of women at increased risk of EC in Western Europe. To achieve an EC-risk model with general validity, a large-scale cohort-consortium approach would be needed to assess and adjust for population variation.

No association between fish consumption and risk of stroke in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain): a 13·8-year follow-up study.

OBJECTIVE: To prospectively assess the associations between lean fish, fatty fish and total fish intakes and risk of stroke in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). DESIGN: Fish intake was estimated from a validated dietary questionnaire. Cox proportional hazards regression models were used to assess the association between the intakes of lean fish, fatty fish and total fish and stroke risk. Models were run separately for men and women. SETTING: Five Spanish regions (Asturias, San Sebastian, Navarra, Granada and Murcia). SUBJECTS: Individuals (n 41 020; 15 490 men and 25 530 women) aged 20-69 years, recruited from 1992 to 1996 and followed-up until December 2008 (December 2006 in the case of Asturias). Only participants with definite incident stroke were considered as cases. RESULTS: During a mean follow-up of 13·8 years, 674 strokes were identified and subsequently validated by record linkage with hospital discharge databases, primary-care records and regional mortality registries, comprising 531 ischaemic, seventy-nine haemorrhagic, forty-two subarachnoid and twenty-two unspecific strokes. After multiple adjustments, no significant associations were observed between lean fish, fatty fish and total fish consumption and the risk of stroke in men or women. In men, results revealed a non-significant trend towards an inverse association between lean fish (hazard ratio=0·84; 95 % CI 0·55, 1·29, P trend=0·06) and total fish consumption (hazard ratio=0·77; 95 % CI 0·51, 1·16, P trend=0·06) and risk of total stroke. CONCLUSIONS: In the EPIC-Spain cohort, no association was found between lean fish, fatty fish and total fish consumption and risk of stroke.

Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition.

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.

Dietary intake of acrylamide and esophageal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

PURPOSE: The relation between dietary acrylamide intake and esophageal cancer (EC) risk, including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), has not been consistent. We evaluated the association between dietary acrylamide intake and EAC, ESCC, and overall EC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Multivariate Cox proportional hazards models were used to estimate the HR and 95 % confidence interval (95 % CI). Since nonlinear relations were observed, HRs were displayed for quartiles of acrylamide intake in µg per day. RESULTS: After a mean follow-up of 11 years, 341 EC were identified, 142 of which were EAC, 176 ESCC, and 23 other histological types or not specified. An increase in EC risk was observed in the second and third quartiles (HRQ2vsQ1 1.75, 95 % CI 1.12-2.74; HRQ3vsQ1 1.66, 95 % CI 1.05-2.61), but not in the fourth quartile, and there was no evidence for a linear dose-response trend. HRs were similarly elevated but not statistically significant when ESCC and EAC were analyzed separately, due to the small number of cases observed. No associations were observed when quartiles were based on energy-adjusted acrylamide intake. CONCLUSIONS: In the EPIC cohort, an association between estimated dietary acrylamide intake and an increased risk of developing EC was observed in the middle quartiles but not in the highest quartile; however, results from other larger cohorts or consortia, and results from biomarker studies, might add to the evidence provided by this analysis, suggesting that acrylamide is not an important risk factor for EC.

Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.

Background and Aims: The microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain of Escherichia coli harboring the pks island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown. Methods: SBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival. Results: In total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5x10-28). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1x10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6x10-6) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was the APC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3x10-80). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88-positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage. Conclusion: SBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.

Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature.

BACKGROUND: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88. METHODS: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases). RESULTS: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066). CONCLUSIONS: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. IMPACT: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.