Showing papers by "Edward Giovannucci published in 2023"

Healthy Eating Patterns and Risk of Total and Cause-Specific Mortality.

Abstract: Importance The current Dietary Guidelines for Americans recommend multiple healthy eating patterns. However, few studies have examined the associations of adherence to different dietary patterns with long-term risk of total and cause-specific mortality. Objective To examine the associations of dietary scores for 4 healthy eating patterns with risk of total and cause-specific mortality. Design, Setting, and Participants This prospective cohort study included initially healthy women from the Nurses' Health Study (NHS; 1984-2020) and men from the Health Professionals Follow-up Study (HPFS; 1986-2020). Exposures Healthy Eating Index 2015 (HEI-2015), Alternate Mediterranean Diet (AMED) score, Healthful Plant-based Diet Index (HPDI), and Alternate Healthy Eating Index (AHEI). Main Outcomes and Measures The main outcomes were total and cause-specific mortality overall and stratified by race and ethnicity and other potential risk factors. Results The final study sample included 75 230 women from the NHS (mean [SD] baseline age, 50.2 [7.2] years) and 44 085 men from the HPFS (mean [SD] baseline age, 53.3 [9.6] years). During a total of 3 559 056 person-years of follow-up, 31 263 women and 22 900 men died. When comparing the highest with the lowest quintiles, the pooled multivariable-adjusted HRs of total mortality were 0.81 (95% CI, 0.79-0.84) for HEI-2015, 0.82 (95% CI, 0.79-0.84) for AMED score, 0.86 (95% CI, 0.83-0.89) for HPDI, and 0.80 (95% CI, 0.77-0.82) for AHEI (P < .001 for trend for all). All dietary scores were significantly inversely associated with death from cardiovascular disease, cancer, and respiratory disease. The AMED score and AHEI were inversely associated with mortality from neurodegenerative disease. The inverse associations between these scores and risk of mortality were consistent in different racial and ethnic groups, including Hispanic, non-Hispanic Black, and non-Hispanic White individuals. Conclusions and Relevance In this cohort study of 2 large prospective cohorts with up to 36 years of follow-up, greater adherence to various healthy eating patterns was consistently associated with lower risk of total and cause-specific mortality. These findings support the recommendations of Dietary Guidelines for Americans that multiple healthy eating patterns can be adapted to individual food traditions and preferences.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts

Abstract: Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42–68) years at blood collection and 63 (49–75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50– < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100– < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95–1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Different correlation of body mass index with body fatness and obesity-related biomarker according to age, sex and race-ethnicity

Abstract: The relationship between body mass index (BMI) and body fatness could differ according to age, sex, and race-ethnicity. We aimed to evaluate in which contexts BMI could be a good measure for body fatness compared to dual-energy X-ray absorptiometry (DXA) derived measures. The study population included 18,061 participants (9141 men and 8920 women) aged 18 and older who tested DXA from the National Health and Nutrition Examination Survey (NHANES) database from 1999 to 2006, and 8107 men and 10,754 women with DXA data from Korea NHANES from 2008 to 2011 to represent the Asian population. We calculated Pearson correlation coefficients between BMI and DXA derived fat mass index (FMI) and percentage body fat (PBF) depending on age, sex, and race-ethnicity. The correlation between BMI, FMI and PBF and obesity-related biomarkers was also estimated among the subgroup with both DXA and information on each biomarker. BMI was strongly correlated with FMI (r = 0.944 in men and 0.976 in women), PBF (r = 0.735 in men and 0.799 in women), and truncal fat mass (r = 0.914 in men and 0.941 in women) with correlations stronger in women than in men except for with waist-height ratio (r = 0.921 in men and 0.911 in women). The correlation between BMI and DXA derived adiposity weakened with age in both sexes. BMI was less correlated with FMI (r = 0.840 in men and 0.912 in women), PBF (r = 0.645 in men and 0.681 in women), and truncal fat mass (r = 0.836 in men and 0.884 in women) in Korean compared to other race-ethnicities. Among obesity-related biomarkers, insulin was the most strongly correlated to body adiposity indices in both sexes and strength of these correlations generally decreased with age. BMI predicted obesity-related biomarkers as well as FMI and truncal fat mass and superior to PBF. BMI could be a good measure for body fatness, particularly among young age groups, women, the US population, but less so in Korean populations. The lower correlation between BMI and body fatness in older compared to younger age groups could be related to increasing PBF and decreasing lean body mass.

Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis: A Mendelian Randomization Study

Abstract: OBJECTIVE We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs). RESEARCH DESIGN AND METHODS Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A1c (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia. RESULTS Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03–1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07–1.17) for gastric ulcer, 1.11 (95% CI, 1.03–1.20) for acute gastritis, 1.07 (95% CI, 1.01–1.13) for chronic gastritis, 1.08 (95% CI, 1.03–1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01–1.07) for diverticular disease, 1.08 (95% CI, 1.02–1.14) for acute pancreatitis, 1.09 (95% CI, 1.05–1.12) for cholelithiasis, 1.09 (95% CI, 1.05–1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17–1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03–1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89–0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively. CONCLUSIONS Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.

Smoking, alcohol consumption, and 24 gastrointestinal diseases: Mendelian randomization analysis

Abstract: Background: Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases. Methods: Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption. Results: Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn’s disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation. Conclusions: This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases. Funding: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.

Association of gallstone disease with risk of colorectal cancer: a systematic review and meta-analysis of observational studies.

Abstract: BACKGROUND Numerous studies have assessed the association of gallstones or cholecystectomy (CE) with risk of colorectal cancer (CRC). However, the findings are mixed. OBJECTIVE To systematically review and meta-analyse the association between the presence of gallstone disease (GD), or CE and the incidence of CRC. Secondary endpoints were the risk based on type of exposure, study design, tumour subsites and sex. METHODS PubMed and EMBASE were searched from September 2020 to May 2021. The protocol was registered on the Open Science Foundation Platform. We identified and classified studies according to their design into prospective cohort, population-based case-control, hospital-based case-control and necropsy studies reporting CRC incidence among individuals with diagnosed GD or after CE (or both). Among 2157 retrieved studies, 65 (3%) met the inclusion criteria. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were extracted by two independent reviewers. We evaluated the quality of the study according to the Newcastle-Ottawa Scale and only studies with a score of 6 and above were included in the final analyses. We pooled log-transformed odds ratios/risk ratios from the available adjusted models to estimate a summary relative risk (RR) and 95% confidence interval (CI) in a random-effects model. The primary outcome was overall CRC incidence. We also conducted secondary analyses according to sex and CRC subsites (proximal colon, distal colon and rectum). The outcome was measured by RRs with 95% CIs. RESULTS The overall association of GD and/or CE with CRC was RR = 1.15 (1.08; 1.24), primarily driven by hospital-based case-control studies [RR = 1.61 (1.29; 2.01)], whereas a more modest association was found in population-based case-control and cohort studies [RR = 1.10 (1.02; 1.19)]. Most hospital-based case-control and necropsy studies reported estimates that were adjusted for age and sex only, leaving room for residual confounding; therefore we restricted to population-based case-control and cohort studies for our subsequent analyses. Similar associations were found for women [RR = 1.21 (1.05; 1.4) and men (RR = 1.24 (1.06; 1.44)]. When assessed by CRC subsites, GD and CE were primarily associated with higher risk of proximal colon cancer [RR = 1.16 (1.07; 1.26)] but not distal colon cancer [RR = 0.99 (0.96; 1.03)] or rectal cancer [RR = 0.94 (0.89; 1.00)]. CONCLUSIONS Gallstones are associated with a modestly increased risk of colon cancer, primarily in the proximal colon.

Helicobacter pylori Seropositivity, ABO Blood Type, and Pancreatic Cancer Risk From 5 Prospective Cohorts

Abstract: BACKGROUND: Helicobacter pylori infection may be a risk factor for pancreatic cancer, particularly infection by strains without the cytotoxin-associated gene A (CagA) virulence factor. Non-O blood type is a known risk factor for pancreatic cancer, and H. pylori gastric colonization occurs largely from bacterial adhesins binding to blood group antigens on gastric mucosa. METHODS: We included 485 pancreatic cancer cases and 1,122 matched controls from 5 U.S. prospective cohorts. Prediagnostic plasma samples were assessed for H. pylori and CagA antibody titers. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer. ABO blood type was assessed using genetic polymorphisms at the ABO gene locus or self-report. RESULTS: Compared with H. pylori–seronegative participants, those who were seropositive did not demonstrate an increased risk of pancreatic cancer (OR 0.83, 95% CI 0.65–1.06). This lack of association was similar among CagA-seropositive (OR 0.75, 95% CI 0.53–1.04) and -seronegative (OR 0.89, 95% CI 0.65–1.20) participants. The association was also similar when stratified by time between blood collection and cancer diagnosis (P-interaction = 0.80). Consistent with previous studies, non-O blood type was associated with increased pancreatic cancer risk, but this increase in risk was similar regardless of H. pylori seropositivity (P-interaction = 0.51). DISCUSSION: In this nested case-control study, history of H. pylori infection as determined by H. pylori antibody serology was not associated with pancreatic cancer risk, regardless of CagA virulence factor status. The elevated risk associated with non-O blood type was consistent in those with or without H. pylori seropositivity.

Overall and abdominal obesity and risks of all-cause and cause-specific mortality in Korean adults: a pooled analysis of three population-based prospective cohorts.

Abstract: BACKGROUND Studies found a J-shaped association between body mass index (BMI) and mortality. However, it is unclear whether the association is driven by biases, particularly confounding by fat-free mass. METHODS We conducted an individual-level pooled analysis of three cohorts of Korean adults (aged ≥ 40 years; n = 153 248). Mortality was followed up through December 2019. Anthropometric data were directly measured at baseline. Fat and fat-free mass were predicted using validated prediction models. Using Cox proportional hazards models, we estimated the associations of BMI and waist circumference (WC) with all-cause and cause-specific mortality. To account for biases, we excluded participants aged ≥ 70 years, deaths that occurred within 5 years of follow-up and ever smokers, and adjusted for fat-free mass index (FFMI). RESULTS During the follow-up of up to 18 years, 6061 deaths were identified. We observed J-shaped association of BMI (nadir at 22-26) and monotonically positive association of WC with all-cause, cardiovascular, and cancer mortality among Korean adults without a history of cancer or cardiovascular disease. In the BMI analysis, excluding ever smokers and adjusting for FFMI attenuated the excess mortality in underweight participants and transformed the J-shaped association into a monotonically positive shape, suggesting an increased mortality at BMI > 22.0. Excluding participants aged ≥ 70 years and deaths that occurred within 5 years of follow-up did not change the results. In the WC analysis, the monotonic positive associations did not change after the control. Similar results were observed among participants with a history of cancer or cardiovascular disease. CONCLUSIONS Our data suggest that both overall and abdominal body fat are associated with increased mortality in Korean adults.

Abstract PR005: Features and susceptibility to dietary-induced alkylating damage in colorectal cancer

Abstract: Introduction: Colorectal cancer (CRC) has several established risk factors, including diet. However, their mutagenic effect has not been observed directly in patients’ tumors and the individuals or ethnic groups who are most susceptible to diet-induced carcinogenesis are yet to be identified. We hypothesized that mutational signature analyses in CRC, coupled with epidemiologic, tumor molecular and patient germline data, can be linked to pre-diagnosis diet and specific germline alterations which can further inform cancer prevention efforts. Methods: We analyzed 900 CRCs with whole-exome sequencing (WES) and prospectively collected pre-diagnosis dietary data from the Nurses’ Health Studies I and II (NHS) and the Health Professionals Follow-up Study (HPFS), as well as 540 The Cancer Genome Atlas (TCGA) tumors and 295 non-Western CRCs from the Pan-Cancer Analysis of Whole Genomes. We additionally examined a sequencing dataset of normal colonic crypts. Following variant calling, mutational signature analyses were performed on cancer specimens using Non-negative Matrix Factorization. We leveraged the WES results to identify all patients that harbored the O-6-Methylguanine-DNA Methyltransferase (MGMT) germline rs16906252 single-nucleotide polymorphism (SNP), which is associated with tumor MGMT promoter hypermethylation and impaired alkylating damage repair. Results: We identified a novel alkylating mutational signature in CRC, which was associated with pre-diagnosis intake of red meats (overall red meat P = 0.017, unprocessed red meat P = 7.8×10-3, processed red meat P = 7.1×10-3, Mann-Whitney test), distal tumor location (P = 1.4×10-4, Mann-Whitney test) and worse CRC-specific survival (P trend = 0.036, multivariable Cox regression). We found a similar mutational signature in normal colonic crypts, suggesting an early oncogenic process. We showed that the alkylating signature’s oncogenicity is mainly mediated by KRAS p.G12D and KRAS p.G13D hotspot mutations. In addition, individuals harboring the MGMT rs16906252 germline SNP had a significant enrichment in tumors with alkylating damage (P = 0.015, Mann-Whitney test) and the effect of the SNP was synergistic with pre-diagnosis red-meat intake (P = 0.0099, Wald Test). Notably, we did not observe the alkylating mutational signature in CRCs from African and East-Asian patients, populations in which the MGMT rs16906252 SNP is largely absent. Conclusions: Through the integration of molecular and epidemiologic data, we identified evidence of red meat-associated alkylating damage in CRCs. This alkylating mutational signature was associated with distal colon location, KRAS oncogenic drivers, and poor CRC-specific survival. In addition, tumor alkylating damage was enriched among individuals harboring the MGMT germline rs16906252 polymorphism, absent in East Asian and African CRC patients and was synergistic with pre-diagnosis red-meat intake. Together, these results have significant implications for dietary-induced carcinogenesis and precision prevention in CRC. Citation Format: Carino Gurjao, Rong Zhong, Koichiro Haruki, Chichun Tan, Yvonne Li, Henry Lee-Six, Brendan Reardon, Tomotaka Ugai, Mingyang Song, Eliezer M. Van Allen, Charles S. Fuchs, Jonathan A. Nowak, Kana Wu, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Jeffrey P. Townsend, Shuji Ogino, Marios Giannakis. Features and susceptibility to dietary-induced alkylating damage in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR005.

Genetic susceptibility to nonalcoholic fatty liver disease and risk for pancreatic cancer: Mendelian randomization.

Abstract: BACKGROUND There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer (PC). Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for PC. METHODS Data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium (PanScan; cases n=5090, controls n=8733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n=4,163, controls n=3,792) were analyzed. We used data on 68 genetic variants with four different MR methods (inverse variance weighting [IVW], MR-Egger, simple median, and penalized weighted median) separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and PC risk, using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for PC risk factors, including obesity and diabetes. RESULTS No association was found between genetically predicted NAFLD and PC risk in the PanScan or PanC4 samples (e.g., PanScan, IVW OR=1.04, 95% CI: 0.88-1.22, MR-Egger OR=0.89, 95% CI: 0.65-1.21; PanC4, IVW OR=1.07, 95% CI: 0.90-1.27, MR-Egger OR=0.93, 95% CI: 0.67-1.28). None of the four MR methods indicated an association between genetically predicted NAFLD and PC risk in either sample. CONCLUSIONS Genetic predisposition to NAFLD is not associated with PC risk. IMPACT Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and PC might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and PC.

Simple Prediction Model for Colorectal Serrated Polyps: Development and External Validation Study in US Prospective Cohorts.

Abstract: Serrated polyps (SPs) are precursors for colorectal cancer (CRC) and contribute disproportionately to post-colonoscopy cancers. Leveraging three US cohorts (43974 women and 5322 men), we developed prediction models for high-risk SPs (sized ≥10 mm or ≥3) among individuals undergoing their first colonoscopy screening. We then validated the model in the Partners Colonoscopy Cohort (51203 women and 39077 men). We evaluated discrimination and calibration using the C-statistic and Hosmer-Lemeshow test, respectively. The age & family history model generated a C-statistic (95% CI) of 0.57 (0.56-0.58) in women and 0.58 (0.55-0.61) in men. Further inclusion of smoking, alcohol, and body mass index (the simple model) increased the C-statistic (95% CI) to 0.68 (0.67-0.69) in women and 0.68 (0.66-0.71) in men (all P<0.001). Adding more predictors did not provide much incremental predictivity. In the validation cohort, moderate discrimination was observed in both women (0.60, 0.58-0.61) and men (0.60, 0.59-0.62). Notably, the simple model also yielded similar C-statistics for a composite endpoint of SPs and high-risk conventional adenomas (HRAs) (women, 0.62, 0.62-0.63; men, 0.63, 0.61-0.64). The model was adequately calibrated in both sets of cohorts. In summary, we developed and externally validated a simple prediction model based on five major risk factors for high-risk SPs that may be useful for healthy lifestyle recommendations and tailored CRC screening.

Proportion and number of cancer cases and deaths attributable to behavioral risk factors in Vietnam

Abstract: Identifying modifiable risk factors that contribute to cancer is essential in setting up preventive strategies. Therefore, this study aimed to estimate the number and proportion of cancer cases and deaths attributable to five behavior‐related risk factors—tobacco smoking, second‐hand smoking, alcohol consumption, high body mass index and insufficient physical activity in Vietnam in 2020. Population attributable fractions were calculated for relationships of risk factors and cancer types based on sufficient evidence according to IARC or strong evidence according to WCRF/AICR. Relative risks were retrieved from meta‐analyses where possible. Prevalence of risk factors was obtained from the most current available nationally representative population surveys in Vietnam. Cancer cases and deaths were obtained from GLOBOCAN 2020. An estimated 40.5% of all cancer cases in men (39 924 cases) and 7.8% in women (6542 cases) were attributable to these risk factors. The proportions of cancer deaths attributable to these risk factors were 44.0% in men (32 807 cases) and 8.9% in women (4235 cases). Tobacco smoking was the leading cause of cancer cases and deaths in men, followed by alcohol consumption and high BMI. In women, high BMI accounted for the highest proportion of cancer cases and second‐hand smoking accounted for the highest proportion of cancer deaths. Lung and upper aerodigestive tract cancer cases and deaths could have been reduced at least by half if these risk factors had been eliminated. To reduce cancer incidence and mortality, preventive actions focusing on tobacco control are likely to have the most significant impact, especially in men.

Dietary Inflammatory and Insulinemic Potentials, Plasma Metabolome and Risk of Colorectal Cancer

Abstract: The inflammatory and insulinemic potentials of diets have been associated with colorectal cancer risk. However, it is unknown whether the plasma metabolite profiles related to inflammatory diets, or to insulinemic diets, underlie this association. The aim of this study was to evaluate the association between metabolomic profile scores related to the food-based empirical dietary inflammatory patterns (EDIP), the empirical dietary index for hyperinsulinemia (EDIH), and plasma inflammation (CRP, IL-6, TNFα-R2, adiponectin) and insulin (C-peptide) biomarkers, and colorectal cancer risk. Elastic net regression was used to derive three metabolomic profile scores for each dietary pattern among 6840 participants from the Nurses’ Health Study and Health Professionals Follow-up Study, and associations with CRC risk were examined using multivariable-adjusted logistic regression, in a case-control study of 524 matched pairs nested in both cohorts. Among 186 known metabolites, 27 were significantly associated with both the EDIP and inflammatory biomarkers, and 21 were significantly associated with both the EDIH and C-peptide. In men, odds ratios (ORs) of colorectal cancer, per 1 standard deviation (SD) increment in metabolomic score, were 1.91 (1.31–2.78) for the common EDIP and inflammatory-biomarker metabolome, 1.12 (0.78–1.60) for EDIP-only metabolome, and 1.65 (1.16–2.36) for the inflammatory-biomarkers-only metabolome. However, no association was found for EDIH-only, C-peptide-only, and the common metabolomic signatures in men. Moreover, the metabolomic signatures were not associated with colorectal cancer risk among women. Metabolomic profiles reflecting pro-inflammatory diets and inflammation biomarkers were associated with colorectal cancer risk in men, while no association was found in women. Larger studies are needed to confirm our findings.

Hyperinsulinemia and risk of lethal prostate cancer.

Abstract: e17008 Background: Epidemiologic studies have found that insulin-like growth factor (IGF)-1 causally increases prostate cancer incidence and mortality, but the effect of insulin is less clear. IGF-1 and insulin act as mitogens by binding non-selectively to their receptors. To this end, this study tests the hypothesis that high circulating insulin increases risk for lethal (fatal or metastatic) prostate cancer among men with non-metastatic prostate cancer. Methods: The study population was drawn from two U.S.-based longitudinal cohorts: the Health Professionals Follow-Up Study (HPFS) of 51,529 health professionals and the Physicians’ Health Study (PHS) of 29,067 physicians. Pre-diagnostic plasma concentration of C-peptide was used as a proxy for insulin and measured on blood collected in 1993-1995 (HPFS) or 1982 (PHS) and stratified into quartiles for analysis. The empiric lifestyle index (based on body mass index (BMI), physical activity, and diet) for hyperinsulinemia (ELIH) was calculated from questionnaire data. Covariates of interest (age and fasting status at blood draw, BMI, height, clinical stage, and tumor grade) were attained from questionnaires and medical records. We followed patients for development of metastasis or death (lethal) through 2019 (HPFS) and 2015 (PHS). SAS 9.4 and R Studio were used for analyses. Chi-squared tests and Mann Whitney U tests were used to compare differences between groups, and Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% CI. Results: The sample included 2,812 men with 353 lethal prostate cancer events and a mean follow-up of 164 months from diagnosis to death. The mean time from blood draw to cancer diagnosis was 8.1 years. Compared to men with non-lethal prostate cancer, those with lethal disease had significantly more severe clinical grade and stage at diagnosis, higher BMI (25.1 vs 24.6), older age at blood draw (64.5 vs 61.9 years), and higher ELIH index. There were no differences by other covariates. There was no association between pre-diagnostic c-peptide levels and cancer-specific survival in a multivariable model that included clinical stage and grade (HR, 95% CI for high vs. low quartiles: 1.17, 0.83, 1.67). High ELIH was positively associated with risk of lethal prostate cancer (HR, 95% CI: 2.41, 1.36, 4.28), even when controlling for C-peptide (HR, 95% CI: 2.18, 1.20, 3.96). Conclusions: C-peptide levels measured prior to cancer diagnosis were not associated with increased mortality from prostate cancer. Higher ELIH was associated with increased risk of lethal prostate cancer among those diagnosed with prostate cancer, which could be partly mediated by hyperinsulinemia, but other dietary, physical activity, or BMI mechanisms could contribute.

Abstract 3006: Metabolomic signatures of metabolic disturbance and inflammation in relation to colorectal cancer risk

Abstract: Background: Metabolic disturbance and inflammation may explain observed associations between higher body mass index (BMI) and increased risk of colorectal cancer (CRC); however, the underlying mechanisms are not fully understood. Objectives: We characterized individual plasma metabolites and metabolomic signatures of metabolic disturbance and inflammation and evaluated their association with prospective CRC risk within the Nurses’ Health Study and the Health Professionals Follow-up Study. Methods: Among 686 colorectal cancer cases and 686 age-matched controls, we used reduced rank regression of markers of metabolic disturbance (BMI, waist circumference, C-peptide, and adiponectin) or inflammation (BMI, C-reactive protein, interleukin-6, and tumor necrosis factor receptor superfamily member 1B) with cross-sectional measures of 353 plasma metabolites to develop a Y-score for metabolic disturbance and Y-score for inflammation among men and women separately. We then used elastic net regression to derive a signature of metabolites, and multiple linear regression to identify individual metabolites, associated with each Y-score. We evaluated the association of individual metabolites and the metabolomic signatures with odds of CRC using conditional logistic regression adjusted for other CRC risk factors. Results: The metabolomic signature of metabolic disturbance consisted of 41 metabolites selected via elastic net regression in men and 72 in women; the metabolomic signature of inflammation consisted of 68 metabolites in men and 119 in women. The metabolic disturbance metabolomic signatures captured, on average, 36% of variation in markers of metabolic disturbance in women and 35% in men; the inflammation signature captured 35% of variation in inflammatory markers in women and 26% in men. The metabolomic signature of metabolic disturbance was associated with increased odds of CRC (odds ratio (OR) comparing highest to lowest quartile = 1.63; 95% confidence interval (CI), 0.92, 2.91; Ptrend = 0.31) and the metabolomic signature of inflammation was associated with increased odds of CRC (OR = 2.01; 95% CI, 1.14, 3.57; Ptrend = 0.008) among men. Neither signature was associated with CRC among women. Of the metabolites associated with metabolic disturbance and inflammation, 13 metabolites were also associated with CRC: 4 metabolites classified as uremic toxins (2 purine nucleosides and 2 amino acid derivates); 3 sphingolipids; 3 glycerophospholipids; 2 sterols related to cholesterol homeostasis; and 3-ureidopropanoate, a uracil metabolism substrate. Conclusion: We identified plasma metabolomic signatures and individual metabolites associated with metabolic disturbance, inflammation, and CRC risk, highlighting pathways such as protein metabolism and lipid homeostasis that may relate adiposity-related metabolic disturbance and inflammation to CRC development. Citation Format: Alaina M. Bever, Dong Hang, Amit D. Joshi, Connor M. Geraghty, Dong Hoon Lee, Fred K. Tabung, Shuji Ogino, Jeffrey A. Meyerhardt, Andrew T. Chan, Edward L. Giovannucci, A. Heather Eliassen, Liming Liang, Meir J. Stampfer, Mingyang Song. Metabolomic signatures of metabolic disturbance and inflammation in relation to colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3006.

Rotating Night Shift Work and Bladder Cancer Risk in Women: Results of Two Prospective Cohort Studies

Abstract: Bladder cancer is the sixth most common cancer in the United States. Night shift work has previously been linked with cancer risk. Whether there is an association between rotating night shift work and bladder cancer in women has not been studied previously. Eligible participants in the Nurses’ Health Study (NHS, n = 82,147, 1988–2016) and Nurses’ Health Study II (NHSII, n = 113,630, 1989–2015) were prospectively followed and a total of 620 and 122 incident bladder cancer cases were documented during the follow-up of NHS and NHSII, respectively. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for bladder cancer incidence. We observed a significantly increased risk of bladder cancer among women with >5 years of night shift work history compared with women who never worked rotating night shifts in NHS (HR = 1.24; 95%CI = 1.01–1.54, p for trend = 0.06), but not in the pooled NHS and NHS II (HR = 1.18; 95%CI = 0.97–1.43, p for trend = 0.08). Secondary analyses stratified by smoking status showed no significant interaction (p = 0.89) between the duration of rotating night shift work and smoking status. In conclusion, our results did not provide strong evidence for an association between rotating night shift work and bladder cancer risk.

Sedentary lifestyle, Physical Activity, and Gastrointestinal Diseases: Evidence from Mendelian Randomization Analysis

Abstract: Objectives: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease is unclear. We performed a Mendelian randomization analysis to examine these associations. Methods: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P<5E-8) level were selected from a genome-wide association study (N<703,901). Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study (N>330,000), the FinnGen study (N>220,000), and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), fasting insulin, and type 2 diabetes for both exposures. Results: Genetically proxied longer LST was associated with increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel disease, diverticular disease, Crohn disease, non-alcoholic fatty liver disease, alcoholic liver disease, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholelithiasis, and acute pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. Conclusion: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases.

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

Abstract: Our previous publication found an increased risk of higher-grade (Gleason sum ≥7) prostate cancer for men with high total cholesterol concentration (≥200 mg/dl) in the Health Professionals Follow-up Study (HPFS). With additional 568 prostate cancer cases, we are now able to investigate this association in more detail. For the nested case-control study, we included 1260 men newly diagnosed with prostate cancer between 1993 and 2004, and 1328 controls. For the meta-analyses, 23 articles studied the relationship between total cholesterol level and prostate cancer incidence were included. Logistic regression models and dose-response meta-analysis were performed. An increased risk of higher-grade (Gleason sum ≥4 + 3) prostate cancer for high vs low quartile of total cholesterol level was observed in the HPFS (ORmultivariable = 1.56; 95% CI = 1.01-2.40). This finding was compatible with the association noted in the meta-analysis of highest vs lowest group of total cholesterol level, which suggested a moderately increased risk of higher-grade prostate cancer (Pooled RR =1.21; 95%CI: 1.11-1.32). Moreover, the dose-response meta-analysis indicated that an increased risk of higher-grade prostate cancer occurred primarily at total cholesterol levels ≥200 mg/dl, where the RR was 1.04 (95%CI: 1.01-1.08) per 20 mg/dl increase in total cholesterol level. However, total cholesterol concentration was not associated with the risk of prostate cancer overall either in the HPFS or in the meta-analysis. Our primary finding, as well as the result of the meta-analysis suggested a modest increased risk of higher-grade prostate cancer, at total cholesterol concentrations exceeding 200 mg/dl.

Influence of analytic methods, data sources, and repeated measurements on the population attributable fraction of lifestyle risk factors

Abstract: Abstract Population attributable risk (PAR%) reflects the preventable fraction of disease. However, PAR% estimates of cancer have shown large variation across populations, methods, data sources, and timing of measurements. Three statistical methods to estimate PAR% were identified from a systematic literature review: the Levin’s formula, the comparative incidence rate method, and the comparative risk assessment method. We compared the variations in PAR% of postmenopausal breast cancer in the Nurses’ Health Study to evaluate the influence by method choice, source of prevalence data, use of single vs repeated exposure measurements, and potential joint effects of obesity, alcohol, physical activity, fruit and vegetable intake. Across models of the three methods, the estimated PAR% using repeated measurements were higher than that using baseline measurement; overall PAR% for the baseline, simple update, and cumulative average models were 13.8%, 21.1%, 18.6% by Levin’s formula; 13.7%, 28.0%, 31.2% by comparative risk assessment; and 17.4%, 25.2%, 29.3% by comparative incidence rate method. The estimated PAR% of the combination of multiple risk factors was higher than the product of the individual PAR%: 18.9% when assuming independence and 31.2% when considering the risk factors jointly. The three methods provided similar PAR% based on the same data source, timing of measurements, and target populations. However, sizable increases in the PAR% were observed for repeated measures over a single measure and for calculations based on achieving all recommendations jointly rather than individually.

Field synopsis of environmental and genetic risk factors of sporadic early-onset colorectal cancer and advanced adenoma.

Abstract: BACKGROUND To systematically appraise and synthesize available epidemiological evidence on the associations of environmental and genetic factors with the risk of sporadic early-onset colorectal cancer (EOCRC) and early-onset advanced colorectal adenoma (EOCRA). METHODS Multiple databases were comprehensively searched to identify eligible observational studies. Genotype data from UK Biobank were incorporated to examine their associations with EOCRC in a nested case-control design. Meta-analyses of environmental risk factors were performed and the strength of evidence was graded based on predefined criteria. Meta-analyses of genetic associations were conducted using the allelic, recessive, and dominant model, respectively. RESULTS A total of 61 studies were included, reporting 120 environmental factors and 62 genetic variants. We found 12 risk factors (current overweight, overweight in adolescence, high waist circumference, smoking, alcohol, sugary beverages intake, sedentary behavior, red meat intake, family history of CRC, hypertension, hyperlipidemia and metabolic syndrome) and three protective factors (vitamin D, folate, and calcium intake) for EOCRC or EOCRA. No significant associations between the examined genetic variants and EOCRC risk were observed. CONCLUSIONS Recent data indicate that the changing patterns of traditional CRC risk factors may explain the rising incidence of EOCRC. However, research on novel risk factors for EOCRC is limited; therefore, we cannot rule out the possibility of EOCRC having different risk factors than LOCRC. IMPACT The potential for the identified risk factors to enhance the identification of at-risk groups for personalized EOCRC screening and prevention and for the prediction of EOCRC risk should be comprehensively addressed by future studies.