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Background: Data on diet quality and pancreatic cancer are limited. We examined the relationship between diet quality, assessed by the Healthy Eating Index-2015 (HEI-2015), the Alternative Healthy Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED) score, the Dietary Approaches to Stop Hypertension (DASH) score and the energy-adjusted Dietary Inflammatory Index (E-DII), and pancreatic cancer incidence in the Multiethnic Cohort Study. Methods: Diet quality scores were calculated from a validated food frequency questionnaire administered at baseline. Cox models were used to calculate HR and 95% confidence intervals (CI) adjusted for age, sex, race/ethnicity, education, diabetes, family history of pancreatic cancer, physical activity, smoking variables, total energy intake, body mass index (BMI), and alcohol consumption. Stratified analyses by sex, race/ethnicity, smoking status, and BMI were conducted. Results: Over an average follow-up of 19.3 years, 1,779 incident pancreatic cancer cases were identified among 177,313 participants (average age of 60.2 years at baseline, 1993-1996). Overall, we did not observe associations between the dietary pattern scores and pancreatic cancer (aMED: 0.98; 95% CI, 0.83-1.16; HEI-2015: 1.03; 95% CI, 0.88-1.21; AHEI-2010: 1.03; 95% CI, 0.88-1.20; DASH: 0.92; 95% CI, 0.79-1.08; E-DII: 1.05; 95% CI, 0.89-1.23). An inverse association was observed with DASH for ever smokers (HR, 0.75; 0.61-0.93), but not for nonsmokers (HR, 1.05; 0.83-1.32). Conclusions: The DASH diet showed an inverse association with pancreatic cancer among ever smokers, but does not show a protective association overall. Impact: Modifiable measures are needed to reduce pancreatic cancer burden in these high-risk populations; our study adds to the discussion of the benefit of dietary changes. [ABSTRACT FROM AUTHOR]

Background: Studies in men of European ancestry suggest prostate-specific antigen (PSA) as a marker of early prostate cancer development that may help to risk-stratify men earlier in life. Methods: We examined PSA levels in men measured up to 10+ years before a prostate cancer diagnosis in association with prostate cancer risk in 2,245 cases and 2,203 controls of African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. We also compared the discriminative ability of PSA to polygenic risk score (PRS) for prostate cancer. Results: Excluding cases diagnosed within 2 and 10 years of blood draw, men with PSA above the median had a prostate cancer OR (95% CIs) of 9.12 (7.66-10.92) and 3.52 (2.50-5.03), respectively, compared with men with PSA below the median. A PSA level above the median identified 90% and 75% of cases diagnosed more than 2 and 10 years after blood draw, respectively. The associations were significantly greater for Gleason =7 versus 8+ disease. At 10+ years, the association of prostate cancer with PSA was comparable with that with the PRS [OR per SD increase: 1.88 (1.45-2.46) and 2.12 (1.55-2.93), respectively]. Conclusions: We found PSA to be an informative marker of prostate cancer risk at least a decade before diagnosis across multiethnic populations. This association was diminished with increasing time, greater for low grade tumors, and comparable with a PRS when measured 10+ years before diagnosis. Impact: Our multiethnic investigation suggests broad clinical implications on the utility of PSA and PRS for risk stratification in prostate cancer screening practices. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with risk of aggressive prostate cancer. It is not known whether neighborhood obesogenic factors are independently associated with prostate cancer risk. Methods: Neighborhood socioeconomic status (nSES) and four neighborhood obesogenic environment factors (urbanicity, mixed-land development, unhealthy food environment, and parks) were assessed for associations with prostate cancer risk among 41,563 African American, Japanese American, Latino, and White males in the Multiethnic Cohort (MEC) Study, California site. Multivariable Cox proportional hazards regression was used to estimate HRs and 95% confidence intervals (CI) for nonaggressive and aggressive prostate cancer, adjusting for individual-level sociodemographic, behavioral, and prostate cancer risk factors. Analyses were stratified by race, ethnicity, and, among Latino males, nativity. Results: Males residing in low-SES, compared with high-SES, neighborhoods had lower risk of nonaggressive prostate cancer [lowest vs. highest quintile HR = 0.81; 95% confidence interval (CI) = 0.68-0.95, Ptrend 0.024], driven by a similar trend among foreign-born Latino males. Foreign-born Latino males in neighborhoods with low mixed-land development had increased risk of non-aggressive disease (lowest vs. highest quintile HR = 1.49; 95% CI = 1.07-2.09). For aggressive disease, the only association noted was between lower mixed-land development and lower risk among White males (Ptrend = 0.040). Conclusions: nSES and obesogenic environment factors were independently associated with prostate cancer risk; associations varied by race, ethnicity, nativity, and disease aggressiveness. Impact: Upstream structural and social determinants of health that contribute to neighborhood obesogenic characteristics likely impact prostate cancer risk differently across groups defined by race, ethnicity, and nativity and by disease aggressiveness. [ABSTRACT FROM AUTHOR]

Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component. Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively). Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer. Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. [ABSTRACT FROM AUTHOR]

Background: People with germline mutation in one of the DNA mismatch repair (MMR) genes have increased colorectal cancer risk. For these high-risk people, study findings of the relationship between alcohol consumption and colorectal cancer risk have been inconclusive. Methods: 1,925 MMR gene mutations carriers recruited into the Colon Cancer Family Registry who had completed a questionnaire on lifestyle factors were included. Weighted Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between alcohol consumption and colorectal cancer. Results: Colorectal cancer was diagnosed in 769 carriers (40%) at a mean (SD) age of 42.6 (10.3) years. Compared with abstention, ethanol consumption from any alcoholic beverage up to 14 g/day and >28 g/day was associated with increased colorectal cancer risk (HR, 1.50; 95% CI, 1.09-2.07 and 1.69; 95% CI, 1.07-2.65, respectively; Ptrend = 0.05), and colon cancer risk (HR, 1.78; 95% CI, 1.27-2.49 and 1.94; 95% CI, 1.19-3.18, respectively; Ptrend = 0.02). However, there was no clear evidence for an association with rectal cancer risk. Also, there was no evidence for associations between consumption of individual alcoholic beverage types (beer, wine, spirits) and colorectal, colon, or rectal cancer risk. Conclusions: Our data suggest that alcohol consumption, particularly more than 28 g/day of ethanol (~2 standard drinks of alcohol in the United States), is associated with increased colorectal cancer risk for MMR gene mutation carriers. Impact: Although these data suggested that alcohol consumption in MMR carriers was associated with increased colorectal cancer risk, there was no evidence of a dose-response, and not all types of alcohol consumption were associated with increased risk. [ABSTRACT FROM AUTHOR]

Background: Microsatellite instability (MSI) and BRAF mutation status are associated with colorectal cancer survival, whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF mutation, sex, and other factors. Methods: This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Prediagnosis BMI was derived from self-reported weight approximately one year before diagnosis and height. Tumor MSI and BRAF mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from delayed-entry Cox proportional hazards models. Results: In multivariable models, high prediagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m²; HR, 1.10; 95% CI, 1.06-1.15), with similar associations stratified by sex (Pinteraction: 0.41), colon versus rectum (Pinteraction: 0.86), MSI status (Pinteraction: 0.84), and BRAF mutation status (Pinteraction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR, 1.32; P value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR, 0.86; P value: 0.29), and approximately the same for MSIhigh and obese BMI (HR, 1.00; P value: 0.98). Conclusions: High prediagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. Impact: High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the role of polymorphisms in four BER genes as potential risk factors for colorectal cancer (CRC) and modifiers of the linkage between diets high in red meat or poultry and CRC risk. Findings revealed a reduced CRC risk in carriers of the APEX1 codon 51Gln/His genotype. In addition, the PARP single nucleotide polymorphism (SNP) has modified the link between higher red meat intake and CRC. The association between higher intake of high-temperature cooked meat was also influenced by SNP.

The article examines the results of a multiethnic cohort study on consumption of well-done meat and its association with N-acetyltransferase1 (NAT1) and NAT2 genotypes and prostate cancer risk. The researchers genotyped 2,106 cases and 2,063 controls for eight single nucleotide polymorphisms in NAT1 and seven single nucleotide polymorphisms in NAT2. The results do not support the hypothesis that heterocyclic amines is linked with the risk of prostate cancer.

The article discusses plasma C-peptide and IGFBP-1 levels association with risk of colorectal adenoma in a multiethnic population. The case-control study involved 554 pathologically confirmed adenoma cases and 786 controls with normal endoscopy from Caucasians, Japanese and Native Hawaiians in Hawaii. The authors found that there is a statistically significant inverse association between plasma IGF binding protein levels and adenoma risk, which remained significant after some adjustments and were not confounded by risk factors.

Background: Mitochondria are involved in many processes that are central to the life and death of a cell. Oxidative phosphorylation (OXPHOS), in particular, is known to be altered in carcinogenesis, leading to an increase in the production of reactive oxidative species and glycolysis, one of the hallmarks of cancer cells. Because of this, genetic variation in the mitochondrial genome, which encodes for part of the OXPHOS pathway, has been suggested to play a role in many cancers, including prostate cancer. Methods: We comprehensively examined the role of the mitochondrial genome and prostate cancer risk in 4,086 prostate cancer cases and 3,698 controls from the Multiethnic Cohort (MEC), testing 350 mitochondrial SNPs (mtSNPs) in five racial/ethnic populations--Africans, Asian Americans, Europeans, Latinos, and Native Hawaiians. Logistic regression was conducted to examine single mitochondrial SNP and haplogroup associations. The sequence kernel association test was conducted for gene and pathway analysis. Results: Eleven mtSNPs and haplogroup N were nominally associated with overall prostate cancer risk at P < 0.05. The mitochondrial DNA-encoded OXPHOS pathway, complexes, and genes were not associated with prostate cancer risk. No significant associations were identified after multiple testing corrections (all FDR q > 0.20). Conclusions: The mitochondrial genome was not associated with prostate cancer risk in our study of 7,784 subjects from the MEC. Impact: Our comprehensive study does not support the role of the mitochondrial genome in the risk of prostate cancer. [ABSTRACT FROM AUTHOR]

The article studies whether higher CYP2A6 activity results in the smoker extracting more nicotine and being exposed to higher levels of tobacco-specific nitrosamine and pyrene. The authors conducted a cross-sectional study of smokers among three main ethnic groups in Hawaii. The authors report that the nicotine metabolite ratio was higher in Whites than in Japanese and intermediate in Hawaiians.

Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer., Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer., Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior., Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies., Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: While cigarette smoking is the leading cause of lung cancer, the majority of smokers do not develop the disease over their lifetime. The inter-individual differences in risk among smokers may in part be due to variations in exposure to smoking-related toxicants., Methods: Using data from a subcohort of 2,309 current smokers at the time of urine collection from the Multiethnic Cohort Study, we prospectively evaluated the association of ten urinary biomarkers of smoking-related toxicants [total nicotine equivalents (TNE), a ratio of total trans-3'-hydroxycotinine (3-HCOT)/cotinine (a phenotypic measure of CYP2A6 enzymatic activity), 4-(methylnitrosamino)-1-3-(pyridyl)-1-butanol (NNAL), S-phenylmercapturic acid (SPMA), 3-hydroxypropyl mercapturic acid (3-HPMA), phenanthrene tetraol (PheT), 3-hydroxyphenanthrene (PheOH), the ratio of PheT/PheOH, cadmium (Cd), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid (8-iso-PGF2α)] with lung cancer risk (n = 140 incident lung cancer cases over an average of 13.4 years of follow-up). Lung cancer risk was estimated using Cox proportional hazards models., Results: After adjusting for decade of birth, sex, race/ethnicity, body mass index, self-reported pack-years, creatinine, and urinary TNE (a biomarker of internal smoking dose), a one SD increase in log total 3-HCOT/cotinine (HR, 1.33; 95% CI, 1.06-1.66), 3-HPMA (HR, 1.41; 95% CI, 1.07-1.85), and Cd (HR, 1.45; 95% CI, 1.18-1.79) were each associated with increased lung cancer risk., Conclusions: Our study demonstrates that urinary total 3-HCOT/cotinine, 3-HPMA, and Cd are positively associated with lung cancer risk. These findings warrant replication and consideration as potential biomarkers for smoking-related lung cancer risk., Impact: These biomarkers may provide additional information on lung cancer risk that is not captured by self-reported smoking history or TNE. See related commentary by Etemadi et al., p. 289., (©2022 American Association for Cancer Research.)

Background: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk., Methods: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing., Results: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (P G×E = 1.96 × 10 -4 ), KRT16 (P G×E = 2.3 × 10 -4 ), CD14 (P G×E = 9.38 × 10 -4 ), and CYP27A1 (P G×E = 1.44 × 10 -3 ). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (P G×E = 3.23 × 10 -5 ). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2., Conclusions: By incorporating functional information, we discovered several novel genes that interacted with NSAID use., Impact: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer., (©2020 American Association for Cancer Research.)

The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health., (©2020 American Association for Cancer Research.)

We previously developed and validated a risk prediction model for colorectal cancer in Japanese men using modifiable risk factors. To further improve risk prediction, we evaluated the degree of improvement obtained by adding a genetic risk score (GRS) using genome-wide association study (GWAS)-identified risk variants to our validated model. We examined the association between 36 risk variants identified by GWAS and colorectal cancer risk using a weighted Cox proportional hazards model in a nested case-control study within the Japan Public Health Center-based Prospective Study. GRS was constructed using six variants associated with risk in this study of the 36 tested. We assessed three models: a nongenetic model that included the same variables used in our previously validated model; a genetic model that used GRS; and an inclusive model, which included both. The c-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated by the 5-fold cross-validation method. We estimated 10-year absolute risks for developing colorectal cancer. A statistically significant association was observed between the weighted GRS and colorectal cancer risk. The mean c-statistic for the inclusive model (0.66) was slightly greater than that for the nongenetic model (0.60). Similarly, the mean IDI and NRI showed improvement when comparing the nongenetic and inclusive models. These models for colorectal cancer were well calibrated. The addition of GRS using GWAS-identified risk variants to our validated model for Japanese men improved the prediction of colorectal cancer risk. Cancer Prev Res; 10(9); 535-41. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Evidence has accumulated that long-term use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protects against colorectal cancer. We tested whether the inverse associations between NSAIDs and colorectal cancer is similarly observed across sexes and five racial/ethnic groups (Japanese, Latino, African American, Native Hawaiian, and white) in the Multiethnic Cohort (MEC) Study., Methods: During a mean follow-up of 16.1 years, we identified 4,882 invasive incident colorectal cancer cases among 183,199 eligible participants. Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (CI)., Results: Use of aspirin and other NSAIDs was associated with a lower incidence of colorectal cancer in men (HR = 0.77; 95% CI, 0.69-0.86 for current vs. never users of aspirin) but not in women (P interaction = 0.005). Among male current users, a reduced risk was observed with ≥6 years of aspirin or total NSAID use. The inverse association with current NSAID use in men was observed in all racial/ethnic groups, except for Native Hawaiians, and was stronger in whites., Conclusions: Our findings suggest that the benefit of NSAIDs for colorectal cancer may be strongest for white men and generalizes to African American, Japanese, and Latino, but not to Native Hawaiian men. The lack of inverse association observed in women and Native Hawaiian men in the MEC should be interpreted with caution., Impact: As only very few ethnic/racial groups are likely to be represented in trials of NSAIDs and colorectal cancer, it is important to conduct prospective observational studies in various populations to test the generalizability of their results. Cancer Epidemiol Biomarkers Prev; 26(2); 162-9. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest No potential conflicts of interest were disclosed., (©2016 American Association for Cancer Research.)