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Background: Filipino Americans constitute 12% and 4% of the respective populations of Hawaii and California, with a large proportion of immigrants experiencing increasing cancer rates. This study investigated the incidence of colorectal, breast, and prostate cancers by generational status in the Multiethnic Cohort. Methods: We analyzed 10,495 Filipino Multiethnic Cohort first-, second-, and third-generation participants, in which 26.8% were of mixed race and ethnicity. Linkage to statewide cancer registries identified 375 breast, 249 colorectal, and 436 prostate cancer incident cases. Cox models were used to calculate HRs and 95% confidence intervals (CI) for the association between generational status and cancer incidence. Models were adjusted for age at cohort entry and cancer-specific covariates that were chosen based on stepwise regression. Results: Compared with the first generation, colorectal cancer showed a significantly higher incidence in the second and third generations with respective HRs of 1.43 (95% CI, 1.04, 1.98) and 1.76 (95% CI, 1.29, 2.38). This association was attenuated after adjustment for relevant covariates. Breast cancer incidence was elevated in the third versus first generation (HR = 1.29; 95% CI, 1.01, 1.63) even in the fully adjusted model, whereas little difference was observed for prostate cancer. Conclusions: In this prospective study, we found differences in incidence by generational status, specifically colorectal cancer among men and female breast cancer. [ABSTRACT FROM AUTHOR]

Background: Low levels of 6-sulfatoxymelatonin, the primary urinary metabolite of melatonin, have been linked to cancer and cardiometabolic outcomes in White and female populations. Methods: We examined the association between adulthood adiposity and 6-sulfatoxymelatonin levels in a racially and ethnically diverse population. Our study included 4,078 men in the Multiethnic Cohort with adiposity measurements at enrollment (1993-1996) and biomarkers measured in urines collected in 1995 and 2005. Multivariable linear regression models were used to estimate the percent change in 6-sulfatoxymelatonin levels and 95% confidence intervals (CI). Associations were examined separately by racial/ethnic group. Results: The prevalence of obesity varied by race and ethnicity, from 10% for Japanese American men to 34% for Native Hawaiian men. Compared with men with normal body mass index (BMI), men who were overweight (-7.8%; 95% CI, -11.9 to -3.5%) and obese (-18.1%; 95% CI, -23.2 to -12.6%) had significantly lower 6-sulfatoxymelatonin levels adjusting for potential confounding factors. Increasing weight gain in adulthood was also associated with lower 6-sulfatoxymelatonin (Ptrend < 0.0001). The inverse associations for BMI and weight change were qualitatively similar across racial and ethnic groups. Conclusions: Obesity is inversely associated with melatonin in a racially diverse population. This finding is relevant given higher rates of obesity among Black, Native Hawaiian, and Latino men, as well as potential racial and ethnic differences in circadian function. [ABSTRACT FROM AUTHOR]

Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. Methods: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) 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 pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. Results: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (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 pancreatic cancer risk in either sample. Conclusions: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. Impact: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer. [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: There is a growing body of evidence supporting the protective effect of statins on the risk of prostate cancer, in particular aggressive disease. Past research has mostly been conducted in North American cohorts of White men. Methods: In the multiethnic cohort (MEC), we investigated the association of prediagnostic statin use with the incidence and mortality of prostate cancer across five racial/ethnic groups (White, African American, Japanese American, Latino, and Native Hawaiian). Results: Among 31,062 male participants who completed a detailed medication questionnaire, 31.4% reported use of statins, 2,748 developed prostate cancer, and 261 died from the disease. After adjusting for potential confounders, prediagnostic statin use was associated with a 32% lower risk of fatal prostate cancer [95% confidence interval (CI) = 0.50-0.91], with the inverse association suggested consistently across the five racial/ethnic groups. Moreover, an 11% lower risk of aggressive prostate cancer (95% CI = 0.76-1.03) was observed in statin users than in nonusers. We found no statistically significant association between prediagnostic statin use and total prostate cancer or nonaggressive disease. Prediagnostic statin use was suggestively associated with a 19% reduction in prostate cancer-specific mortality (95% CI = 0.59-1.10) and an 8% reduction in all-cause mortality (95% CI = 0.79-1.07). Conclusions: In the MEC, prediagnostic use of statin was associated with lower risks of aggressive forms of prostate cancer. Impact: Our findings provide further support for the potential benefits of statins in reducing the risk and mortality of prostate cancer, especially aggressive disease. [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: The circadian hormone melatonin has anticancer properties, and prior studies suggest a positive association between low melatonin and prostate cancer risk. The purpose of this study was to examine urinary melatonin levels and prostate cancer in a racially/ethnically diverse cohort. Methods: We conducted a nested case-control study, including 1,263 prostate cancer cases and 2,346 controls, sampled from participants in the Multiethnic Cohort Study with prediagnostic urine samples assayed for 6-sulfatoxymelatonin, the primary melatonin metabolite. Conditional logistic regression was used to examine the association between melatonin levels and the development of prostate cancer outcomes (all incident cases, advanced, lethal, high-grade, and aggressive), overall and by race/ethnicity. Results: Among 1,263 cases, 135 were advanced stage, 101 were lethal cases, and 282 were high-grade disease. Median melatonin levels were similar in controls [17.12 ng/mL; interquartile range (IQR), 19.78] and cases (17.93 ng/mL; IQR, 19.76), and we found no significant association between urinary melatonin levels and prostate cancer risk overall or in any clinical or racial subgroup. Conclusions: In this diverse cohort, there was no significant association between melatonin and any prostate cancer outcome, nor were there any differences by racial/ethnic group. [ABSTRACT FROM AUTHOR]

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. [ABSTRACT FROM AUTHOR]

Background: Auto-antibodies to tumor suppressor p53 are found in a subset of patients with colorectal cancer. A recent prospective study in the United States has reported a significant 1.8-fold increased odds for colorectal cancer development with prediagnostic seropositivity to p53. In this study, we sought to examine this association in a U.S. colorectal cancer cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early biomarker for colorectal cancer. Methods: Auto-antibodies to p53 were measured in prediagnostic blood samples of 3,702 incident colorectal cancer cases and 3,702 controls, matched by age, race, and sex, from 9 U.S. prospective cohorts. The association of seropositivity to p53 with colorectal cancer risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression. Results: Overall, 5% of controls and 7% of cases were seropositive to p53, resulting in a statistically significant 33% increased colorectal cancer risk [odds ratio (OR), 1.33; 95% confidence interval (CI), 1.09-1.61]. By follow-up time, the association was only significant with colorectal cancer diagnoses within 4 years after blood draw (OR, 2.27; 95% CI, 1.62-3.19), but not thereafter (OR, 0.97; 95% CI, 0.76-1.24). Conclusions: In this large consortium of prospective cohorts, we found that prediagnostic seropositivity to tumor suppressor p53 was significantly associated with an over 2-fold increased odds of developing colorectal cancer within 4 years after blood draw. [ABSTRACT FROM AUTHOR]

Background: Incidence rates of epithelial ovarian cancer (EOC) vary across racial/ethnic groups, yet little is known about the impact of hormone-related EOC risk factors in non-Whites. Methods: Among 91,625 female Multiethnic Cohort Study participants, 155 incident EOC cases were diagnosed in Whites, 93 in African Americans, 57 in Native Hawaiians, 161 in Japanese Americans, and 141 in Latinas. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between race/ethnicity and EOC risk and between hormone-related factors and EOC risk across racial/ethnic groups. Results: Compared with Whites, African Americans and Japanese Americans had a lower multivariable-adjusted EOC risk; Native Hawaiians had a suggestive higher risk. Parity and oral contraceptive (OC) use were inversely associated with EOC risk (Pint race/ethnicity ≥ 0.43); associations were strongest among Japanese Americans (e.g., ≥4 vs. 0 children; HR = 0.45; CI, 0.26-0.79). Age at natural menopause and postmenopausal hormone (PMH) use were not associated with EOC risk in the overall population, but were positively associated with risk in Latinas (e.g., ≥5 years vs. never PMH use; HR = 2.13; CI, 1.30-3.49). Conclusions: We observed strong associations with EOC risk for parity and OC use in Japanese Americans and PMH use and age at natural menopause in Latinas. However, differences in EOC risk among racial/ethnic groups were not fully explained by established hormone-related risk factors. Impact: Our study indicates there are racial/ethnic differences in EOC risk and risk factors, and could help improve prevention strategies for non-White women. [ABSTRACT FROM AUTHOR]

Background: The four-kallikrein (4K) panel has been demonstrated to improve prediction of aggressive prostate cancer compared with prostate-specific antigen (PSA) among men with moderately elevated PSA levels. However, the development and testing of the 4K panel has been conducted primarily in White men, with limited data in African Americans and no studies in other racial and ethnic groups. Methods: We evaluated the 4K panel in a nested case-control study among African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 were measured among 1,667 incident prostate cancer cases and 691 controls with PSA =2 ng/mL. We evaluated the discriminative ability of the 4K panel within and across all racial/ethnic groups. Results: The 4K panel enhanced discrimination of overall prostate cancer compared with free plus total PSA and total PSA alone (AUC 0.748 vs. 0.711 and 0.669, respectively). Discrimination was further enhanced for Gleason 8+ prostate cancer, aggressive prostate cancer, and death due to prostate cancer, and to a lesser degree for nonaggressive prostate cancer. Improvement of the 4K panel over PSA was observed in each population. Adding a prostate cancer polygenic risk score slightly improved upon the discriminative ability of the 4K panel. Conclusions: The superior discriminative ability of the 4K panel over PSA for overall and aggressive prostate cancer across multiethnic populations indicates the broad clinical applicability of the 4K panel. [ABSTRACT FROM AUTHOR]

Background: Visceral adipose tissue (VAT) may play a greater role than subcutaneous fat in increasing cancer risk but is poorly estimated in epidemiologic studies. Methods: We developed a VAT prediction score by regression equations averaged across 100 least absolute shrinkage and selection operator models in a cross-sectional study of 1,801 older adults in the Multiethnic Cohort (MEC). The score was then used as proxy for VAT in case-control studies of postmenopausal breast (950 case-control pairs) and colorectal (831 case-control pairs) cancer in an independent sample in MEC. Abdominal MRI-derived VAT; circulating biomarkers of metabolic, hormonal, and inflammation dysfunctions; and ORs for incident cancer adjusted for BMI and other risk factors were assessed. Results: The final score, composed of nine biomarkers, BMI, and height, explained 11% and 15% more of the variance in VAT than BMI alone in men and women, respectively. The area under the receiver operator curve for VAT >150 cm² was 0.90 in men and 0.86 in women. The VAT score was associated with risk of breast cancer [OR (95% confidence interval [CI]) by increasing tertiles: 1.00, 1.09 (0.86-1.39), 1.48 (1.16-1.89); Ptrend = 0.002] but not with colorectal cancer (P = 0.84), although an association [1.00, 0.98 (0.68-1.39), 1.24 (0.88-1.76); Ptrend = 0.08] was suggested for this cancer after excluding cases that occurred within 7 years of blood draw (Pheterogeneity = 0.06). Conclusions: The VAT score predicted risks of postmenopausal breast cancer and can be used for risk assessment in diverse populations. Impact: These findings provide specific evidence for a role of VAT in breast cancer. [ABSTRACT FROM AUTHOR]

Background: As the stronger association of obesity with postmenopausal breast cancer in Asian than white women may be due to body fat distribution, we examined the relation of adiposity measures with percent mammographic density (PMD), a strong predictor of breast cancer incidence. Methods: A total of 938 women from five ethnic groups (69.1 ± 2.7 years) in the Adiposity Phenotype Study (APS) underwent DXA and MRI imaging. PMD was assessed in routine mammograms using a computer-assisted method. Spearman correlation coefficients were computed and general linear models were applied to estimate regression coefficients (ß) for PMD per 0.5 SD units of adiposity measures while adjusting for known confounders, including DXA total body fat. Results: For 701 (75%) of the participants (69.1 ± 2.7 years), valid mammograms were obtained. Whereas total body fat, the trunk-to-periphery fat ratio (TPFR), visceral fat (VAT), and subcutaneous fat (SAT) were inversely correlated with PMD (P < 0.0001), the VAT/SAT ratio correlated positively (rspearman = 0.10; P = 0.01). In fully adjusted models, PMD remained inversely related to TPFR and SAT and disappeared for VAT, while it was strengthened for VAT/SAT (β = 0.51; P = 0.009). This relation was stronger in Japanese Americans than other ethnic groups. Conclusions: This is the first study to show an association of a high VAT/SAT ratio with greater PMD, a marker of breast cancer risk after taking into account total body fat. [ABSTRACT FROM AUTHOR]

Background: Measurement reliability and biological stability need to be considered when developing sampling protocols for population-based fecal microbiome studies. Methods: Stool samples were collected biannually over a 2-year period and sequenced for the V1-V3 region of the 16S rRNA gene in 50 participants from the Multiethnic Cohort Study. We evaluated the temporal stability of the fecal microbiome on a community level with permutational multivariate analysis of variance (PERMANOVA), as well as on taxa and diversity measures with intraclass correlation coefficients. Results: Interindividual differences were the predominant source of fecal microbiome variation, and variation within individual was driven more by changing abundances than by the complete loss or introduction of taxa. Phyla and diversity measures were reliable over the 2 years. Most genera were stable over time, although those with low abundances tended to be more dynamic. Reliability was lower among participants who used antibiotics, with the greatest difference seen in samples taken within 1 month of reported use. Conclusions: The fecal microbiome as a whole is stable over a 2-year period, although certain taxa may exhibit more temporal variability. Impact: When designing large epidemiologic studies, a single sample is sufficient to capture the majority of the variation in the fecal microbiome from 16S rRNA gene sequencing, while multiple samples may be needed for rare or less-abundant taxa. [ABSTRACT FROM AUTHOR]

Cohort studies have been central to the establishment of the known causes of cancer. To dissect cancer etiology in more detail--for instance, for personalized risk prediction and prevention, assessment of risks of subtypes of cancer, and assessment of small elevations in risk--there is a need for analyses of far larger cohort datasets than available in individual existing studies. To address these challenges, the NCI Cohort Consortium was founded in 2001. It brings together 58 cancer epidemiology cohorts from 20 countries to undertake large-scale pooling research. The cohorts in aggregate include over nine million study participants, with biospecimens available for about two million of these. Research in the Consortium is undertaken by >40 working groups focused on specific cancer sites, exposures, or other research areas. More than 180 publications have resulted from the Consortium, mainly on genetic and other cancer epidemiology, with high citation rates. This article describes the foundation of the Consortium; its structure, governance, and methods of working; the participating cohorts; publications; and opportunities. The Consortium welcomes new members with cancer-oriented cohorts of 10,000 or more participants and an interest in collaborative research. [ABSTRACT FROM AUTHOR]

Background: Coffee intake has been associated with risk of various cancers, but the findings, mostly from studies in white populations, are inconsistent. We examined the association of coffee consumption with overall cancer incidence and specific cancer sites in a large prospective study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites. Methods: 167,720 participants of the Multiethnic Cohort Study in Hawaii and Los Angeles were included. Baseline coffee intake was assessed by a validated food-frequency questionnaire. HRs and 95% confidence intervals (CIs) for sixteen cancers associated with coffee intake were calculated using Cox regressions. Results: During a mean follow-up of 15.3 years, 34,031 incident cancer cases were identified among study participants. Coffee intake was associated inversely with liver (=4 cups/day vs. none: HR = 0.57; 95% CI, 0.38-0.87; Ptrend < 0.001), ovarian (HR = 0.33; 95% CI, 0.17-0.65; Ptrend = 0.007), and thyroid (HR = 0.44; 95% CI, 0.23-0.87; Ptrend = 0.007) cancers and melanoma (HR = 0.72; 95% CI, 0.52-0.99; Ptrend = 0.002). Coffee intake was also inversely associated with endometrial cancer among women with a body mass index >30 kg/m2 (HR = 0.31; 95% CI, 0.14-0.72; Ptrend = 0.04). The associations were similar across five ethnic groups (Pheterogeneity > 0.06) and were mainly observed among those who drank caffeinated coffee. Conclusions: On the basis of our prospective data in diverse populations, we found a decreased risk of liver, ovarian, thyroid, and endometrial cancers and melanoma associated with higher coffee intake. Impact: These results suggest that coffee drinking may protect against liver, ovarian, thyroid, and endometrial cancers, and melanoma. [ABSTRACT FROM AUTHOR]

Background: Obesity has been more consistently associated with breast cancer than type II diabetes. This analysis examined the combination of the two factors in the Multiethnic Cohort (MEC). Methods: Women ages 45-75 years entered the MEC in 1993-1996 by completing a questionnaire. Type II diabetes status was self-reported at baseline, two follow-up questionnaires, and confirmed by administrative data. Cancers were identified from tumor registries and deaths through vital records until 2010. Cox regression was applied to estimate HRs and 95% confidence intervals (CI) for BMI and type II diabetes status alone and in combination. Results: Among 103,721 (25,146 white, 20,255 African American, 7,681 Native Hawaiian, 28,012 Japanese American, 22,627 Latina) women with 14,558 type II diabetes cases, 6,692 women developed breast cancer during 14.8 ± 4.1 years of follow-up. Type II diabetes was significantly associated with breast cancer risk (HR, 1.15; 95% CI, 1.07-1.23), but including body mass index (BMI) lowered the HR to 1.08 (95% CI, 1.00-1.16). Ethnic-specific BMI-adjusted models showed elevated risks for type II diabetes in Latinas only (HR, 1.30; 95% CI, 1.11-1.52). In contrast, obesity predicted statistically significant 21%-46% higher risks, after type II diabetes adjustment, in all ethnic groups except Latinas (HR, 1.17; 95% CI, 0.99-1.38). Conclusions: As reported previously, inclusion of BMI weakened the association of type II diabetes with breast cancer. Type II diabetes status, but not BMI, was primarily associated with higher breast cancer risk in Latinas. Impact: The role of obesity and type II diabetes in breast cancer etiology may differ by ethnicity suggesting metabolic differences related to obesity. [ABSTRACT FROM AUTHOR]