Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at ...increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations.
We obtained data from the Colon Cancer Family Registry for a cohort of 127 women who had a diagnosis of endometrial cancer and who carried a mutation in one of four MMR genes (30 carried a mutation in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2). We used the Kaplan-Meier method to estimate 10- and 20-year cumulative risks for each cancer. We estimated the age-, country-, and calendar period-specific standardized incidence ratios (SIRs) for each cancer, compared with the general population.
Following endometrial cancer, women carrying MMR gene mutations had the following 20-year risks of other cancer cancers: colorectal cancer (48%, 95% confidence interval CI = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%). Compared with the general population, these women were at statistically significantly elevated risks of colorectal cancer (SIR = 39.9, 95% CI = 27.2 to 58.3), cancer of the kidney, renal pelvis, or ureter (SIR = 28.3, 95% CI = 11.9 to 48.6), urinary bladder cancer (SIR = 24.3, 95% CI = 8.56 to 42.9), and breast cancer (SIR = 2.51, 95% CI = 1.17 to 4.14).
Women with Lynch syndrome who are diagnosed with endometrial cancer have increased risks of several cancers, including breast cancer.
The Healthy Eating Index-2015 (HEI-2015) was created to assess conformance of dietary intake with the Dietary Guidelines for Americans (DGA) 2015-2020. We assessed the association between the ...HEI-2015 and mortality from all-cause, cardiovascular disease (CVD), and cancer in the Multiethnic Cohort (MEC). White, African American, Native Hawaiian, Japanese American, and Latino adults (
> 215,000) from Hawaii and California completed a quantitative food-frequency questionnaire at study enrollment. HEI-2015 scores were divided into quintiles for men and women. Radar graphs were used to demonstrate how dietary components contributed to HEI-2015 scores. Mortality was documented over 17-22 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox proportional hazards models. High HEI-2015 scores were inversely associated with risk of mortality from all-cause, CVD, and cancer for men and women (
-trend <0.0001 for all models). For men, the HRs (CIs) for all-cause, CVD, and cancer comparing the highest to the lowest quintile were 0.79 (0.76, 0.82), 0.76 (0.71, 0.82), and 0.80 (0.75, 0.87), respectively. For women, the HRs were 0.79 (0.76, 0.82), 0.75 (0.70, 0.81), and 0.84 (0.78, 0.91), respectively. These results, in a multiethnic population, demonstrate that following a diet aligned with the DGAs 2015-2020 recommendations is associated with lower risk of mortality from all-cause, CVD, and cancer.
Diabetes is an emerging risk factor for hepatocellular carcinoma (HCC), but prospective data from different ethnic populations are scarce. We examined the association between diabetes and HCC in ...168679 African Americans, Native Hawaiians, Japanese Americans, Latinos and whites in the Multiethnic Cohort.
During a 15.7-year follow up period, 470 incident HCC cases were identified. Risk factor data were obtained from the baseline questionnaire. Cox regressions were used to calculate hazard rate ratios (RRs) and 95% confidence intervals (CIs) for HCC associated with self-reported diabetes. The population attributable risk percent associated with diabetes was also calculated. All statistical tests were two-sided.
The RRs for developing HCC (vs whites) were 2.73 (95% CI = 2.00 to 3.72) for Latinos, 2.48 (95% CI = 1.59 to 3.87) for Hawaiians, 2.16 (95% CI = 1.52 to 3.07) for African Americans, and 2.05 (95% CI = 1.50 to 2.81) for Japanese. Diabetes was associated with HCC across ethnic groups (RRLatinos = 3.36 95% CI = 2.41 to 4.70, RRHawaiians = 2.50 95% CI = 1.11 to 5.64, RRJapanese = 2.34 95% CI = 1.60 to 3.41, RRwhites = 2.15 95% CI = 0.95 to 4.90, and RRAfrican Americans = 2.02 95% CI = 1.17 to 3.48). We estimated that 27% of HCC cases in Latinos, 18% in Hawaiians, 13% in African Americans, 12% in Japanese, and 6% in whites were attributed to diabetes.
Latinos were at the highest risk of developing HCC, followed by Native Hawaiians, African Americans, Japanese and whites. Diabetes is a risk factor for HCC in all ethnic groups, and eliminating diabetes could potentially reduce HCC incidence in all ethnic groups, with the largest potential for reduction in Latinos.
Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom ...the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR > 1 corresponds to higher risks for maternal mutations. For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75–1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81–1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52–1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Therefore, despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we do not recommend that POEs be incorporated into the clinical guidelines or advice for such carriers.
The lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these ...differences, as disparities in risk may be related to differences in nicotine dose and metabolism.
We conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans, and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined.
Among 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (P < 5×10(-8)). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (P = 1.60 × 10(-155)). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explains 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, P = 2.56 × 10(-43)) was in high LD (r(2) = 0.99) with rs115765562.
Genetic variation in UGT2B10 contributes significantly to nicotine and cotinine glucuronidation but not to nicotine dose.
The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk.
Abstract
Whether women are more susceptible than men to smoking-related lung cancer has been a topic of controversy. To address this question, we compared risks of lung cancer associated with smoking ...by sex. Altogether, 585,583 participants from 3 Norwegian cohorts (Norwegian Counties Study, 40 Years Study, and Cohort of Norway (CONOR) Study) were followed until December 31, 2013, through linkage of data to national registries. We used Cox proportional hazards models and 95% confidence intervals to estimate risks. During nearly 12 million person-years of follow-up, 6,534 participants (43% women) were diagnosed with lung cancer. More men than women were heavier smokers. Compared with never smokers, male and female current smokers with ≥16 pack-years of smoking had hazard ratios for lung cancer of 27.24 (95% confidence interval (CI): 22.42, 33.09) and 23.90 (95% CI: 20.57, 27.76), respectively (P for heterogeneity = 0.30). In contrast, for current smokers, in a model with pack-years measured continuously, men had a hazard ratio of 1.43 (95% CI: 1.39, 1.48) and women a hazard ratio of 1.64 (95% CI: 1.57, 1.71) for each 10–pack-year increment of smoking (P for heterogeneity < 0.01). Our results suggest that women have an increased susceptibility to lung cancer compared with men, given the same lifetime smoking exposure.
Introduction: Both smoking and alcohol consumption have been associated with modestly increased risks of colorectal cancer
(CRC). Reports have suggested that these associations may differ by tumor ...molecular subtype, with stronger associations for
microsatellite unstable (MSI-H) tumors.
Methods: We used a population-based case-unaffected sibling design including 2,248 sibships (2,253 cases; 4,486 siblings)
recruited to the Colon Cancer Family Registry to evaluate the association between smoking, alcohol consumption, and CRC. Associations
were assessed using conditional logistic regression, treating sibship as the matching factor.
Results: Although there were no statistically significant associations between any smoking variable and CRC overall, smoking
did confer an increased risk of certain types of CRC. We observed an association between pack-years of smoking and rectal
cancer odds ratio (OR), 1.85; 95% confidence interval (CI), 1.23-2.79 for >40 pack-years versus nonsmokers; P trend = 0.03, and there was an increased risk of MSI-H CRC with increasing duration of smoking (OR, 1.94; 95% CI, 1.09-3.46 for
>30 years of smoking versus nonsmokers). Alcohol intake was associated with a modest increase in risk for CRC overall (OR,
1.21; 95% CI, 1.03-1.44 for 12+ drinks per week versus nondrinkers), with more marked increases in risk for MSI-L CRC (OR,
1.85; 95% CI, 1.06-3.24) and rectal cancer (OR, 1.48; 95% CI, 1.08-2.02).
Conclusions: We found associations between cigarette smoking and increased risks of rectal cancer and MSI-H CRC. Alcohol intake
was associated with increased risks of rectal cancer and MSI-L CRC. These results highlight the importance of considering
tumor phenotype in studies of risk factors for CRC. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2745–50)
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.
Abstract
In studies of anthropometric measures and prostate cancer risk, conducted primarily in White men, positive associations with advanced disease have been reported. We assessed body size in ...relation to incident prostate cancer risk in 79,950 men from the Multiethnic Cohort, with 8,819 cases identified over 22 years (1993–2015). Height was associated with increased risk of advanced prostate cancer (≥68 inches (≥ 173 cm) vs. < 66 inches (168 cm); hazard ratio (HR) = 1.24, 95% confidence interval (CI): 1.04, 1.48) and high-grade disease (HR = 1.15, 95% CI: 1.02, 1.31). Compared with men of normal weight, men overweight at baseline were at higher risk of high-grade cancer (HR = 1.15, 95% CI: 1.04, 1.26). Greater weight was positively associated with localized and low-grade disease in Blacks and Native Hawaiians (by race, P for heterogeneity = 0.0002 and 0.008, respectively). Weight change since age 21 years was positively associated with high-grade disease (for ≥ 40 pounds (18 kg) vs. 10 pounds (4.5 kg), HR = 1.20, 95% CI: 1.05, 1.37; P for trend = 0.005). Comparing highest versus lowest quartile, waist-to-hip ratio was associated with a 1.78-fold increase (95% CI: 1.28, 2.46) in the risk of advanced prostate cancer. Positive associations with the majority of anthropometric measures were observed in all 5 racial/ethnic groups, suggesting a general impact of anthropometric measures on risk across populations.
To assess whether plasma neurofilament light chain (NfL) levels are elevated before amyotrophic lateral sclerosis (ALS) diagnosis and to evaluate whether prediagnostic NfL levels are associated with ...metabolic alterations.
We conducted a matched case-control study nested in 3 large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study) and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels.
Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 SD increase 2.68, 95% CI 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI 0.78-1.73). A total of 21 metabolites were correlated with prediagnostic NfL levels in ALS cases (
< 0.05), but none of these remained significant after multiple comparison adjustments.
Plasma NfL levels were elevated in prediagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease.
This study provides Class II evidence that plasma NfL levels are elevated in prediagnostic ALS.
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