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Background: We examined whether the association between alcohol consumption and colorectal cancer (CRC) incidence was stronger for tumors with higher contributions of defective mismatch repair (dMMR)-related tumor mutational signatures., Methods: We used data from 227 916 men and women who participated in the Nurses' Health Study (1980-2016), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 4 years through validated food frequency questionnaires. Relative contributions of 2 defective mismatch repair-related tumor mutational signatures with single-based substitutions (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC patients. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the tumor mutational signatures. All statistical tests were 2-sided., Results: We documented 825 incident CRC patients with available tumor mutational signature data over 26 to 36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (Ptrend = .02 for heterogeneity) compared with tumors with lower contributions of this tumor mutational signature. Compared with nondrinkers, drinkers who imbibed 15 g/d or more of alcohol had a high risk of c-dMMRb/SBS26-high CRC (multivariable-adjusted hazard ratio = 2.43, 95% confidence interval = 1.55 to 3.82) but not c-dMMRb/SBS26-low CRC (multivariable-adjusted hazard ratio = 0.86, 95% confidence interval = 0.57 to 1.28) or c-dMMRb/SBS26-moderate CRC (multivariable-adjusted hazard ratio = 1.14, 95% confidence interval = 0.76 to 1.71). No significant differential associations were observed for c-dMMRa/SBS15 (Ptrend = .41 for heterogeneity)., Conclusions: High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

Background: To date, few epidemiologic studies have been conducted to elucidate lifestyle-related risk factors for multiple myeloma in Asia. We investigated the association of body mass index (BMI), smoking, and alcohol intake with the risk of multiple myeloma mortality through a pooled analysis of more than 800,000 participants in the Asia Cohort Consortium., Methods: The analysis included 805,309 participants contributing 10,221,623 person-years of accumulated follow-up across Asia Cohort Consortium cohorts. HRs and 95% confidence intervals (95% CI) for the association between BMI, smoking, and alcohol at baseline and the risk of multiple myeloma mortality were assessed using a Cox proportional hazards model with shared frailty., Results: We observed a statistically significant dose-dependent association between BMI categories and the risk of multiple myeloma mortality (<18.5 kg/m 2 : HR = 0.80, 95% CI: 0.52-1.24; 18.5-24.9 kg/m 2 : reference; 25.0-29.9 kg/m 2 : HR = 1.17, 95% CI: 0.94-1.47; ≥30 kg/m 2 : HR = 1.61, 95% CI: 0.99-2.64, P trend = 0.014). By sex, this association was more apparent in women than in men (P for heterogeneity between sexes = 0.150). We observed no significant associations between smoking or alcohol consumption and risk of multiple myeloma mortality., Conclusions: This study showed that excess body mass is associated with an increased risk of multiple myeloma mortality among Asian populations. In contrast, our results do not support an association between smoking or alcohol consumption and the risk of multiple myeloma mortality in Asian populations., Impact: This study provides important evidence on the association of BMI, smoking, and alcohol with the risk of multiple myeloma mortality in Asian populations., (©2019 American Association for Cancer Research.) more...

The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.) more...

Smoking and alcohol are important modifiable risk factors for human cancers. However, few epidemiological studies have investigated their association with the risk of myelodysplastic syndromes (MDS). Here, we investigated the association of smoking and alcohol consumption and the risk of MDS in a large-scale population-based cohort study in Japan. We included 95 510 Japanese subjects (45 451 men and 50 059 women; age 40-69 years at baseline) and identified 70 MDS cases (50 men and 20 women) during 18·3 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox regression model adjusted for potential confounders. Smoking was marginally associated with an increased risk of MDS among men, with a HR for current smokers relative to never smokers of 2·11 (95% CI: 0·91-4·89). In contrast, alcohol consumption was associated with a dose-dependent decrease in the risk of MDS among men (nondrinkers: reference, occasional drinkers: HR = 0·48, 0·16-1·41; 0-299 g/week: HR = 0·37, 0·19-0·73; ≥300 g/week: HR = 0·49, 0·22-1·08, P for trend = 0·010). This study showed that alcohol has a significant protective effect on the risk of MDS. In addition, this study might indicate that smoking increases the risk of MDS among Japanese population, as it does in Western populations., (© 2017 John Wiley & Sons Ltd.) more...

Background We examined whether the association between alcohol consumption and colorectal cancer (CRC) incidence was stronger for tumors with higher contributions of defective mismatch repair (dMMR)–related tumor mutational signatures. Methods We used data from 227 916 men and women who participated in the Nurses' Health Study (1980-2016), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 4 years through validated food frequency questionnaires. Relative contributions of 2 defective mismatch repair–related tumor mutational signatures with single-based substitutions (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC patients. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the tumor mutational signatures. All statistical tests were 2-sided. Results We documented 825 incident CRC patients with available tumor mutational signature data over 26 to 36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (P trend = .02 for heterogeneity) compared with tumors with lower contributions of this tumor mutational signature. Compared with nondrinkers, drinkers who imbibed 15 g/d or more of alcohol had a high risk of c-dMMRb/SBS26-high CRC (multivariable-adjusted hazard ratio = 2.43, 95% confidence interval = 1.55 to 3.82) but not c-dMMRb/SBS26-low CRC (multivariable-adjusted hazard ratio = 0.86, 95% confidence interval = 0.57 to 1.28) or c-dMMRb/SBS26-moderate CRC (multivariable-adjusted hazard ratio = 1.14, 95% confidence interval = 0.76 to 1.71). No significant differential associations were observed for c-dMMRa/SBS15 (P trend = .41 for heterogeneity). Conclusions High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway. [ABSTRACT FROM AUTHOR] more...

Simple Summary: This paper presents an extended version of the Cox regression model to examine heterogeneous effects of risk factors on disease subtypes defined by a continuous biomarker. This approach can be easily applied to cancer studies and is accessible to researchers via user-friendly R scripts. Molecular pathologic diagnosis is important in clinical (oncology) practice. Integration of molecular pathology into epidemiological methods (i.e., molecular pathological epidemiology) allows for investigating the distinct etiology of disease subtypes based on biomarker analyses, thereby contributing to precision medicine and prevention. However, existing approaches for investigating etiological heterogeneity deal with categorical subtypes. We aimed to fully leverage continuous measures available in most biomarker readouts (gene/protein expression levels, signaling pathway activation, immune cell counts, microbiome/microbial abundance in tumor microenvironment, etc.). We present a cause-specific Cox proportional hazards regression model for evaluating how the exposure–disease subtype association changes across continuous subtyping biomarker levels. Utilizing two longitudinal observational prospective cohort studies, we investigated how the association of alcohol intake (a risk factor) with colorectal cancer incidence differed across the continuous values of tumor epigenetic DNA methylation at long interspersed nucleotide element-1 (LINE-1). The heterogeneous alcohol effect was modeled using different functions of the LINE-1 marker to demonstrate the method's flexibility. This real-world proof-of-principle computational application demonstrates how the new method enables visualizing the trend of the exposure effect over continuous marker levels. The utilization of continuous biomarker data without categorization for investigating etiological heterogeneity can advance our understanding of biological and pathogenic mechanisms. [ABSTRACT FROM AUTHOR] more...

Background: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case‐control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. Methods: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene‐environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. Results: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03–1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)‐positive BC (OR = 1.19, 95% CI 1.05–1.36, p = 0.008), progesterone receptor (PR)‐positive BC (OR = 1.19, 95% CI 1.03–1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)‐negative BC (OR = 1.25, 95% CI 1.05–1.48, p = 0.012). No evidence of a gene‐environment interaction was observed between rs671 and alcohol intake (p = 0.537). Conclusion: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER‐positive, PR‐positive, and HER2‐negative tumor types. [ABSTRACT FROM AUTHOR] more...