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High alcohol intake and breast density increase breast cancer (BC) risk, but their interrelationship is unknown. We examined whether volumetric density modifies and/or mediates the alcohol-BC association. BC cases (n = 2233) diagnosed from 2006 to 2013 in the San Francisco Bay area had screening mammograms 6 or more months before diagnosis; controls (n = 4562) were matched on age, mammogram date, race or ethnicity, facility, and mammography machine. Logistic regression was used to estimate alcohol-BC associations adjusted for age, body mass index, and menopause; interaction terms assessed modification. Percent mediation was quantified as the ratio of log (odds ratios [ORs]) from models with and without density measures. Alcohol consumption was associated with increased BC risk (2-sided P trend  = .004), as were volumetric percent density (OR = 1.45 per SD, 95% confidence interval [CI] = 1.36 to 1.56) and dense volume (OR = 1.30, 95% CI = 1.24 to 1.37). Breast density did not modify the alcohol-BC association (2-sided P  > .10 for all). Dense volume mediated 25.0% (95% CI = 5.5% to 44.4%) of the alcohol-BC association (2-sided P  = .01), suggesting alcohol may partially increase BC risk by increasing fibroglandular tissue., (© The Author(s) 2021. Published by Oxford University Press.)

We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Marginal zone lymphoma (MZL), comprised of nodal, extranodal, and splenic subtypes, accounts for 5%-10% of non-Hodgkin lymphoma cases. A detailed evaluation of the independent effects of risk factors for MZL and its subtypes has not been conducted., Methods: Data were pooled from 1052 MZL cases (extranodal [EMZL] = 633, nodal [NMZL] = 157, splenic [SMZL] = 140) and 13766 controls from 12 case-control studies. Adjusted unconditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Novel findings for MZL subtypes include increased risk for B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14), hepatitis C virus seropositivity (EMZL OR = 5.29, 95% CI = 2.48 to 11.28), self-reported peptic ulcers (EMZL OR = 1.83, 95% CI = 1.35 to 2.49), asthma without other atopy (SMZL OR = 2.28, 95% CI = 1.23 to 4.23), family history of hematologic cancer (EMZL OR = 1.90, 95% CI = 1.37 to 2.62) and of non-Hodgkin lymphoma (NMZL OR = 2.82, 95% CI = 1.33 to 5.98), permanent hairdye use (SMZL OR = 6.59, 95% CI = 1.54 to 28.17), and occupation as a metalworker (NMZL OR = 3.56, 95% CI = 1.67 to 7.58). Reduced risks were observed with consumption of any alcohol (EMZL fourth quartile OR = 0.48, 95% CI = 0.28 to 0.82) and lower consumption of wine (NMZL first to third quartile ORs < 0.45) compared with nondrinkers, and occupation as a teacher (EMZL OR = 0.58, 95% CI = 0.37 to 0.88)., Conclusion: Our results provide new data suggesting etiologic heterogeneity across MZL subtypes although a common risk of MZL associated with B-cell activating autoimmune conditions was found., (Published by Oxford University Press 2014.)

Background: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are two subtypes of non-Hodgkin lymphoma. A number of studies have evaluated associations between risk factors and CLL/SLL risk. However, these associations remain inconsistent or lacked confirmation. This may be due, in part, to the inadequate sample size of CLL/SLL cases., Methods: We performed a pooled analysis of 2440 CLL/SLL cases and 15186 controls from 13 case-control studies from Europe, North America, and Australia. We evaluated associations of medical history, family history, lifestyle, and occupational risk factors with CLL/SLL risk. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: We confirmed prior inverse associations with any atopic condition and recreational sun exposure. We also confirmed prior elevated associations with usual adult height, hepatitis C virus seropositivity, living or working on a farm, and family history of any hematological malignancy. Novel associations were identified with hairdresser occupation (OR = 1.77, 95% CI = 1.05 to 2.98) and blood transfusion history (OR = 0.79, 95% CI = 0.66 to 0.94). We also found smoking to have modest protective effect (OR = 0.9, 95% CI = 0.81 to 0.99). All exposures showed evidence of independent effects., Conclusions: We have identified or confirmed several independent risk factors for CLL/SLL supporting a role for genetics (through family history), immune function (through allergy and sun), infection (through hepatitis C virus), and height, and other pathways of immune response. Given that CLL/SLL has more than 30 susceptibility loci identified to date, studies evaluating the interaction among genetic and nongenetic factors are warranted., (Published by Oxford University Press 2014.)

Background: Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design., Methods: We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control., Results: The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes., Conclusions: The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology., (Published by Oxford University Press 2014.)

Background: Little is known about the etiology of hairy cell leukemia (HCL), a rare B-cell lymphoproliferative disorder with marked male predominance. Our aim was to identify key risk factors for HCL., Methods: A pooled analysis of individual-level data for 154 histologically confirmed HCL cases and 8834 controls from five case-control studies, conducted in Europe and Australia, was undertaken. Age-, race and/or ethnicity-, sex-, and study-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression., Results: The usual patterns for age and sex in HCL were observed, with a median age of 55 years and sex ratio of 3.7 males to females. Cigarette smoking was inversely associated with HCL (OR = 0.51, 95% CI = 0.37 to 0.71) with dose-response relationships observed for duration, frequency, and lifetime cigarette smoking (P(trend) < .001). In contrast, occupation as a farmer was positively associated with HCL (OR = 2.34, 95% CI = 1.36 to 4.01), with a dose-response relationship observed for duration (OR = 1.82, 95% CI = 0.85 to 3.88 for ≤ 10 years vs never; and OR = 2.98, 95% CI = 1.50 to 5.93 for >10 years vs never; P(trend) = .025). Adult height was also positively associated with HCL (OR = 2.69, 95% CI = 1.39 to 5.29 for upper vs lower quartile of height). The observed associations remained consistent in multivariate analysis., Conclusions: Our observations of an increased risk of HCL from farming exposures and decreased risk from smoking exposures, independent of one another, support a multifactorial origin and an etiological specificity of HCL compared with other non-Hodgkin lymphoma subtypes. The positive association with height is a novel finding that needs replication., (Published by Oxford University Press 2014.)