Barry I Graubard’s research while affiliated with National Cancer Institute (USA), National Institutes of Health and other places

In most countries, males have ~2–3 times higher incidence of primary liver cancer than females. Sex hormones have been hypothesized to contribute to these differences, but the evidence remains unclear. Using data from the UK Biobank, which included ~200,000 males and ~180,000 postmenopausal females who provided blood samples at recruitment, we estimated hazard ratios (HR2) and 95% confidence intervals (CI) for a doubling in hormone concentration from multivariable adjusted Cox regression for circulating total testosterone, sex‐hormone binding globulin (SHBG), and free testosterone concentrations and risk of primary liver cancer. After a median of 11.8 years of follow‐up, 531 cases of primary liver cancer were observed, of which 366 occurred in males and 165 occurred in females. Total testosterone and SHBG were shown to be positively associated with liver cancer risk in both males and females (Total testosterone HR2: 3.42, 95% CI:2.42–4.84 and 1.29, 0.97–1.72, respectively; SHBG HR2: 5.44, 4.42–6.68 and 1.52, 1.09–2.12, respectively). However, free testosterone was inversely associated with primary liver cancer in males (HR2: 0.42, 0.32–0.55) and no association was observed in females. When analyses compared two main liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), there was evidence of heterogeneity; associations for total testosterone and SHBG concentrations were only positively associated with HCC in both males (HR2: 3.56, 2.65–4.79 and 7.72, 6.12–9.73, respectively) and females (HR2: 1.65, 1.20–2.27 and 6.74, 3.93–11.5, respectively) but not with ICC. Further research understanding the mechanisms of how sex‐steroids may influence liver cancer risk is needed.

Importance The impact of dietary fat intake on long-term human health has attracted substantial research interest, and the health effects of diverse dietary fats depend on available food sources. Yet there is a paucity of data elucidating the links between dietary fats from specific food sources and health. Objective To study associations of dietary plant and animal fat intake with overall mortality and cardiovascular disease (CVD) mortality. Design, Setting, and Participants This large prospective cohort study took place in the US from 1995 to 2019. The analysis of men and women was conducted in the National Institutes of Health–AARP Diet and Health Study. Data were analyzed from February 2021 to May 2024. Exposures Specific food sources of dietary fats and other dietary information were collected at baseline, using a validated food frequency questionnaire. Main Outcomes and Measures Hazard ratios (HRs) and 24-year adjusted absolute risk differences (ARDs) were estimated using multivariable-adjusted Cox proportional hazards regression. Results The analysis included 407 531 men and women (231 881 [56.9%] male; the mean [SD] age of the cohort was 61.2 [5.4] years). During 8 107 711 person-years of follow-up, 185 111 deaths were ascertained, including 58 526 CVD deaths. After multivariable adjustment (including adjustment for the relevant food sources), a greater intake of plant fat (HRs, 0.91 and 0.86; adjusted ARDs, −1.10% and −0.73%; P for trend < .001), particularly fat from grains (HRs, 0.92 and 0.86; adjusted ARDs, −0.98% and −0.71%; P for trend < .001) and vegetable oils (HRs, 0.88 and 0.85; adjusted ARDs, −1.40% and −0.71%; P for trend < .001), was associated with a lower risk for overall and CVD mortality, respectively, comparing the highest to the lowest quintile. In contrast, a higher intake of total animal fat (HRs, 1.16 and 1.14; adjusted ARDs, 0.78% and 0.32%; P for trend < .001), dairy fat (HRs, 1.09 and 1.07; adjusted ARDs, 0.86% and 0.24%; P for trend < .001), or egg fat (HRs, 1.13 and 1.16; adjusted ARDs, 1.40% and 0.82%; P for trend < .001) was associated with an increased risk for mortality for overall and CVD mortality, respectively, comparing the highest to the lowest quintile. Replacement of 5% energy from animal fat with 5% energy from plant fat, particularly fat from grains or vegetable oils, was associated with a lower risk for mortality: 4% to 24% reduction in overall mortality, and 5% to 30% reduction in CVD mortality. Conclusions and Relevance The findings from this prospective cohort study demonstrated consistent but small inverse associations between a higher intake of plant fat, particularly fat from grains and vegetable oils, and a lower risk for both overall and CVD mortality. A diet with a high intake of animal-based fat, including fat from dairy foods and eggs, was also shown to be associated with an elevated risk for both overall and CVD mortality.

Purpose. There is clear evidence that deleterious germline variants in CHEK2 increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk in CHEK2 germline pathogenic variant heterozygotes. Patients and Methods. Germline CHEK2 variants were extracted from two exome-sequenced biobanks linked to the electronic health record: UK Biobank (n= 469,765) and Geisinger MyCode (n=170,503). Variants were classified as per American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) criteria. Heterozygotes harbored a CHEK2 pathogenic/likely pathogenic (P/LP) variant; controls harbored benign/likely benign CHEK2 variation or wildtype CHEK2. Tumor phenotype and demographic data were retrieved; to adjust for relatedness, association analysis was performed with SAIGE-GENE+ with Bonferroni correction. Results. In CHEK2 heterozygotes in both MyCode and UK Biobank, there was a significant excess risk of all cancers tested, including breast cancer (C50; OR=1.54 and 1.84, respectively), male genital organ cancer (C60-C63; OR=1.61 and 1.77 respectively), urinary tract cancer (C64-C68; OR=1.56 and 1.75, respectively) and lymphoid, hematopoietic, and related tissue cancer (C81-C96; OR=1.42 and 2.11, respectively). Compared to controls, age-dependent cancer penetrance in CHEK2 heterozygotes was significantly younger in both cohorts; no significant difference was observed between the penetrance of truncating and missense variants for cancer in either cohort. Overall survival was significantly decreased in CHEK2 heterozygotes in UK Biobank but there was no statistical difference in MyCode. Conclusion. Using genomic ascertainment in two population-scale cohorts, this investigation quantified the prevalence, penetrance, cancer phenotype and survival in CHEK2 heterozygotes. Tailored treatment options and surveillance strategies to manage those risks are warranted.

Background Although the relation between statin use and liver cancer risk has been extensively examined, few studies have examined other cholesterol‐lowering medications in relation to liver cancer risk. The authors examined five classes of nonstatin medications and liver cancer risk. Methods A nested case–control including 3719 cases and 14,876 matched controls was conducted within the Clinical Practice Research Datalink. Additional matches on type 2 diabetes and chronic liver disease were also implemented. The medications examined included cholesterol absorption inhibitors, bile acid sequestrants, fibrates, niacin, and omega‐3 fatty acids. Conditional logistic regression estimated odds ratios and 95% confidence intervals. Results Cholesterol absorption inhibitor use was associated with reduced liver cancer risk in the overall analysis (odds ratio, 0.69; 95% confidence interval, 0.50–0.96) and in analyses based on type 2 diabetes and chronic liver disease status. Although bile acid sequestrant use was associated with increased liver cancer risk in the overall analysis (odds ratio, 5.31; 95% confidence interval, 3.53–7.97), the results of the analyses based on type 2 diabetes and chronic liver disease status were inconsistent. [Correction added on 19 August 2024, after first online publication: In the preceding sentence, the value ‘3.534’ has been changed to ‘3.54’.]. No associations were observed for the other medications. Conclusions Cholesterol absorption inhibitors may be associated with reduced liver cancer risk. Whether bile acid sequestrant use was associated with increased risk was only partially supported in the current study.

Accurate cancer risk estimation is crucial to clinical decision-making, such as identifying high-risk people for screening. However, most existing cancer risk models incorporate data from epidemiologic studies, which usually cannot represent the target population. While population-based health surveys are ideal for making inference to the target population, they typically do not collect time-to-cancer incidence data. Instead, time-to-cancer specific mortality is often readily available on surveys via linkage to vital statistics. We develop calibrated pseudoweighting methods that integrate individual-level data from a cohort and a survey, and summary statistics of cancer incidence from national cancer registries. By leveraging individual-level cancer mortality data in the survey, the proposed methods impute time-to-cancer incidence for survey sample individuals and use survey calibration with auxiliary variables of influence functions generated from Cox regression to improve robustness and efficiency of the inverse-propensity pseudoweighting method in estimating pure risks. We develop a lung cancer incidence pure risk model from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial using our proposed methods by integrating data from the National Health Interview Survey and cancer registries.

In cohort studies, it can be infeasible to collect specimens on an entire cohort. For example, to estimate sensitivity of multiple Multi-Cancer Detection (MCD) assays, we desire an extra 80mL of cell-free DNA (cfDNA) blood, but this much extra blood is too expensive for us to collect on everyone. We propose a novel epidemiologic study design that efficiently oversamples those at highest baseline disease risk from whom to collect specimens, to increase the number of future cases with cfDNA blood collection. The variance reduction ratio from our risk-based subsample versus a simple random (sub)sample (SRS) depends primarily on the ratio of risk model sensitivity to the fraction of the cohort selected for specimen collection subject to constraining the risk model specificity. In a simulation where we chose 34% of Prostate, Lung, Colorectal, and Ovarian Screening Trial cohort at highest risk of lung cancer for cfDNA blood collection, we could enrich the number of lung cancers 2.42-fold and the standard deviation of lung-cancer MCD sensitivity was 31-33% reduced versus SRS. Risk-based collection of specimens on a subsample of the cohort could be a feasible and efficient approach to collecting extra specimens for molecular epidemiology.