Mary K. Downer

Dietary Intake, FTO genetic variants, and adiposity: A combined analysis of over 16,000 children and adolescents

The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1–18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 × 10−4), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 × 10−4): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 × 10−10) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents.

Dairy intake in relation to prostate cancer survival

Dairy intake has been associated with increased risk of advanced prostate cancer. Two US cohort studies reported increased prostate cancer‐specific mortality with increased high‐fat milk intake. We examined whether dairy and related nutrient intake were associated with prostate cancer progression in a Swedish patient population with high dairy consumption. We prospectively followed 525 men with newly diagnosed prostate cancer (diagnosed 1989–1994). We identified and confirmed deaths through February 2011 (n = 222 prostate cancer‐specific, n = 268 from other causes). Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between food or nutrient intake and prostate cancer‐specific death. On average, patients consumed 5.0 servings/day of total dairy products at diagnosis. In the whole population, high‐fat milk intake was not associated with prostate cancer‐specific death (95% CI: 0.78, 2.10; p‐trend = 0.32; multivariate‐adjusted model). However, among patients diagnosed with localized prostate cancer, compared to men who consumed <1 servings/day of high‐fat milk, those who drank ≥3 servings/day had an increased hazard of prostate cancer mortality (HR = 6.10; 95% CI: 2.14, 17.37; p‐trend = 0.004; multivariate‐adjusted model). Low‐fat milk intake was associated with a borderline reduction in prostate cancer death among patients with localized prostate cancer. These associations were not observed among patients diagnosed with advanced stage prostate cancer. Our data suggest a positive association between high‐fat milk intake and prostate cancer progression among patients diagnosed with localized prostate cancer. Further studies are warranted to investigate this association and elucidate the mechanisms by which high‐fat milk intake may promote prostate cancer progression.

Mercury exposure and risk of cardiovascular disease: a nested case-control study in the PREDIMED (PREvention with MEDiterranean Diet) study

BackgroundSubstantial evidence suggests that consuming 1–2 servings of fish per week, particularly oily fish (e.g., salmon, herring, sardines) is beneficial for cardiovascular health due to its high n-3 polyunsaturated fatty acid content. However, there is some concern that the mercury content in fish may increase cardiovascular disease risk, but this relationship remains unclear.MethodsThe PREDIMED trial included 7477 participants who were at high risk for cardiovascular disease at baseline. In this study, we evaluated associations between mercury exposure, fish consumption and cardiovascular disease. We randomly selected 147 of the 288 cases diagnosed with cardiovascular disease during follow-up and matched them on age and sex to 267 controls. Instrumental neutron activation analysis was used to assess toenail mercury concentration. In-person interviews, medical record reviews and validated questionnaires were used to assess fish consumption and other covariates. Information was collected at baseline and updated yearly during follow-up. We used conditional logistic regression to evaluate associations in the total nested case-control study, and unconditional logistic regression for population subsets.ResultsMean (±SD) toenail mercury concentrations (μg per gram) did not significantly differ between cases (0.63 (±0.53)) and controls (0.67 (±0.49)). Mercury concentration was not associated with cardiovascular disease in any analysis, and neither was fish consumption or n-3 fatty acids. The fully-adjusted relative risks for the highest versus lowest quartile of mercury concentration were 0.71 (95% Confidence Interval [CI], 0.34, 1.14; ptrend = 0.37) for the nested case-control study, 0.74 (95% CI, 0.32, 1.76; ptrend = 0.43) within the Mediterranean diet intervention group, and 0.50 (95% CI, 0.13, 1.96; ptrend = 0.41) within the control arm of the trial. Associations remained null when mercury was jointly assessed with fish consumption at baseline and during follow-up. Results were similar in different sensitivity analyses.ConclusionsWe found no evidence that mercury exposure from regular fish consumption increases cardiovascular disease risk in a population of Spanish adults with high cardiovascular disease risk and high fish consumption. This implies that the mercury content in fish does not detract from the already established cardiovascular benefits of fish consumption.Trial registrationISRCTN35739639.

Change in Alcohol Intake in Relation to Weight Change in a Cohort of US Men with 24 Years of Follow‐Up

The aim of this study was to prospectively investigate the potential effects of alcohol by subtype on reported long‐term weight change.

Chapter 8 – More Fish, Less Meat

Epidemiological evidence suggesting a protective effect of fish intake on cardiovascular disease dates back to ecological studies from the 1970s. Since then, it has become clear that the specific nutritional composition of fish, namely, its high levels of two long-chain omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), confer strong cardiovascular benefits. Intermediary physiological benefits of fish intake via EPA and DHA include lowering plasma triglycerides, reducing heart rate and blood pressure, improving myocardial filling and efficiency, decreasing inflammation, and antiarrhythmic effects. Prospective observational studies and randomized controlled trials have consistently found that fish intake is associated not only with these intermediary benefits but with major reductions in several cardiovascular disease outcomes, most notably coronary heart disease mortality. Conversely, meat intake is associated with increased risk of cardiovascular disease, likely due to its high saturated fat content (palmitic acid, stearic acid), which has been shown to raise LDL cholesterol, which in turn increases risk of cardiovascular disease. In addition to discussing evidence and mechanisms related to fish and meat intake and cardiovascular disease, this chapter also discusses concerns regarding mercury contamination related to fish consumption and cardiovascular disease.

Abstract A015: Molecular tumor profiling to identify mechanisms linking statin use with lower risk of lethal prostate cancer: Results from the Health Professionals Follow-up Study

Introduction: Epidemiologic data support an inverse association between statin use and risk of lethal prostate cancer, but contributing mechanisms have not been elucidated. Herein, using data from the Health Professionals Follow-up Study (HPFS), we updated our previous analysis of statins and lethal prostate cancer with a decade of additional follow-up, and incorporated immunohistochemistry (IHC)-based biomarkers and gene expression profiling to identify putative molecular mechanisms contributing to the association. Methods: We included data from 44,076 HPFS participants who were cancer free in 1990, with follow-up through 2012. Participants reported prediagnostic statin use on biennial questionnaires. Statin use was categorized as current vs. never/past use, with current users further categorized as long-term vs. short-term users (≥6 vs. Results: During 22 years of follow-up, 6,144 men were diagnosed with prostate cancer; 1,051 (17%) had advanced disease and 827 (13%) developed lethal prostate cancer. Of cases with molecular subtype available, 48% were ERG-positive and 14% PTEN-null. In multivariable analysis, relative to never/past use, current statin use was inversely associated with risk of advanced (HR 0.84; 95% CI 0.68-1.04) and lethal (HR 0.78; 95% CI 0.68-1.01) prostate cancer. These associations were more pronounced in long-term users, where ≥6 years of prediagnosis statin use was significantly associated with a lower risk of advanced (HR 0.72; 95% CI 0.53-0.97) and lethal prostate cancer (HR 0.64; 95% CI 0.45-0.92), relative to nonuse. Long-term statin use was not associated with overall prostate cancer risk, whether ERG-positive (HR 0.89; 95% CI 0.59-1.35) or ERG-negative (HR 1.06; 95% CI 0.74-1.50). However, relative to nonuse, a longer duration of prediagnosis statin use was associated with reduced risk of PTEN-null cancers (HR 0.42; 95% CI 0.20-0.90), but not PTEN-intact disease (HR 1.18; 95% CI 0.95-1.46; p-heterogeneity=0.01). In GSEA, we identified T cell, B cell, and phosphatidylinositol (PI3K) signaling among the top pathways enriched in tumor-adjacent normal prostate tissue of current statin users, relative to never users. Intriguingly, no gene sets were differentially expressed by statin use in the tumor. Discussion: Our updated findings from the HPFS are consistent with our prior findings and other epidemiologic data supporting a role for statins in lethal prostate cancer prevention. Molecular classification of tumors identified PTEN/PI3K signaling and inflammation/immune activation as two potential mechanisms contributing to this association. Elucidating molecular mechanisms mediating the association between statin use and lower risk of lethal prostate cancer will provide support for a causal effect of statins on lethal prostate cancer risk and could inform statin clinical trials with appropriate intermediate endpoints. Citation Format: Emma H. Allott, Ericka M. Ebot, Amparo G. Gonzalez-Feliciano, Sarah C. Markt, Kathryn M. Wilson, Thomas U. Ahearn, Travis A. Gerke, Mary K. Downer, Konrad H. Stopsack, Jennifer R. Rider, Stephen J. Freedland, Elizabeth A. Platz, Meir J. Stampfer, Edward L. Giovannucci, Christopher J. Sweeney, Stephen P. Finn, Lorelei A. Mucci. Molecular tumor profiling to identify mechanisms linking statin use with lower risk of lethal prostate cancer: Results from the Health Professionals Follow-up Study [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A015.

A prospective study of aspirin use and prostate cancer risk by TMPRSS2:ERG status

Background: In a case–control study, aspirin use was associated with a lower risk of a common prostate cancer molecular subtype, the TMPRSS2:ERG gene fusion. We sought to validate this finding in a prospective cohort. Methods: In the Health Professionals Follow-up Study, 49,395 men reported on aspirin use on biennial questionnaires and were followed for prostate cancer incidence over 23 years. TMPRSS2:ERG status was assessed by IHC for presence of ERG on archival tumor specimens for 912 patients with prostate cancer, of whom 48% were ERG-positive. Results: In multivariable models, we found no association between regular use of aspirin and risk of ERG-positive prostate cancer (HR, 1.02; 95% confidence interval, 0.85–1.23), nor any association with duration or frequency of aspirin use. In restricting to cases with either high Gleason grade or advanced stage disease, there remained no association with aspirin use. Conclusions: Data from this prospective study with repeated assessments of aspirin use do not support the hypothesis that aspirin use is associated with a lower risk of ERG-positive prostate cancer. Impact: Aspirin use is unlikely to lower the risk of this common molecular subtype of prostate cancer. However, there is emerging data supporting the role of other lifestyle and genetic factors underlying the development of the TMPRSS2:ERG fusion. Cancer Epidemiol Biomarkers Prev; 27(10); 1231–3. ©2018 AACR.

Regular aspirin use and gene expression profiles in prostate cancer patients

PurposePharmacoepidemiology studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that aspirin induces transcriptional changes in tumors or normal prostate tissue.MethodsWe analyzed the prostatic transcriptome from men diagnosed with prostate cancer during follow-up of the Physicians’ Health Study 1 (PHS, n = 149), initially a randomized controlled trial of aspirin. Aspirin target genes were identified through systematic literature review and a drug target database. We compared target gene expression according to regular aspirin use at cancer diagnosis and used whole-transcriptome gene set enrichment analysis to identify gene sets associated with aspirin use. Results were validated in the Health Professionals Follow-up Study (HPFS, n = 254) and in Connectivity Map.ResultsOf 12 target genes identified from prior studies and 540 genes from the drug target database, none were associated with aspirin use. Twenty-one gene sets were enriched in tumor tissue of aspirin users, 18 of which were clustered around ribosome function and translation. These gene sets were associated with exposure to cyclooxygenase inhibitors in Connectivity Map. Their association with cancer prognosis was U-shaped in both cohorts. No gene sets were enriched in normal tissue. In HPFS, neither the target genes nor the gene sets were associated with aspirin use.ConclusionsRegular aspirin use may affect ribosome function in prostate tumors. Other putative target genes had similar expression in tumors from aspirin users and non-users. If results are corroborated by experimental studies, a potential benefit of aspirin may be limited to a subset of prostate cancer patients.

MP38-09 PROSTATE-SPECIFIC ANTIGEN (PSA) LEVELS IN MEN AGED 60 TO 70 AND DEVELOPMENT OF LETHAL PROSTATE CANCER OVER 30 YEARS: IMPLICATIONS FOR RISK-STRATIFIED SCREENING

METHODS: Participants were selected from three populationbased Swedish cohorts followed without screening: 871 men aged 37 70 with PSA 3 10 ng / mL at blood draw and subsequently diagnosed with prostate cancer of whom 326 were diagnosed with high-grade disease (Gleason grade 7; Gleason grade group (GGG) 2). Multivariable logistic regression was used to predict high versus low-grade prostate cancer at diagnosis in terms of lead-time: time between elevated PSA and clinical diagnosis. Multivariable linear regression was used to test the association between lead time and PSA. RESULTS: After adjustment for cohort and age, the odds of high-grade disease increased 1.11 (95% C.I. 1.08, 1.14) per year increase in lead time (p<0.0001), with no evidence of differences by age group or cohort. Higher PSA predicted a shorter lead time of 0.44 (95% C.I. 0.25, 0.63; p<0.0001) years per 1 ng / mL higher PSA after adjustment for cohort and age. There was no interaction between PSA and grade, suggesting that the longer lead time of high-grade tumors is not simply related to age. PSA was significantly associated with grade after adjusting for lead time, cohort, and age (OR1⁄41.09; 95% CI 1.00, 1.19; p1⁄40.048) suggesting that both grade and PSA increase over time. A limitation is our assumption that men with an elevated PSA subsequently diagnosed with cancer would have biopsy-detectable cancer at the time of PSA elevation. CONCLUSIONS: Our data support grade-progression, that were we to follow a prostate over time we would see a transition from benign to GGG 1, then to GGG 2 or higher disease. We cannot know whether this effect is because a GGG 1 becomes GGG 2, or a new focus of GGG 2 arises in a prostate already containing a GGG 1 tumor.

Why Epidemiological Studies of Physical Activity in Prostate Cancer Often Underestimate its Benefits

Wang et al [1] conducted a rigorous analysis investigating physical activity and survival after prostate cancer diagnosis. Major strengths of this study include a large sample size, almost 20 yr of follow-up, and information on physical activity both before and after prostate cancer diagnosis. Among men later diagnosed with nonmetastatic (Mx/M0) prostate cancer, those with higher levels of prediagnostic physical activity (equivalent to 4.4 h/wk of brisk walking) had a 37% lower risk of progression to prostate cancer– specific mortality compared to sedentary men. Postdiagnostic recreational physical activity was associated with a lower risk of progression to prostate cancer–specific mortality, regardless of tumor stage. These findings contribute valuable evidence to the growing body of literature supporting the benefits of physical activity on prostate cancer progression. Moreover, because of inevitable methodological challenges inherent to epidemiological studies, it seems likely that these remarkably strong inverse associations between recreational physical activity and prostate cancer are underestimated, for several reasons. First, there is a substantial measurement error for physical activity assessment, causing an underestimate of the magnitude of the inverse associations. Self-reported (and objectively measured) exposures are always subject to measurement error, but physical activity is particularly difficult to report accurately, as it occurs throughout the day with large withinand between-person variations in type, duration, and intensity. Most of the validated physical activity questionnaires list various types with duration categories for each. Each physical activity item is typically assigned a single standardized metabolic equivalent of task