Harvard T.H. Chan School of Public Health

Few studies have formally tested the interaction between diet and the gut microbiome in the context of cardiometabolic health, particularly with the microbiome considered as a potential mediator rather than a target of dietary effects. Here, we investigated 307 male participants in the Health Professionals Follow-Up Study who provided up to four stool samples each, yielding 925 shotgun metagenomes and 340 metatranscriptomes, long-term dietary information, and biomarkers of glucose homeostasis, lipid metabolism, and inflammation from blood samples. We demonstrate that a healthy Mediterranean-style dietary pattern is associated with functional and taxonomic components of the gut microbiome, and that its protective associations with cardiometabolic health vary, depending on microbial composition. In particular, the protective association between adherence to the Mediterranean diet and cardiometabolic disease risk was significantly stronger among participants with decreased abundance of Prevotella copri. Our findings represent a step forward in the concept of precision nutrition and have the potential to inform more effective and precise dietary approaches for the prevention of cardiometabolic disease mediated through alterations in the gut microbiome.

Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20-30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on similar to 6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P < 0.0001). Our findings that zonal differences in normal tissue persist in tumor tissue and that these differences are associated with Gleason score and sample type suggest that subtypes potentially resulting from different etiologic pathways might arise in these zones. Zone of origin may be important to consider in prostate tumor biomarker research.

Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). Results: We observed no significant association between genetic variants and prostate cancer survival. Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study.Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.

Purpose: Gleason score strongly predicts prostate cancer mortality; however, scoring varies among pathologists, and many men are diagnosed with intermediate-risk Gleason score 7. We previously developed a 157-gene signature for Gleason score using a limited gene panel. Using a new whole-transcriptome expression dataset, we verified the previous signature's performance and developed a new Gleason signature to improve lethal outcome prediction among men with Gleason score 7.Experimental Design: We generated mRNA expression data from prostate tumor tissue from men in the Physicians' Health Study and Health Professionals Follow-Up Study (N = 404) using the Affymetrix Human Gene 1.0 ST microarray. The Prediction Analysis for Microarrays method was used to develop a signature to distinguish high (>= 8) versus low (<= 6) Gleason score. We evaluated the signature's ability to improve prediction of lethality among men with Gleason score 7, adjusting for 3+4/4+3 status, by quantifying the area under the receiver operating characteristic (ROC) curve (AUC). Results: We identified a 30-gene signature that best distinguished Gleason score <= 6 from >= 8. The AUC to predict lethal disease among Gleason score 7 men was 0.76 [95% confidence interval (CI), 0.67-0.84] compared with 0.68 (95% CI, 0.59-0.76) using 3 + 4/4 + 3 status alone (P = 0.0001). This signature was a nonsignificant (P = 0.09) improvement over our previous signature (AUC = 0.72). Conclusions: Our new 30-gene signature improved prediction of lethality among men with Gleason score 7. This signature can potentially become a useful prognostic tool for physicians to improve treatment decision making.

Chronic excess alcohol intake has been associated with irreversible hearing loss and acute alcohol intake may temporarily impair auditory function; however, some evidence suggests that long-term moderate alcohol intake may be related to lower risk of hearing loss. This study prospectively examined the association between total alcohol and individual alcoholic beverage consumption and risk of hearing loss in women. Data were prospectively collected from 65,424 participants in the Nurses' Health Study II (NHS II), aged 27-44 years at baseline (follow-up 1991-2009). Alcohol consumption was assessed using a validated questionnaire every 4 years. An incident case was defined as a self-reported hearing problem that began after 1991. Cox proportional hazards multivariate regression was used to adjust for potential confounders. During 1,024,555 person-years of follow-up, 12,384 cases of hearing loss occurred. After multivariate adjustment, there was no significant association between total alcohol consumption and risk of hearing loss. In exploratory analyses, beer consumption was associated with increased risk and wine consumption was associated with reduced risk. No significant association was observed for consumption of liquor. Total alcohol consumption is not associated with risk of hearing loss in women. The modest associations observed for beer (direct) and wine (inverse) may be due to chance or residual confounding but merit further study.

Melatonin has anticarcinogenic properties in experimental models. We undertook a case-cohort study of 928 Icelandic men without prostate cancer (PCa) nested within the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort to investigate the prospective association between first morning-void urinary 6-sulfatoxymelatonin (aMT6s) levels and the subsequent risk for PCa, under the hypothesis that men with lower aMT6s levels have an increased risk for advanced PCa. We used weighted Cox proportional hazards models to assess the association between first morning-void aMT6s levels and PCa risk, adjusting for potential confounders. A total of 111 men were diagnosed with incident PCa, including 24 with advanced disease. Men who reported sleep problems at baseline had lower morning aMT6s levels compared with those who reported no sleep problems. Men with morning aMT6s levels below the median had a fourfold statistically significant increased risk for advanced disease compared with men with levels above the median (hazard ratio: 4.04; 95% confidence interval, 1.26-12.98). These results require replication in larger prospective studies with longer follow-up. Patient summary: In this report, we evaluated the prospective association between urinary aMT6s levels and risk of PCa in an Icelandic population. We found that lower levels of aMT6s were associated with an increased risk for advanced PCa.

Vigorous activity is associated with lower risk of prostate cancer progression, but the biologic mechanisms are unknown. Exercise affects vascularization of tumors in animal models, and small, irregularly shaped vessels in prostate tumors are associated with fatal prostate cancer. We hypothesized that men who engaged in vigorous activity or brisk walking would have larger, more regularly shaped vessels in their prostate tumors. We prospectively examined whether physical activity was associated with prostate tumor microvessel morphology among 571 men in the Health Professionals Follow-up Study using ordinal logistic regression. Vessel size (mu m(2)), vessel lumen regularity (perimeter(2)/4 . pi . area), and microvessel density (number/high-powered field) were ascertained in tumor sections stained for endothelial cell marker CD34. Vigorous activity [metabolic equivalent task (MET) >= 6], nonvigorous activity (MET < 6), and walking pace were assessed a median of 14 months before diagnosis. Prostate tumors from men who reported a brisk walking pace (3+ mph) had larger, more regularly shaped blood vessels compared with those of men who walked at a less than brisk pace [vessel regularity OR, 1.59; 95% confidence interval (CI), 1.11-2.27; P value, 0.01; vessel size OR, 1.48; 95% CI, 1.04-2.12; P value, 0.03]. Brisk walking was not associated with microvessel density; total vigorous and nonvigorous activities were not associated with vessel size, shape, or number. Brisk walking may be associated with larger, more regularly shaped vessels in prostate tumors. Additional research elucidating the effect of physical activity on prostate tumor biology is needed.

Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response, and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and first morning void urinary 6-sulfatoxymelatonin levels.We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across 12 circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n = 24 cases), the Health Professionals Follow-Up Study (HPFS) (n = 40 cases), and the Physicians' Health Study (PHS) (n = 105 cases). We used linear regression to evaluate the association between SNPs and first morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP sets in the pathway (gene based) were associated with our outcomes.None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p values = 0.01, 0.01, and 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPs in TIMELESS (four SNPs), NPAS2 (six SNPs), PER3 (two SNPs) and CSNK1E (one SNP) were nominally associated with 6-sulfatoxymelatonin levels.We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.

Background: Observational studies suggest potential chemopreventive benefits of statins on prostate cancer outcomes, but data on the impact of postdiagnostic use are sparse. Methods: We examined the association of postdiagnostic statin use and risk of lethal prostate cancer (metastases or prostate cancer death, N = 242) among 3,949 men diagnosed with localized prostate cancer from the Health Professionals Follow-Up Study between 1992 and 2008 and followed through 2010 (33,302 person years). We used Cox proportional hazards regression models to estimate relative risks and 95% confidence intervals (CI), adjusting for age, time period, time from diagnosis to questionnaire, body mass index, vigorous physical activity, smoking, aspirin use, clinical stage, PSA at diagnosis, Gleason score, primary treatment, and comorbidities. Results: We found no statistically significant association between postdiagnostic current use of statins or duration of statin usage and the outcome of lethal prostate cancer [N = 242 cases; multivariate HR = 0.97 (95% CI, 0.72-1.31) for current use yes/no; HR = 0.85 (95% CI, 0.59-1.22) for 1 to 5 years of use, 0.96 (95% CI, 0.66-1.38) for 6+ years of use vs. never use]. Conclusions: We observed little evidence that statin usage after diagnosis of localized prostate cancer reduces risk of progression to metastatic disease or prostate cancer-specific death.Impact: These results do not support statins as a chemopreventive agent for prostate cancer progression.

Many prostate cancer survivors experience compromised health-related quality of life (HRQOL) as a result of prostate cancer. We examined relationships between types and intensities of activity and sedentary behavior and prostate cancer-related HRQOL, overall, and by demographic, disease, and treatment characteristics.Associations between post-diagnosis activity and sedentary behavior and HRQOL domains (urinary incontinence, urinary irritation/obstruction, bowel, sexual, and vitality/hormonal) were prospectively examined in men diagnosed with non-metastatic prostate cancer in the Health Professionals Follow-up Study (n = 1917) using generalized linear models.After adjusting for potential confounders, higher duration of total, non-vigorous, and walking activity was associated with higher vitality/hormonal functioning scores (p-trends, < 0.0001). Effects were small (d = 0.16-0.20) but approached clinical significance for men in the highest vs. lowest activity categories. Survivors who walked a parts per thousand yen90 min/week at a normal pace, or faster, reported higher hormone/vitality scores (p = 0.001) than men walking < 90 min at an easy pace. Weightlifting was associated with increased urinary incontinence (p-trend, 0.02). Total activity was associated with higher hormone/vitality functioning in men who were a parts per thousand yen5 years post-treatment, had more advanced disease (Gleason score a parts per thousand yen7), and had a parts per thousand yen1 comorbid condition. No relationships were observed between vigorous activity or sedentary behavior and HRQOL.Increased duration of non-vigorous activity and walking post-diagnosis was positively associated with better hormone/vitality functioning. Specifically, engaging in a parts per thousand yen5 h of non-vigorous activity or a parts per thousand yen3 h of walking per week may be beneficial.Encouraging men to engage in non-vigorous activity and walking may be helpful for managing prostate cancer-related HRQOL.