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Biological and experimental evidence support restoration of normal zinc levels in malignant prostate cells as a promising prostate cancer treatment, yet the influence of zinc supplementation after diagnosis on prostate cancer survival in a human population is unknown.We prospectively assessed post-diagnostic zinc supplementation in relation to prostate cancer survival among 5,788 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study (1986-2019). We used Cox regression models to estimate the multivariable hazard ratios and 95% confidence intervals of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality according to post-diagnostic zinc supplement use and dosage.During a median follow-up of 11 years, we documented 527 lethal prostate cancer events and 3,198 all-cause deaths. Fifteen percent of men reported zinc supplement use post-diagnosis. Compared to nonusers, post-diagnostic zinc supplement use was associated suggestively with a lower risk of lethal prostate cancer (HR [95% CI], 0.82 [0.60-1.13]) and significantly with all-cause mortality (0.84 [0.74-0.96]). The inverse association was mostly observed among men who used post-diagnostic zinc supplements of 1-24 mg/d (lethal prostate cancer: 0.55 [0.32-0.96]; all-cause mortality: 0.77 [0.64-0.93]), while higher dosage did not show a lower risk.Post-diagnostic low-dose zinc supplement use among nonmetastatic prostate cancer patients was associated with lower risk of lethal prostate cancer and all-cause mortality. A potential benefit of low-dose post-diagnostic zinc supplement for prostate cancer survival merits further study.

Prostate cancer has a heterogeneous prognosis. Most previous studies have focused on the identification of prognostic biomarkers in the prostate cancer tumor. However, it is increasingly recognized that the tumor microenvironment contributes to prostate cancer aggressiveness and progression. We therefore examined whole transcriptome expression of the prostate stroma and associations with aggressive and lethal prostate cancer. We performed RNA sequencing (Illumina TruSeq Exome Capture) of 272 tumor-adjacent and 120 benign-adjacent macrodissected prostate stromal samples from 293 men with prostate cancer from the Health Professionals Follow-up Study and Physicians’ Health Study. We performed differential expression analysis comparing gene expression and pathways by Gleason score and lethal outcome. We also tested a previously developed stromal gene signature of Gleason score in these datasets. Comparing high- with low-Gleason score cancers, 26 genes (P < 0.001) and 12 pathways (FDR < 0.20) were significantly differentially expressed in tumor-adjacent stroma, including pathways related to stroma composition remodeling and DNA repair, with 73 genes and 65 pathways significant in benign-adjacent stroma. Comparing lethal with nonlethal prostate cancer, 11 genes were differentially expressed in tumor-adjacent and 15 genes in benign-adjacent stroma, and pathways involved in inflammatory response were differentially enriched in both tumor and benign-adjacent stroma. In addition, our previously identified Gleason stromal gene signature was validated to be associated with Gleason score in these data.Implications: Our study uncovers stroma-specific genes and pathways that are differentially enriched with high Gleason score and lethal prostate cancer, demonstrating that the molecular investigation of the tumor microenvironment can provide additional information about prostate cancer prognosis.

Metastases are the main cause of morbidity and mortality from solid tumors. Surprisingly, population-based cancer registries in various countries, including the National Cancer Institute's Surveillance, Epidemiology, and End Results program in the United States, only capture data on individuals diagnosed with cancers that are metastatic at diagnosis (M1). Metastatic recurrences of previously diagnosed, initially nonmetastatic tumors are missed. Devasia and colleagues specify an illness-death model for chronic disease and estimate that in prostate cancer, which has a large pool of primary disease that may or may not progress to metastases, about half of all metastatic cancers arise as recurrences from initially nonmetastatic disease. Capturing all incident metastatic cancer cases across all tumor types in population-based cancer registries, not only based on initial stage at diagnosis, would be critical to better understand the disparities in metastatic disease burden and the effectiveness of primary prevention, screening, and therapies for primary and metastatic disease. See related article by Devasia et al., p. 659

The most common somatic event in primary prostate cancer is a fusion between the androgen-related TMPRSS2 gene and the ERG oncogene. Tumors with these fusions, which occur early in carcinogenesis, have a distinctive etiology. A smaller subset of other tumors harbor fusions between TMPRSS2 and members of the ETS transcription factor family other than ERG. To assess the genomic similarity of tumors with non-ERG ETS fusions and those with fusions involving ERG, this study derived a transcriptomic signature of non-ERG ETS fusions and assessed this signature and ERG-related gene expression in 1,050 men with primary prostate cancer from three independent population-based and hospital-based studies. Although non-ERG ETS fusions involving ETV1, ETV4, ETV5, or FLI1 were individually rare, they jointly accounted for one in seven prostate tumors. Genes differentially regulated between non-ERG ETS tumors and tumors without ETS fusions showed similar differential expression when ERG tumors and tumors without ETS fusions were compared (differences explained: R2 = 69–77%), including ETS-related androgen receptor (AR) target genes. Differences appeared to result from similarities among ETS tumors rather than similarities among non-ETS tumors. Gene sets associated with ERG fusions were consistent with gene sets associated with non-ERG ETS fusions, including fatty acid and amino acid metabolism, an observation that was robust across cohorts. Implications: Considering ETS fusions jointly may be useful for etiologic studies on prostate cancer, given that the transcriptome is profoundly impacted by ERG and non-ERG ETS fusions in a largely similar fashion, most notably genes regulating metabolic pathways.

Multivitamin supplement is commonly used among older adults in the United States. Evidence on multivitamin use and prostate cancer risk is limited, and some suggested potential risk for clinically important subtypes of cancer.A total of 48,137 men from the Health Professionals Follow-up Study were followed from 1986 to 2017. Multivitamin use and frequency were self-reported at baseline and updated biennially. Clinical features of prostate cancer included advanced, lethal and high-grade outcomes. Cox proportional hazards models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) of multivitamin use and incidence of prostate cancer.The median followup for men without prostate cancer diagnosis or death was 30.7 years. We documented 7,108 incident prostate cancer cases including 564 advanced and 1,065 lethal. Overall, we observed a null association between multivitamin use and risk of prostate cancer. Compared to never-users, men who used multivitamin 10 or more tablets per week had similar risk of advanced (HR: 1.14, 95% CI: 0.77-1.70, PRegular or long-duration multivitamin use among older, generally well-nourished men was not associated with either increased or lower risk of overall or aggressive prostate cancer.

Background Individual health behaviours have been associated with fatal prostate cancer (PCa). Their combined association with fatal PCa after diagnosis is unknown. Methods This prospective cohort included 4518 men diagnosed with nonmetastatic PCa from the Health Professionals Follow-up Study. Exposures included a three-factor score integrating post-diagnostic fatal PCa risk factors (“2021 PCa Behaviour Score”), six-factor score integrating incident aggressive PCa risk factors (“2015 PCa Behaviour Score”), and two scores integrating recommendations for cancer prevention and survival, respectively. Multivariable Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for fatal PCa. Results Over a median 10.2 years, we observed 219 PCa deaths. Each additional point of one of the PCa-specific health behaviour scores (2015 PCa Behaviour Score) was associated with a 19% reduced fatal PCa risk (HR: 0.81, 95%CI: 0.68–0.97). The 2021 PCa Behaviour Score and scores integrating national recommendations were not associated with fatal PCa. Conclusions While a PCa-specific health behaviour score was associated with a reduced risk of fatal PCa, we did not otherwise observe strong evidence of associations between post-diagnostic scores and fatal PCa. Avoiding tobacco, healthy body size, and physical activity may decrease PCa death risk, but further research is needed to inform cancer survivorship recommendations.

Purpose: Oncogenic alterations of the PI3K/AKT pathway occur in >40% of patients with metastatic castration-resistant prostate cancer, predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown. Experimental Design: Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions; copy-number alterations; and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used the siRNA-based knockdown of PIK3R1 for functional studies. FDG-PET/CT examinations were performed with a hybrid positron emission tomography (PET)/CT scanner for some prostate cancer patients in the MSK-IMPACT cohort. Results: Analyzing 1,417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared with primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F-fluorodeoxyglucose in PET imaging, suggesting increased glycolysis. Conclusions: Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin–PI3K–glycolytic pathway regulation in prostate cancer.

Adverse neighborhood social and natural (greenspace) environments may contribute to prostate cancer (CaP) etiology, but mechanisms are unclear. We examined associations between neighborhood environment and prostate intratumoral inflammation in 967 men diagnosed with CaP with available tissue from 1986-2009 in the Health Professionals Follow-up Study. Exposures were linked to work or residential addresses in 1988. We estimated indices of neighborhood socioeconomic status (nSES) and segregation (Index of Concentration at Extremes (ICE)) using Census tract-level data. Surrounding greenness was estimated using seasonal averaged Normalized Difference Vegetation Index (NDVI). Surgical tissue underwent pathological review for acute and chronic inflammation, corpora amylacea, and focal atrophic lesions. Adjusted odds ratios (aOR) for inflammation (ordinal) and focal atrophy (binary) were estimated using logistic regression. No associations were observed for acute or chronic inflammation. Each IQR increase in NDVI within 1230m (aOR: 0.74, 95% CI: 0.59, 0.93), ICE-income (aOR: 0.79, 95% CI: 0.61, 1.04) and ICE-race/income (aOR: 0.79, 95% CI: 0.63, 0.99) was associated with lower postatrophic hyperplasia. IQR increases in nSES (aOR: 0.76, 95% CI: 0.57, 1.02) and ICE-race/income (aOR: 0.73, 95% CI: 0.54, 0.99) were associated with lower tumor corpora amylacea. Histopathological inflammatory features of prostate tumors may be influenced by neighborhood

Avocados contain nutrients and phytochemicals that make it promising for cancer prevention, and chemopreventive properties have been demonstrated in prior studies. Prospective studies on avocado consumption and cancer risk have yet to be conducted. This study included data from 45,289 men in the Health Professionals Follow-Up Study (HPFS, 1986–2016) and 67,039 women in the Nurses’ Health Study (NHS, 1986–2014). Avocado consumption was assessed using validated food frequency questionnaires every 4 years. Cox proportional hazards models calculated multivariable HRs and 95% confidence intervals (CI) for associations between avocado consumption and risk of total and site-specific cancers in each cohort. In HPFS, consumption of ≥1 weekly serving of avocados was associated with decreased risk of total (HR, 0.85; 95% CI, 0.80–0.91), colorectal (HR, 0.71; 95% CI, 0.59–0.85), lung (HR, 0.71; 95% CI, 0.57–0.90), and bladder cancer (HR, 0.72; 95% CI, 0.57–0.90). In NHS, avocado consumption was associated with increased risk of breast cancer (HR, 1.21; 95% CI, 1.07–1.37). No associations were observed between avocado consumption and risk of total cancer (HR, 1.06; 95% CI, 0.98–1.14) or other site-specific cancers in NHS. Considering the surprising breast cancer finding, analyses were repeated using data from 93,230 younger women in the parallel NHSII (1991–2017). In NHSII, avocado consumption was not associated with breast cancer risk (HR, 0.93; 95% CI, 0.76–1.13). Overall, avocado consumption may be associated with reduced risk of total and some site-specific cancers in men. The positive association with breast cancer risk in NHS was not seen in the younger NHSII.Prevention Relevance:The results of this prospective study suggest that avocado consumption may be associated with decreased risk of total and some site-specific cancers in men.See related Spotlight, p. 187

Supplementary Table S1 shows associations of avocado consumption and risk of cancer excluding current smokers, with similar results as the overall cohort.

Supplemental figure 1: Examples of cribriform and noncribriform carcinoma; Supplemental figure 2: Scheme of Sample Selection; Supplemental figure 3: Examples of PTEN Immunostaining of Tissue Microarray (TMA) Cores, HPFS/ PHS Prostate Cancer Cohorts; Supplementary figure 4: Invasive Cribriform Carcinoma is Associated with High Gleason Score and Tumor Stage (TCGA datasets); Supplementary figure 5. Difference in FGA between Cribriform Carcinoma (ICC) and Noncribriform Carcinoma (NC4) as well as between Gleason scores (in TCGA dataset); Supplementary figure 6: Cribriform Morphology in PTENloss and SPOPmut Transgenic Mouse Prostate Model.

Difference in FGA between Cribriform Carcinoma (ICC) and Noncribriform Carcinoma (NC4) as well as between Gleason scores.

Function and aberration of differentially methylated genes between Cribriform and noncribriform.

Obesity and inactivity have been associated with advanced-stage prostate cancer, and poor prostate cancer outcomes, though the underlying mechanism(s) is unknown. To determine whether telomere shortening, which has been associated with lethal prostate cancer, may be a potential underlying mechanism, we prospectively evaluated the association between measures of adiposity, physical activity, and telomere length in 596 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays, we measured telomere length in cancer and benign cells using a telomere-specific FISH assay. Adiposity and activity were assessed via questionnaire within 2 years of diagnosis. Adjusting for age, pathologic stage, and grade, the median and SD of the per cell telomere signals were determined for each man for stromal cells and cancer cells by adiposity and activity categories. Overweight/obese men (54%) were similar to normal weight men on most factors, but had higher Gleason sum and lower activity levels. Overweight/obese men had 7.4% shorter telomeres in stromal cells than normal weight men (P = 0.06). The least active men had shorter telomeres in stromal cells than more active men (Ptrend = 0.002). Men who were overweight/obese and the least active had the shortest telomeres in stromal cells (20.7% shorter; P = 0.0005) compared with normal weight men who were the most active. Cancer cell telomere length and telomere length variability did not differ by measures of adiposity or activity. Telomere shortening in prostate cells may be one mechanism through which lifestyle influences prostate cancer risk and outcomes. Cancer Prev Res; 8(8); 737–42. ©2015 AACR.

Perspective on this Article from A Large Prospective Study of SEP15 Genetic Variation, Interaction with Plasma Selenium Levels, and Prostate Cancer Risk and Survival

Supplementary Table S1. Descriptive factors for KP study population, broken down by study. Supplementary Table S2. Genome-wide significant SNPs found in our cohort. Supplementary Table S3. Cis-eQTL expression of rs4646284. Supplementary Table S4. Results at the 105 loci previously found to be associated with prostate cancer. Supplementary Table S5. Risk score of and variance explained by the 105 previously reported hits. Supplementary Figure S1. Manhattan and Q-Q plots of each race/ethnicity and meta-analysis. Supplementary Figure S2. Local plots of novel replicated rs4646284 and suggestive rs2659124. Supplementary Figure S3. Cis-eQTL of SLC22A1 and SLC22A3. Supplementary Figure S4. Comparison of ORs of KP to previous reports by race/ethnicity. Supplementary Figure S5. KP AUC estimates.

Supplemental Table 1 and 2. Association of pre-diagnostic BMI, waist circumference, weight change from age 21, total physical activity and vigorous physical activity with telomere length (Supplemental Table 1) and telomere variability (Supplemental Table 2) in cancer cells, stromal cells, basal cells, and luminal epithelial cells in men surgically treated for clinically localized prostate cancer, HPFS.

Table S1: IDs of Cribriform (ICC) & Non-cribriform (NC4) TCGA cases; Table S2: Comparison between cribriform and non-cribriform based on TCGA clusters; Table S3: Somatic Copy Number Variation (SCNV) enriched in Cribriform Carcinoma (ICC) compared to Noncribriform (NC4), corrected for Fraction Genome Altered (FGA) and Gleason Score (GS).

Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (n = 164) had distinctive molecular features when compared with NC4 (n = 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed PTEN and MAP3K7 losses and gains at 3q; (ii) increased SPOPmut and ATMmut; (iii) enrichment for mTORC1 and MYC pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with SPOPmut (n = 38) and PTENloss (n = 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years; n = 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05–2.49], independent from Gleason score (GS).Implications:ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.

Supplementary materials, Supplementary Tables 1-12, Supplementary Figures 1-2

Table S9: Differentially methylated CpG islands in invasive cribriform vs Noncribriform; Table S10: mRNA expression of the differentially hypermethylated in cribriform with concomitant reduction of mRNA expression.

Supplementary Table 1. Differentially expressed genes between tumor- and benign-adjacent stroma Supplementary Table 2. Differentially enriched pathways between tumor- and benign-adjacent stroma Supplementary Table 3. Differentially expressed genes between high- and low-Gleason score in tumor-adjacent stroma Supplementary Table 4. Differentially expressed genes between high- and low-Gleason score in benign-adjacent stroma Supplementary Table 5. Differentially enriched pathways between high- and low-Gleason score in tumor-adjacent stroma Supplementary Table 6. Differentially enriched pathways between high- and low-Gleason score in benign-adjacent stroma Supplementary Table 7. Differentially expressed genes between cribriform and non-cribriform patterns Supplementary Table 8. Differentially enriched pathways between cribriform and non-cribriform patterns Supplementary Table 9. Differentially expressed genes between lethal and non-lethal cases in tumor-adjacent stroma Supplementary Table 10. Differentially expressed genes between lethal and non-lethal cases in benign-adjacent stroma Supplementary Table 11. Differentially enriched pathways between lethal and non-lethal cases in tumor-adjacent stroma Supplementary Table 12. Differentially enriched pathways between lethal and non-lethal cases in benign-adjacent stroma Supplementary Figure 1. Single sample gene set enrichment signature scores by Gleason score and lethal outcome in tumor-adjacent stromal samples. Supplementary Figure 2. Correlation of log2 fold change values between the current data and the LCM data (GSE97284)

Supplementary Data from Family History of Prostate and Breast Cancer Integrated with a Polygenic Risk Score Identifies Men at Highest Risk of Dying from Prostate Cancer before Age 75 Years

Purpose:Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown.Experimental Design:We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer–specific death. We assessed to what extent family history of prostate or breast cancer, combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants, identifies men at risk of prostate cancer and prostate cancer death across the age span.Results:During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer–specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the HR was 6.95 [95% confidence interval (CI), 5.57–8.66] for prostate cancer and 4.84 (95% CI, 2.59–9.03) for prostate cancer death. Men in the two upper PRS quartiles (50%–100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years.Conclusions:Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.

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Frequency of germline ASPN D-repeat-length in JHH prostate cancer cases and controls.

Purpose:Alterations in DNA damage repair (DDR) pathway genes occur in 20%–25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable.Experimental Design:We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2 null with BRCA2 wild-type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids.Results:We observed significant enrichment of the SRC signaling pathway in BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in BRCA2-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in BRCA2-null prostate cancer cells. Moreover, SRC knockdown increased PARPi sensitivity in BRCA2-null prostate cancer cells.Conclusions:This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.

Frequency of risk SNP genotypes in the ERG+ cases, ERG- cases, and controls

Supplementary Figure S1

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Supplemental Table 1: Minor allele frequencies and Hardy Weinberg Equilibrium (HWE) p-values for SNPs across antioxidant & transport related genes. Supplemental Table 2: Full results for the associations between antioxidant SNPs x selenium supplementation. Supplemental Table 3: Full results for the associations between antioxidant, transport, & DNA repair SNPs x vitamin E supplementation and risk of high-grade and overall prostate cancer (N=1,538) in SELECT. Supplemental Table 4: Full results for the independent associations of SNPs and risk high-grade and overall prostate cancer in the placebo arm of SELECT.