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Background: Men engaged in high physical activity have lower risks of advanced and fatal prostate cancer. Mechanisms underlying this association are not well understood but may include systemic and tumor-specific effects. We investigated potential mechanisms linking physical activity and gene expression in prostate tissue from men with prostate cancer. Methods: We included a subset of 118 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 1986 and 2005 with whole-transcriptome gene expression profiling on tumor and adjacent normal prostate tissue and physical activity data. Long-term vigorous physical activity was self-reported as the average time spent engaged in various forms of recreational physical activity at baseline and biennially until prostate cancer diagnosis. Gene set enrichment analysis was performed among KEGG and Hallmark gene sets to identify pathways with differential expression based on vigorous physical activity. Results: In adjacent normal tissue, we identified 25 KEGG gene sets enriched (downregulated) in the highest compared with lowest quintile of vigorous physical activity at an FDR <0.10, including a number of cancer- and immune-related pathways. Although no gene sets reached statistical significance in tumor tissue, top gene sets differentially expressed included TGF beta, apoptosis, and p53 signaling pathways. Conclusions: These findings suggest that physical activity may influence the tumor microenvironment. Future studies are needed to confirm these findings and further investigate potential mechanisms linking physical activity to lethal prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Inflammation and focal atrophy are common features adjacent to prostate tumors. Limited evidence exists on whether these features have prognostic significance. Methods: In the Health Professionals Follow-Up Study and Physicians' Health Study, we studied 1,035 men diagnosed with prostate cancer. A genitourinary pathologist centrally reviewed tumor and normal areas of hematoxylin and eosin slides from prostate cancer specimens for the presence of acute and chronic inflammation, and four subtypes of focal atrophy. Cox proportional hazards models adjusted for potential confounders were used to estimate HRs and 95% confidence intervals (CI) for the association of these features with lethal prostate cancer, defined as development of metastatic disease or death during follow-up. Results: During a median of 12 years of follow-up, 153 men developed lethal prostate cancer. A total of 84% of men had histologic evidence of chronic inflammation and 30% had acute inflammation. Both chronic and acute inflammation were inversely associated with lethal prostate cancer in age- and lifestyle-adjusted models. Chronic inflammation remained inversely associated with lethal prostate cancer after additionally adjusting for prognostic clinical features (HR = 0.45; 95% CI, 0.30-0.69 for mild and HR = 0.51; 95% CI, 0.33-0.80 for moderate to severe). None of the atrophic lesions were associated with lethal prostate cancer. Conclusions: Our data suggest that the presence of inflammation, particularly chronic inflammation, in prostate cancer tissue is associated with better prognosis among patients with prostate cancer. Impact: This is the largest prospective cohort study to examine the association between inflammation, focal atrophy, and lethal prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The largest molecular subtype of primary prostate cancer is defined by the TMPRSS2:ERG gene fusion. Few studies, however, have investigated etiologic differences by TMPRSS2:ERG status. Because the fusion is hormone-regulated and a man's hormonal milieu varies by height and obesity status, we hypothesized that both may be differentially associated with risk of TMPRSS2:ERG-defined disease. Methods: Our study included 49,372 men from the prospective Health Professionals Follow-up Study. Participants reported height and weight at baseline in 1986 and updated weight biennially thereafter through 2009. Tumor ERG protein expression (a TMPRSS2:ERG marker) was immunohistochemically assessed. We used multivariable competing risks models to calculate HRs and 95% confidence intervals (CIs) for the risk of ERG-positive and ERG-negative prostate cancer. Results: During 23 years of follow-up, we identified 5,847 incident prostate cancers, among which 913 were ERG-assayed. Taller height was associated with an increased risk of ERG-positive disease only [per 5 inches HR 1.24; 95% confidence interval (CI), 1.03-1.50; Pheterogeneity = 0.07]. Higher body mass index (BMI) at baseline (per 5 kg/m² HR 0.75; 95% CI, 0.61-0.91; Pheterogeneity = 0.02) and updated BMI over time (per 5 kg/m² HR 0.86; 95% CI, 0.74-1.00; Pheterogeneity = 0.07) were associated with a reduced risk of ERG-positive disease only. Conclusions: Our results indicate that anthropometrics may be uniquely associated with TMPRSS2:ERG-positive prostate cancer; taller height may be associated with greater risk, whereas obesity may be associated with lower risk. Impact: Our study provides strong rationale for further investigations of other prostate cancer risk factors that may be distinctly associated with subtypes. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer has a propensity to invade and grow along nerves, a phenomenon called perineural invasion (PNI). Recent studies suggest that the presence of PNI in prostate cancer has been associated with cancer aggressiveness. Methods: We investigated the association between PNI and lethal prostate cancer in untreated and treated prostate cancer cohorts: the Swedish Watchful Waiting Cohort of 615 men who underwent watchful waiting, and the U.S. Health Professionals Follow-Up Study of 849 men treated with radical prostatectomy. One pathologist performed a standardized histopathologic review assessing PNI and Gleason grade. Patients were followed from diagnosis until metastasis or death. Results: The prevalence of PNI was 7% and 44% in the untreated and treated cohorts, respectively. PNI was more common in high Gleason grade tumors in both cohorts. PNI was associated with enhanced tumor angiogenesis, but not tumor proliferation or apoptosis. In the Swedish study, PNI was associated with lethal prostate cancer [OR 7.4; 95% confidence interval (CI), 3.6-16.6; P < 0.001]. A positive, although not statistically significant, association persisted after adjustment for age, Gleason grade, and tumor volume (OR 1.9; 95% CI, 0.8-5.1; P = 0.17). In the U.S. study, PNI predicted lethal prostate cancer independent of clinical factors (HR 1.8; 95% CI, 1.0, 3.3; P =0.04). Results: The prevalence of PNI was 7% and 44% in the untreated and treated cohorts, respectively. PNI was more common in high Gleason grade tumors in both cohorts. PNI was associated with enhanced tumor angiogenesis, but not tumor proliferation or apoptosis. In the Swedish study, PNI was associated with lethal prostate cancer [OR 7.4; 95% confidence interval (CI), 3.6-16.6; P < 0.001]. A positive, although not statistically significant, association persisted after adjustment for age, Gleason grade, and tumor volume (OR 1.9; 95% CI, 0.8-5.1; P = 0.17). In the U.S. study, PNI predicted lethal prostate cancer independent of clinical factors (HR 1.8; 95% CI, 1.0, 3.3; P =0.04). Impact: Our findings suggest that PNI should be a standardized component of histopathologic review, and highlights a mechanism underlying prostate cancer metastasis. [ABSTRACT FROM AUTHOR]

The article offers information on a study on prostate cancer and the expression of prostate-specific membrane antigen (PSMA) protein in tumor tissue. Topics include overexpression of PSMA in serum and tumor tissue, biochemical recurrence in surgically treated prostate cancer, and disease-specific mortality. Results show that high tumor PSMA expression is not an independent predictor of lethal prostate cancer, but it may account for malignant features of tumor angiogenesis and Gleason grade.

The article presents a study that investigated the association between phosphatase and tensin homolog (PTEN) expression and prostate cancer mortality. The study explored the potential effect modification by IGF-IR, a direct activator of the phosphoinositide-3-kinase (PI3K) pathway, and evaluated protein expression in tumor using tumor tissues.

The article discusses a research study on the association of prostate cancer risk with common polymorphisms of adiponectin (ADIPOQ) and receptor genes (ADIPOR1/R2). Researchers evaluated 29 common single-nucleotide polymorphisms (SNP) in ADIPOQ of 13 subjects, ADIPOR2 in 11 subjects and ADIPOR1 in 5 subjects. Results showed that four ADIPOQ tagging polymorphisms have significant association with the overall risk for prostate cancer.

The article discusses a research study on the prognostic significance of prostatic intraepithelial neoplasia (PIN), focal prostatic atrophy and inflammation in prostate cancer. Men with prostate cancer in Sweden were assessed for PIN, Gleason grade and inflammation in four prostatic atrophy subtypes including simple atrophy (SA), simple atrophy with cyst formation and postatrophic hyperplasia (PAH). Conclusions indicated the prognostic significance of PIN and inflammation on prostate cancer.

The article presents a study regarding the link between the p63 cytoplasmic expression deviation death caused by prostate cancer. The study includes the 298 men participants with prostate cancer ages 51 to 84 years and underwent immunohistochemical staining of their tissue and Cox proportional hazards regression in order to explore the connection of protein expression of p63 and the said cancer. Researchers have determined the connection between p63 deviant expression and the fatal cancer.

Gleason grade is universally used for pathologic scoring of the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate-specific antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high-grade tumors. We studied 1,207 Physicians' Health Study and Health Professionals Follow-up Study participants diagnosed with prostate cancer from 1982 to 2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982-1/1993), 19.9% stage ≥T3, to the latest (5/2000-12/2004), 3% stage T, none T4. The proportion of Gleason score ≥8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (P = 0.04) suggests that the relationship between grade and stage varies by time period. As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest that grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance. [ABSTRACT FROM AUTHOR]

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., (©2022 American Association for Cancer Research.)

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., (©2022 American Association for Cancer Research.)

Anticancer therapies have been limited by the emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error-prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether the treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease, we observed upregulation of GAS6, whereas ablation of GAS6's receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC, and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators., Significance: EGFR-mutant lung cancers treated with kinase inhibitors often evolve resistance due to secondary mutations. We report that in similarity to the bacterial SOS response stimulated by antibiotics, endogenous mutators are activated in drug-treated cells, and this heralds tolerance. Blocking the process prevented resistance in xenograft models, which offers new treatment strategies. This article is highlighted in the In This Issue feature, p. 2483., (©2022 The Authors; Published by the American Association for Cancer Research.)

Gleason score, a measure of prostate tumor differentiation, is the strongest predictor of lethal prostate cancer at the time of diagnosis. Metabolomic profiling of tumor and of patient serum could identify biomarkers of aggressive disease and lead to the development of a less-invasive assay to perform active surveillance monitoring. Metabolomic profiling of prostate tissue and serum samples was performed. Metabolite levels and metabolite sets were compared across Gleason scores. Machine learning algorithms were trained and tuned to predict transformation or differentiation status from metabolite data. A total of 135 metabolites were significantly different ( P adjusted < 0.05) in tumor versus normal tissue, and pathway analysis identified one sugar metabolism pathway ( P adjusted = 0.03). Machine learning identified profiles that predicted tumor versus normal tissue (AUC of 0.82 ± 0.08). In tumor tissue, 25 metabolites were associated with Gleason score (unadjusted P < 0.05), 4 increased in high grade while the remainder were enriched in low grade. While pyroglutamine and 1,5-anhydroglucitol were correlated (0.73 and 0.72, respectively) between tissue and serum from the same patient, no metabolites were consistently associated with Gleason score in serum. Previously reported as well as novel metabolites with differing abundance were identified across tumor tissue. However, a "metabolite signature" for Gleason score was not obtained. This may be due to study design and analytic challenges that future studies should consider. IMPLICATIONS: Metabolic profiling can distinguish benign and neoplastic tissues. A novel unsupervised machine learning method can be utilized to achieve this distinction., (©2020 American Association for Cancer Research.)

Background: Inflammation and focal atrophy are common features adjacent to prostate tumors. Limited evidence exists on whether these features have prognostic significance., Methods: In the Health Professionals Follow-Up Study and Physicians' Health Study, we studied 1,035 men diagnosed with prostate cancer. A genitourinary pathologist centrally reviewed tumor and normal areas of hematoxylin and eosin slides from prostate cancer specimens for the presence of acute and chronic inflammation, and four subtypes of focal atrophy. Cox proportional hazards models adjusted for potential confounders were used to estimate HRs and 95% confidence intervals (CI) for the association of these features with lethal prostate cancer, defined as development of metastatic disease or death during follow-up., Results: During a median of 12 years of follow-up, 153 men developed lethal prostate cancer. A total of 84% of men had histologic evidence of chronic inflammation and 30% had acute inflammation. Both chronic and acute inflammation were inversely associated with lethal prostate cancer in age- and lifestyle-adjusted models. Chronic inflammation remained inversely associated with lethal prostate cancer after additionally adjusting for prognostic clinical features (HR = 0.45; 95% CI, 0.30-0.69 for mild and HR = 0.51; 95% CI, 0.33-0.80 for moderate to severe). None of the atrophic lesions were associated with lethal prostate cancer., Conclusions: Our data suggest that the presence of inflammation, particularly chronic inflammation, in prostate cancer tissue is associated with better prognosis among patients with prostate cancer., Impact: This is the largest prospective cohort study to examine the association between inflammation, focal atrophy, and lethal prostate cancer., (©2019 American Association for Cancer Research.)

Unlabelled: Assessing the extent of PI3K pathway activity in cancer is vital to predicting sensitivity to PI3K-targeting drugs, but the best biomarker of PI3K pathway activity in archival tumor specimens is unclear. Here, PI3K pathway activation was assessed, in clinical tissue from 1,021 men with prostate cancers, using multiple pathway nodes that include PTEN, phosphorylated AKT (pAKT), phosphorylated ribosomal protein S6 (pS6), and stathmin. Based on these markers, a 9-point score of PI3K activation was created using the combined intensity of the 4-markers and analyzed its association with proliferation (Ki67), apoptosis (TUNEL), and androgen receptor (AR) status, as well as pathologic features and cancer-specific outcomes. In addition, the PI3K activation score was compared with mRNA expression profiling data for a large subset of men. Interestingly, those tumors with higher PI3K activation scores also had higher Gleason grade (P = 0.006), increased AR (r = 0.37; P < 0.001) and Ki67 (r = 0.24; P < 0.001), and decreased TUNEL (r = -0.12; P = 0.003). Although the PI3K activation score was not associated with an increased risk of lethal outcome, a significant interaction between lethal outcome, Gleason and high PI3K score (P = 0.03) was observed. Finally, enrichment of PI3K-specific pathways was found in the mRNA expression patterns differentiating the low and high PI3K activation scores; thus, the 4-marker IHC score of PI3K pathway activity correlates with features of PI3K activation., Implications: The relationship of this activation score to sensitivity to anti-PI3K agents remains to be tested but may provide more precision guidance when selecting patients for these therapies., (©2015 American Association for Cancer Research.)

Background: Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality and the potential effect modification by IGF-IR, a direct activator of the phosphoinositide-3-kinase (PI3K) pathway., Methods: Protein expression in tumor was evaluated using tumor tissues obtained from 805 participants of the Physicians' Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression and its interaction with IGF-IR, in relation to lethal prostate cancer (cancer-specific death or distant metastases)., Results: Low PTEN expression was associated with an increased risk of lethal prostate cancer [HR, 1.7; 95% confidence interval (CI), 0.98-3.2; Ptrend = 0.04]. The association was attenuated after adjustment for Gleason grade, tumor stage, and prostate-specific antigen (PSA) at diagnosis. A significant negative interaction between PTEN and IGF-IR was found (Pinteraction = 0.03). Either reduction in PTEN or increase in IGF-IR expression was sufficient to worsen prognosis. Models including PTEN and IGF-IR expression offer additional predicting power to prostate cancer survival, compared to those only including demographic and clinical factors., Conclusions: Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF-IR expression remains at normal level., Impact: PTEN and IGF-IR expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer., (©2013 AACR.)

Background: Whether the genomic rearrangement transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear., Methods: Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random-effects models to estimate associations between rearrangement status and outcomes., Results: The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.78-1.26] or lethal disease (HR, 0.93; 95% CI, 0.61-1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis [risk ratio (RR)(≥T3 vs. T2), 1.23; 95% CI, 1.16-1.30) but not with biochemical recurrence (RR, 1.00; 95% CI, 0.86-1.17) or lethal disease (RR, 0.99; 95% CI, 0.47-2.09)., Conclusions: These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy., Impact: This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy., (©2012 AACR)

BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be associated with prostate cancer progression through regulation of the cell cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumor samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1-positive tumors had substantially increased tumor proliferation index compared with negative tumors (47.0 Ki67-positive nuclei versus 10.3, P = 0.0016) and were more likely to develop lethal cancer compared with BRCA1-negative tumors (hazard ratio, 4.6; 95% confidence interval, 2.4-8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell cycle control and show that BRCA1 is a marker of clinical prostate cancer prognosis. Cancer Res; 70(8); 3136-9. (c)2010 AACR.