Prospective serum metabolomic profiling of lethal prostate cancer.

Impaired metabolism may play an important role in the pathogenesis of lethal prostate cancer, yet there is a paucity of evidence regarding the association. We conducted a large prospective serum metabolomic analysis of lethal prostate cancer in 523 cases and 523 matched controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from baseline fasting serum collection to prostate cancer death was 18 years (maximum 30 years). We identified 860 known biochemicals through an ultrahigh-performance LC-MS/MS platform. Conditional logistic regression models estimated odds ratios (OR) and 95% confidence intervals of risk associated with 1-standard deviation (s.d.) increases in log-metabolite signals. We identified 34 metabolites associated with lethal prostate cancer with a false discovery rate (FDR) < 0.15. Notably, higher serum thioproline, and thioproline combined with two other cysteine-related amino acids and redox metabolites, cystine and cysteine, were associated with reduced risk (1-s.d. OR = 0.75 and 0.71, respectively; p ≤ 8.2 × 10-5 ). By contrast, the dipeptide leucylglycine (OR = 1.36, p = 8.2 × 10-5 ), and three gamma-glutamyl amino acids (OR = 1.28-1.30, p ≤ 4.6 × 10-4 ) were associated with increased risk of lethal prostate cancer. Cases with metastatic disease at diagnosis (n = 179) showed elevated risk for several lipids, including especially the ketone body 3-hydroxybutyrate (BHBA), acyl carnitines, and dicarboxylic fatty acids (1.37 ≤ OR ≤ 1.49, FDR < 0.15). These findings provide a prospective metabolomic profile of lethal prostate cancer characterized by altered biochemicals in the redox, dipeptide, pyrimidine, and gamma-glutamyl amino acid pathways, whereas ketone bodies and fatty acids were associated specifically with metastatic disease.

Dietary choline and betaine intakes and risk of total and lethal prostate cancer in the Atherosclerosis Risk in Communities (ARIC) Study.

PURPOSE: Two prior cohort studies suggested that choline, but not betaine intake, is associated with an increased risk of advanced prostate cancer (PCa). Given that evidence remains limited, we evaluated whether intakes of choline and derivative betaine are associated with total and lethal PCa risk and PCa death in men with PCa. METHODS: We included 6,528 men (24.4% African American) without a cancer diagnosis at baseline (1987-1989) followed through 2012. Dietary intake was assessed using a food frequency questionnaire coupled with a nutrient database. We used Cox proportional hazards regression to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) of total and lethal PCa risk overall and by race. RESULTS: Choline intake was not associated with total (n = 811) or lethal (n = 95) PCa risk overall or by race. Betaine intake was inversely associated with lethal (tertile 3 vs 1, HR 0.59, 95% CI 0.35-1.00, p trend = 0.04), but not total PCa risk; patterns for lethal PCa were similar by race. Neither nutrient was associated with PCa death in men with PCa. CONCLUSIONS: Choline intake was not associated with total or lethal PCa or with PCa death in men with PCa. Betaine intake was inversely associated with lethal, but not total PCa risk or with PCa death in men with PCa. Our results do not support the hypothesis that higher choline intake increases lethal PCa risk, but do suggest that higher betaine intake may be associated with lower lethal PCa risk. Further investigation with a larger number of lethal cases is needed.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer.

BACKGROUND: Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. METHODS: A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. RESULTS: In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients (P = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2, c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) (P = 0.01). CONCLUSIONS: While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men.

Germline mutations in PPFIBP2 are associated with lethal prostate cancer.

BACKGROUND: Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa. METHODS: A case-case study of 1414 PCa patients with lethal PCa and low-risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2. Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan-Meier survival analysis. RESULTS: In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low-risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss-of-function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10-5 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034). CONCLUSIONS: While larger studies are needed, germline mutations in a novel gene, PPFIBP2, differentiated risk for lethal PCa from low-risk cases and were associated with shorter survival times after diagnosis.

Prostate cancer progression and mortality: a review of diet and lifestyle factors.

PURPOSE: To review and summarize evidence on the role of diet and lifestyle factors and prostate cancer progression, with a specific focus on habits after diagnosis and the risk of subsequent disease recurrence, progression, or death. METHODS: Given the well-documented heterogeneity of prostate cancer and the long survivorship of the majority of diagnoses, our goal was to summarize and describe modifiable risk factors for clinically relevant prostate cancer. We focused where possible on epidemiologic studies of post-diagnostic habits and prostate cancer progression, defined as recurrence (e.g., PSA risk, secondary treatment), metastasis, or death. Where data were limited, we also describe evidence on risk factors and indicators of prostate cancer aggressiveness at diagnosis. RESULTS: A variety of dietary and lifestyle factors appear to affect prostate cancer progression. Several generally widely recommended lifestyle factors such as not smoking, maintaining a healthy body weight, and regular vigorous physical exercise also appear to affect prostate cancer progression. Several dietary factors, such as tomato sauce/lycopene, cruciferous vegetables, healthy sources of vegetable fats, and coffee, may also have a role in reducing risk of prostate cancer progression. CONCLUSION: Diet and lifestyle factors, in particular exercise and smoking cessation, may reduce the risk of prostate cancer progression and death. These promising findings warrant further investigation, as their overall impact might be large.

The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the Prostate-specific Antigen-era.

Widespread prostate-specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6,024 men. Among men aged 70-79, tumor was found in 36% of Caucasians and 51% of African-Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well-recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow-up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential.

Immunohistochemical expression of ERG in the molecular epidemiology of fatal prostate cancer study.

BACKGROUND: Gene fusions between the ERG transcription factor and the androgen-regulated gene TMPRSS2 occur in a subset of prostate cancers and contribute to transformation of prostatic epithelial cells. Prior reports have used fluorescence in situ hybridization (FISH) or quantitative PCR (QPCR) to determine the presence of TMPRSS2-ERG fusions or ERG expression, respectively. Recently, several groups have reported on immunohistochemistry (IHC) to measure ERG expression, which is much more readily performed in clinical practice. However, the prior studies examining ERG expression by IHC had small sample sizes or they failed to clarify the association of ERG protein expression with important clinico-pathological features or prostate cancer-specific mortality. METHODS: To address these deficits, we evaluated ERG expression by IHC in 208 radical prostatectomy samples from the Kaiser Permanente Molecular Epidemiology of Fatal Prostate Cancer (MEFPC) study, a case-control study of prostate cancer-specific mortality. RESULTS: Nuclear ERG expression was seen in neoplastic prostate epithelia in 49 of the samples (23.7%). ERG expression in tumor cells was associated with higher tumor stage (OR = 2.0, 95% confidence interval 1.0-4.0, P value = 0.04). ERG immunoreactivity was positively associated with prostate cancer-specific mortality, although the confidence interval was wide (OR = 1.9, 95% confidence interval 0.88-4.0, P value = 0.10). CONCLUSIONS: Our results demonstrate that ERG protein expression is readily quantifiable with an existing commercial antibody. Evaluating ERG protein expression may improve our ability to identify the subset of more aggressive, invasive prostate cancers.

Addition of a Genetic Risk Score for Identification of Men with a Low Prostate-specific Antigen Level in Midlife at Risk of Developing Lethal Prostate Cancer.

Men with a low prostate-specific antigen (PSA) level (<1 ng/ml) in midlife may extend the rescreening interval (if aged 40-59 yr) or forgo future PSA screening (if aged >60 yr) owing to their low risk of aggressive prostate cancer (PCa). However, there is a subset of men who develop lethal PCa despite low baseline PSA. We investigated how a PCa polygenic risk score (PRS) in addition to baseline PSA impacts the prediction of lethal PCa among 483 men aged 40-70 yr from the Physicians' Health Study followed over a median of 33 yr. We examined the association of the PRS with the risk of lethal PCa (lethal cases vs controls) using logistic regression adjusted for baseline PSA. The PCa PRS was associated with risk of lethal PCa (odds ratio per 1 standard deviation in PRS [OR] 1.79, 95% confidence interval [CI] 1.28-2.49). The association between the PRS and lethal PCa was stronger for those with PSA <1 ng/ml (OR 2.23, 95% CI 1.19-4.21) than for men with PSA ≥1 ng/ml (OR 1.61, 95% CI 1.07-2.42). Our PCa PRS improved the identification of men with PSA <1 ng/ml at greater risk of future lethal PCa who should consider ongoing PSA testing. Patient summary: A subset of men develop fatal prostate cancer despite having low prostate-specific antigen (PSA) levels in middle age. A risk score based on multiple genes can help in predicting men who may be at risk of developing lethal prostate cancer and who should be advised to have regular PSA measurements.

Investigation of androgen receptor-dependent alternative splicing has identified a unique subtype of lethal prostate cancer.

A complete proteomics study characterizing active androgen receptor (AR) complexes in prostate cancer (PCa) cells identified a diversity of protein interactors with tumorigenic annotations, including known RNA splicing factors. Thus, we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression. We selected two AR-interacting RNA splicing factors, Src associated in mitosis of 68 kDa (SAM68) and DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5) to examine their associative roles in AR-dependent alternative RNA splicing. To assess the true physiological role of AR in alternative RNA splicing, we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets. As a result, we were able to highlight alternative splicing events of clinical significance. Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression. The physiological significance in PCa was investigated through the application of clinical exon array analysis, where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria. Using a clinical dataset with patients categorized as prostate cancer-specific death (PCSD), these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes. Overall, these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa. Moreover, AR-mediated alternative spicing contributes to aggressive PCa progression, where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.

Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer.

Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa.

Serrate RNA Effector Molecule (SRRT) Is Associated with Prostate Cancer Progression and Is a Predictor of Poor Prognosis in Lethal Prostate Cancer.

Arsenite-resistance protein 2, also known as serrate RNA effector molecule (ARS2/SRRT), is known to be involved in cellular proliferation and tumorigenicity. However, its role in prostate cancer (PCa) has not yet been established. We investigated the potential role of SRRT in 496 prostate samples including benign, incidental, advanced, and castrate-resistant patients treated by androgen deprivation therapy (ADT). We also explored the association of SRRT with common genetic aberrations in lethal PCa using immunohistochemistry (IHC) and performed a detailed analysis of SRRT expression using The Cancer Genome Atlas (TCGA PRAD) by utilizing RNA-seq, clinical information (pathological T category and pathological Gleason score). Our findings indicated that high SRRT expression was significantly associated with poor overall survival (OS) and cause-specific survival (CSS). SRRT expression was also significantly associated with common genomic aberrations in lethal PCa such as PTEN loss, ERG gain, mutant TP53, or ATM. Furthermore, TCGA PRAD data revealed that high SRRT mRNA expression was significantly associated with higher Gleason scores, PSA levels, and T pathological categories. Gene set enrichment analysis (GSEA) of RNAseq data from the TCGA PRAD cohort indicated that SRRT may play a potential role in regulating the expression of genes involved in prostate cancer aggressiveness. Conclusion: The current data identify the SRRT's potential role as a prognostic for lethal PCa, and further research is required to investigate its potential as a therapeutic target.

Aspirin Use and Lethal Prostate Cancer in the Health Professionals Follow-up Study.

BACKGROUND: Aspirin use probably protects against some malignancies but its effects on lethal prostate cancer (PC) are unclear. OBJECTIVE: To investigate the association between regular aspirin use and lethal PC. DESIGN, SETTING, AND PARTICIPANTS: Participants were aged 40-75 yr at baseline in 1986 and have been followed with biennial questionnaires. The risk analysis includes 49 409 men. The survival analysis includes 5980 PC patients without metastatic disease at diagnosis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used Cox proportional hazards regression to examine the association between current, past, or never regular aspirin use (≥2 d/wk) in relation to lethal (metastatic or fatal) PC. We also examined years of use among current users and years since stopping among past users. In the risk analysis, aspirin was updated throughout follow-up. In the survival analysis, aspirin use after diagnosis was assessed. RESULTS AND LIMITATIONS: Some 29% of participants used aspirin regularly at baseline, which increased to 60% by 2010. In the risk analysis, 804 men were diagnosed with lethal PC. Current regular aspirin was associated with a lower risk of lethal prostate cancer (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.66-0.96) compared to never users. In the survival analysis, 451 of the men diagnosed with nonmetastatic PC later developed lethal disease. Current postdiagnostic aspirin was associated with a lower risk of lethal PC (HR 0.80, 95% CI 0.64-1.00) and overall mortality (HR 0.79, 95% CI 0.69-0.90). When restricted to highly screened men, the risk analysis associations were stronger and survival analysis associations remained statistically significant. Reverse causation and residual confounding remain concerns, as demonstrated by the attenuated results in sensitivity analyses. CONCLUSIONS: Regular aspirin use was associated with a lower risk of lethal PC. Postdiagnostic use was associated with better survival after diagnosis. PATIENT SUMMARY: We found that it may be advisable for prostate cancer patients to take aspirin to improve their survival for both prostate cancer mortality and other mortality outcomes.

Elevated Serum Cytokines and Trichomonas vaginalis Serology at Diagnosis Are Not Associated With Higher Gleason Grade or Lethal Prostate Cancer.

BACKGROUND: Inflammation and infections have been associated with prostate cancer progression. We assessed whether elevated serum cytokines or T. vaginalis seropositivity at the time of diagnosis was associated with higher grade or lethal prostate cancer. PATIENTS AND METHODS: Men with localized or metastatic prostate cancer were included in this study. Cytokine serum levels including interleukin (IL)-1α, IL-1ß, IL-2, IL-6, IL-8, monocyte chemotactic protein 1 (CCL-2), tumor necrosis factor α, and growth-regulated oncogene α (CXCL-1) using a multiplex enzyme-linked immunosorbent assay and T. vaginalis serology were measured in blood samples at diagnosis. RESULTS: A total of 324 patients were identified at time of localized disease and 118 at time of metastatic disease. Of the 189 patients with localized disease and clinical follow-up data (median, 73 months), 28 developed lethal disease. There was no association between circulating cytokine levels above median concentrations nor T. vaginalis seropositivity and risk of intermediate- to high-risk or lethal prostate cancer. CONCLUSION: Higher levels of serum cytokine levels and T. vaginalis seropositivity at diagnosis are not associated with high-grade or lethal prostate cancer and do not aid risk stratification of localized prostate cancer.

Investigation of androgen receptor-dependent alternative splicing has identified a unique subtype of lethal prostate cancer / 亚洲男科学杂志(英文版)

A complete proteomics study characterizing active androgen receptor (AR) complexes in prostate cancer (PCa) cells identified a diversity of protein interactors with tumorigenic annotations, including known RNA splicing factors. Thus, we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression. We selected two AR-interacting RNA splicing factors, Src associated in mitosis of 68 kDa (SAM68) and DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5) to examine their associative roles in AR-dependent alternative RNA splicing. To assess the true physiological role of AR in alternative RNA splicing, we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets. As a result, we were able to highlight alternative splicing events of clinical significance. Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression. The physiological significance in PCa was investigated through the application of clinical exon array analysis, where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria. Using a clinical dataset with patients categorized as prostate cancer-specific death (PCSD), these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes. Overall, these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa. Moreover, AR-mediated alternative spicing contributes to aggressive PCa progression, where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death.

BACKGROUND: Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. OBJECTIVE: To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively. RESULTS AND LIMITATIONS: The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed. CONCLUSIONS: Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. PATIENT SUMMARY: Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.

Regular Aspirin Use and the Risk of Lethal Prostate Cancer in the Physicians' Health Study.

BACKGROUND: Regular aspirin use probably protects against some malignancies including prostate cancer (PC), but its impact on lethal PC is particularly unclear. OBJECTIVE: To investigate the association between regular aspirin and (1) the risk of lethal PC in a large prospective cohort and (2) survival after PC diagnosis. DESIGN, SETTING, AND PARTICIPANTS: In 1981/82, the Physicians' Health Study randomized 22 071 healthy male physicians to aspirin, ß-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2015 for PC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the relationship between regular aspirin (>3 tablets/week) and lethal PC (metastases or PC death). Cox proportional-hazards models estimated hazard ratios (HRs) for the risk of lethal PC in the whole cohort and postdiagnosis survival among men initially diagnosed with nonlethal PC. RESULTS AND LIMITATIONS: Risk analysis revealed that 502 men developed lethal PC by 2009. Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68, 95% confidence interval [CI] 0.52-0.89; past: HR 0.54, 95% CI 0.40-0.74) compared to never users. In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68, 95% CI 0.52-0.90) and overall mortality (HR 0.72, 95% CI 0.61-0.9). We could not assess aspirin dose, and inconsistencies were observed in some sensitivity analyses. CONCLUSIONS: Current regular aspirin use was associated with a lower risk of lethal PC among all participants. Current postdiagnostic use was associated with improved survival after diagnosis, consistent with a potential inhibitory effect of aspirin on PC progression. A randomized trial is warranted to confirm or refute these findings. PATIENT SUMMARY: We examined the potential effect of regular aspirin use on lethal prostate cancer. We found that taking aspirin was associated with a lower risk of lethal prostate cancer, and taking it after diagnosis may help to prevent prostate cancer from becoming fatal.

Diagnostic characteristics of lethal prostate cancer.

BACKGROUND: The diagnostic characteristics of men who eventually die from prostate cancer (PCa) and the extent to which early diagnostic strategies have affected these characteristics are unclear. We aimed to investigate trends in survival and clinical presentation at diagnosis in men who eventually died from PCa. PATIENTS AND METHODS: Based on the national database, the Danish Prostate Cancer Registry, a nationwide population-based study of all 19,487 men who died from PCa in Denmark between 1995 and 2013 was conducted. Trends in median survival and trends in age, prostate-specific antigen (PSA), clinical stage, and Gleason score (GS) at diagnosis were analysed. RESULTS: A total of 46.9%, 16.8%, and 36.3% had metastatic (M+), locally advanced/lymph node positive (LaN+), and localised disease, respectively, at diagnosis. Only 0.15% had localised disease, GS ≤ 6 and PSA<10. Over time, the proportion of men with M+ disease at diagnosis decreased from 54.0-38.3% (p < 0.0001), whereas the proportion LaN + disease increased from 8.6-27.3% (p < 0.0001). The proportion of localised disease remained stable at 33.2-41.9%. Median survival increased 2.11 years from 1.88 (95% CI: 1.68-2.08) in 1995 to 3.99 (95% CI: 3.71-4.28) years in 2013, p < 0.0001. CONCLUSIONS: In a large population-based study, the results confirmed concurrent literature that the majority of men who eventually died from PCa had LaN+ or M+ disease at diagnosis. The proportion of men with M+ disease at diagnosis decreased significantly over time, parallelled by an increase in median survival. Taken together, this indicates a lead-time effect on survival, which presently, however, is not substantial enough to result in a reduced PCa-specific mortality.

Long Non-coding RNAs in Prostate Cancer with Emphasis on Second Chromosome Locus Associated with Prostate-1 Expression.

Long non-coding RNAs (lncRNAs) are a class of RNA with transcripts longer than 200 nucleotides that lack functional open reading frames. They play various roles in human carcinoma, such as dysregulating gene expression in prostate cancer (PCa), which results in cancer initiation, development, and progression. The non-coding RNA SChLAP1 (second chromosome locus associated with prostate-1) is highly expressed in approximately 25% of PCas with higher prevalence in metastatic compared to localized PCa. Its expression is detectable non-invasively in PCa patient urine samples. Experimental data suggest that targeting SChLAP1 may represent a novel therapeutic application in PCa. This contribution focuses on the role of lncRNAs SChLAP1 expression in PCa diagnosis and prognosis.

Overexpression of the Long Non-coding RNA SChLAP1 Independently Predicts Lethal Prostate Cancer.

The long noncoding RNA SChLAP1 is overexpressed in a subset of prostate cancers (PCa), and high SChLAP1 expression by in situ hybridization (ISH) independently predicts biochemical recurrence after radical prostatectomy. Importantly, although biochemical recurrence is a significant clinical outcome, it is not a validated surrogate for PCa-related mortality. Thus, we evaluated the association between SChLAP1 expression and development of lethal PCa in a large cohort of American men with PCa and long-term follow-up. SChLAP1 ISH was performed on tissue microarrays containing representative formalin-fixed, paraffin-embedded PCa tissue from all patients and scored using a semiquantitative method (ISH score range 0-400). Hazard ratios (HRs) for the association between SChLAP1 expression and time to development of lethal PCa were estimated using multivariable Cox regression analysis. Of the 937 patients evaluated, 89 (9.5%) had high SChLAP1 expression (ISH score ≥100), which in patients treated with radical prostatectomy was strongly associated with development of lethal PCa independent of age, Gleason score, pathologic stage, and PTEN status (HR 2.2, 95% confidence interval 1.1-4.1). These results suggest that SChLAP1 may be a useful tissue-based biomarker for identifying PCa patients at higher risk of lethal progression. PATIENT SUMMARY: We examined expression of the RNA molecule SChLAP1 in a large group of prostate cancer patients with long-term follow-up and found that patients with high SChLAP1 expression had a significantly higher chance of developing lethal disease.