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 morning void urinary 6-sulfatoxymelatonin levels.
We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across twelve 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 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, 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPS in TIMELESS (4 SNPs), NPAS2 (6 SNPs), PER3 (2 SNPs) and CSNK1E (1 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.
Circadian genes; prostate cancer; genetic polymorphisms
Epidemiologic evidence on the association of antioxidant intake and prostate cancer incidence is inconsistent. Total antioxidant intake and prostate cancer incidence has not previously been examined. Using the ferric reducing antioxidant potential (FRAP) assay, the total antioxidant content (TAC) of diet and supplements were assessed in relation to prostate cancer incidence. A prospective cohort of 47,896 men aged 40-75 years was followed from 1986 to 2008 for prostate cancer incidence (N=5,656), and they completed food frequency questionnaires (FFQ) every 4 years. A FRAP value was assigned to each item in the FFQ, and for each individual, TAC scores for diet, supplements and both (total) were calculated. Major contributors of TAC intake at baseline were: coffee (28%), fruit and vegetables (23%) and dietary supplements (23%). In multivariate analyses for dietary TAC a weak inverse association was observed; (highest versus lowest quintiles: 0.91 (0.83-1.00, p-trend=0.03) for total prostate cancer, 0.81 (0.64-1.01, p-trend=0.04) for advanced prostate cancer); this association was mainly due to coffee. No association of total TAC on prostate cancer incidence was observed. A positive association with lethal and advanced prostate cancer was observed in the highest quintile of supplemental TAC intake: 1.28 (0.98-1.65, p-trend<0.01) and 1.15 (0.92-1.43), p-trend=0.04). The weak association between dietary antioxidant intake and reduced prostate cancer incidence may be related to specific antioxidants in coffee, to non-antioxidant coffee compounds, or other effects of drinking coffee. The indication of increased risk for lethal and advanced prostate cancer with high TAC intake from supplements warrants further investigation.
Prostate cancer; Antioxidants; Oxidative stress; Diet; Risk factors
TMPRSS2:ERG is a hormonally regulated gene fusion present in about half of prostate tumors. We investigated whether obesity, which deregulates several hormonal pathways, interacts with TMPRSS2:ERG to impact prostate cancer outcomes.
The study included 1243 participants in the prospective Physicians’ Health Study and Health Professionals Follow-Up Study diagnosed with prostate cancer between 1982 and 2005. ERG overexpression (a TMPRSS2:ERG marker) was assessed by immunohistochemistry of tumor tissue from radical prostatectomy or transurethral resection of the prostate. Body mass index (BMI) and waist circumference, measured on average 1.3 years and 5.3 years before diagnosis, respectively, were available from questionnaires. Data on BMI at baseline was also available. We used Cox regression to calculate hazard ratios and 95% confidence intervals (CIs). All statistical tests were two-sided.
During a mean follow-up of 12.8 years, 119 men developed lethal disease (distant metastases or prostate cancer death). Among men with ERG-positive tumors, the multivariable hazard ratio for lethal prostate cancer was 1.48 (95% CI = 0.98 to 2.23) per 5-unit increase in BMI before diagnosis, 2.51 (95% CI = 1.26 to 4.99) per 8-inch increase in waist circumference before diagnosis, and 2.22 (95% CI = 1.35 to 3.63) per 5-unit increase in BMI at baseline. The corresponding hazard ratios among men with ERG-negative tumors were 1.10 (95% CI = 0.76 to1.59; P
interaction = .24), 1.14 (95% CI = 0.62 to 2.10; P
interaction = .09), and 0.78 (95% CI = 0.52 to 1.19; P
interaction = .001).
These results suggest that obesity is linked with poorer prostate cancer prognosis primarily in men with tumors harboring the gene fusion TMPRSS2:ERG.
Over-expression of prostate-specific membrane antigen (PSMA) in tumor tissue and serum has been linked to increased risk of biochemical recurrence in surgically treated prostate cancer patients, but no studies have assessed its association with disease-specific mortality.
We examined whether high PSMA protein expression in prostate tumor tissue was associated with lethal disease, and with tumor biomarkers of progression, among participants of two US-based cohorts (n=902, diagnosed 1983–2004). We used Cox proportional hazards regression to calculate multivariable hazard ratios (HR) and 95% confidence intervals (CI) of lethal prostate cancer, defined as disease-specific death or development of distant metastases (n=95). Partial Spearman rank correlation coefficients were used to correlate PSMA with tumor biomarkers.
During an average 13 years of follow-up, higher PSMA expression at prostatectomy was significantly associated with lethal prostate cancer (age-adjusted HRQuartile(Q)4vs.Q1=2.42; p-trend<0.01). This association was attenuated and non-significant (multivariable-adjusted HRQ4vs.Q1=1.01; p-trend=0.52) after further adjusting for Gleason score and PSA at diagnosis. High PSMA expression was significantly (p<0.05) correlated with higher Gleason score and PSA at diagnosis, increased tumor angiogenesis, lower vitamin D receptor and androgen receptor expression, and absence of ERG expression.
High tumor PSMA expression was not an independent predictor of lethal prostate cancer in the current study. PSMA expression likely captures, in part, malignant features of Gleason grade and tumor angiogenesis.
PSMA is not a strong candidate biomarker for predicting prostate cancer-specific mortality in surgically treated patients.
prostate-specific membrane antigen; prostate cancer; tumor biomarkers; prognosis; angiogenesis
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 IGF1R, a direct activator of the PI3K pathway.
Protein expression in tumor were 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 IGF1R, in relation to lethal prostate cancer (cancer-specific death or distant metastases).
Low PTEN expression was associated with an increase risk of lethal prostate cancer (HR = 1.7, 95% CI: 0.98-3.2, P for trend = 0.04). The association was attenuated after adjustment for Gleason grade, tumor stage, and PSA at diagnosis. A significant negative interaction between PTEN and IGF1R was found (P for interaction = 0.03). Either reduction in PTEN or increase in IGF1R expression was sufficient to worsen prognosis. Models including PTEN and IGF1R expression offer additional predicting power to prostate cancer survival, comparing to those only including demographic and clinical factors.
Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF1R expression remains at normal level.
PTEN and IGF1R expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer.
Prostate cancer; PTEN; Tumor biomarker; Survival; Interaction
The rodent carcinogen acrylamide was discovered in 2002 in commonly consumed foods. Epidemiological studies have observed positive associations between acrylamide intake and endometrial, ovarian and breast cancer risks, which suggests that acrylamide may have sex-hormonal effects.
We cross-sectionally investigated the relationship between acrylamide intake and plasma levels of sex hormones and SHBG among 687 postmenopausal and 1300 premenopausal controls from nested case-control studies within the Nurses’ Health Studies.
There were no associations between acrylamide and sex hormones or SHBG among premenopausal women overall or among never-smokers. Among normal-weight premenopausal women, acrylamide intake was statistically significantly positively associated with luteal total and free estradiol levels. Among postmenopausal women overall and among never-smokers, acrylamide was borderline statistically significantly associated with lower estrone sulfate levels but not with other estrogens, androgens, prolactin or SHBG. Among normal weight women, (borderline) statistically significant inverse associations were noted for estrone, free estradiol, estrone sulfate, DHEA, and prolactin, while statistically significant positive associations for testosterone and androstenedione were observed among overweight women.
Overall, this study did not show conclusive associations between acrylamide intake and sex hormones that would lend unequivocal biological plausibility to the observed increased risks of endometrial, ovarian and breast cancer. The association between acrylamide and sex hormones may differ by menopausal and overweight status. We recommend other studies investigate the relationship between acrylamide and sex hormones in women, specifically using acrylamide biomarkers.
The present study showed some interesting associations between acrylamide intake and sex hormones that urgently need confirmation.
Current prognostic indicators are imperfect predictors of outcome in men with clinicallylocalized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies.
Telomere; prostate cancer; prognostic marker
Shiftwork has been implicated as a risk factor for prostate cancer. Results from prior studies have been mixed but generally support an association between circadian disruption and prostate cancer. Our aim was to investigate the relationship between shiftwork and prostate-specific antigen (PSA) test obtained as part of the National Health and Nutrition Examination Survey (NHANES) study.
We combined three NHANES surveys (2005–2010) to obtain current work schedule among employed men aged 40 to 65 years with no prior history of cancer (except nonmelanoma skin cancer). Men who reported working regular night shifts or rotating shifts were considered shiftworkers. We obtained the total and percentage free PSA test results for these men and dichotomized total PSA into less than 4.0ng/mL or 4.0ng/mL or greater and total PSA of 4.0ng/mL or greater combined with percentage free PSA less than or equal to 25%. Using multivariable logistic regression models, we compared PSA level among current shiftworkers and nonshiftworkers. All statistical tests were two-sided.
We found a statistically significant, age-adjusted association between current shiftwork and elevated PSA at the 4.0ng/mL or greater level (odds ratio = 2.48, 95% confidence interval [CI] = 1.08 to 5.70; P = .03). The confounder-adjusted odds ratio was 2.62 (95% CI = 1.16 to 5.95; P = .02). The confounder-adjusted odds ratio for those with total PSA of 4.0ng/mL or greater and free PSA less than or equal to 25% was 3.13 (95% CI = 1.38 to 7.09; P = .01).
We observed a strong positive association with shiftwork and elevated PSA level. Our data support the notion that sleep or circadian disruption is associated with elevated PSA, indicating that shiftworking men likely have an increased risk of developing prostate cancer.
Gleason grade is universally used for pathologic scoring 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 1982–2004 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 T3, 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 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 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.
prostate cancer; Gleason score; dedifferentiation
5α-reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear.
To determine the association between 5ARI use and development of high-grade or lethal prostate cancer.
Design, Setting, and Participants
Prospective observational study of 38,058 men followed for prostate cancer diagnosis and outcomes between 1996–2010 in the Health Professionals Follow-up Study.
Use of 5ARIs between 1996–2010.
Main Outcome Measures
Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing.
During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high-grade (Gleason 8–10), 1238 were Gleason grade 7, and 1600 were low-grade (Gleason 2–6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (HR 0.77; 95% CI, 0.65–0.91). 5ARI users had a reduced risk of Gleason 7 (HR 0.67; 95% CI, 0.49–0.91) and low-grade (Gleason 2–6) prostate cancer (HR 0.74; 95% CI, 0.57–0.95). 5ARI use was not associated with risk of high-grade (Gleason 8–10, HR 0.97; 95% CI, 0.64–1.46) or lethal disease (HR 0.99; 95% CI, 0.58–1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use 0.95; 95% CI, 0.92–0.99), localized (HR 0.95; 95% CI, 0.90–1.00), and low-grade disease (HR 0.92; 95% CI, 0.85–0.99). There was no association for lethal, high-grade, or grade 7 disease.
Conclusions and Relevance
While 5ARI use was not associated with developing high-grade or lethal prostate cancer, they were associated with a reduction in low-grade, Gleason 7 and overall prostate cancer. Since the number of patients with high-grade or lethal prostate cancer in our cohort was limited, we cannot rule out potential risk of harm with 5ARI use.
Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions.
The Physicians’ Health Study (PHS) is a prospective cohort of 22,071 US physicians; we utilized a nested case-control study of 1,352 PCa cases and 1,382 controls. We assessed four SNPs capturing common variation within the SEPP1 locus. In a subset of men (n=80), we evaluated SEPP1 mRNA expression in tumors.
Two SNPs were significantly associated with PCa risk. For rs11959466, each T allele increased risk (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02,1.69; ptrend=0.03). For rs13168440, the rare homozygote genotype decreased risk compared to the common homozygote (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with plasma selenium; increasing selenium levels were associated with decreased PCa risk only among men with the minor allele (pinteraction=0.01). SEPP1 expression was significantly lower in men with lethal PCa than long-term survivors.
SEPP1 genetic variation was associated with PCa incidence; replication of these results in an independent dataset is necessary. These findings further support a causal link between selenium and PCa, and suggest that the effect of selenium may differ by genetics.
genetic variation; selenium; prostate cancer
While positive associations have consistently been reported between sleep disruption and breast cancer, less is known about its potential role in prostate cancer.
Within the prospective AGES-Reykjavik cohort study, we followed 2,102 men recruited in 2002–2006 until the end of 2009. Participants answered questions on sleep disruption. Information on the occurrence of prostate cancer was obtained through record-linkages across the Icelandic Cancer Registry. We used Cox regression models with 95% confidence intervals [CIs] to estimate hazard ratios [HR] of prostate cancer by symptoms of sleep disruption.
During follow-up, 135 men (6.4%) were diagnosed with prostate cancer. Compared to men without sleep disruption, those with problems falling and staying asleep were at significantly increased risk of prostate cancer [HR, 1.7 (95% CI, 1.0–2.9) and 2.1 (95% CI, 1.2–3.7)], respectively, with increasing sleep disruption severity. When restricted to advanced prostate cancer (≥ stage T3 or lethal disease), these associations became even stronger [HRs 2.1 (95% CI, 0.7–6.2) and 3.2 (95% CI, 1.1–9.7)]. The results did not change after excluding from the analyses men who woke up during the night, indicative of nocturia, suggesting limited risk of reverse association.
Our data suggest that certain aspects of sleep disruption may confer an increased risk of prostate cancer and call for additional, larger studies with longer follow-up times.
Prostate cancer is one of the leading public health concerns in men; if confirmed in future studies the association between sleep disruption and prostate cancer risk may open new avenues for prevention.
prostate cancer; circadian disruption; sleep disruption; cohort study; melatonin; light at night
To study associations between single nucleotide polymorphisms (SNPs) in RNASEL, a gene implicated in inflammation and prostate cancer risk, and outcomes following radiation therapy (RT).
We followed participants in the prospective US Health Professionals Follow-Up Study treated with RT for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence.
We followed 434 patients treated with RT for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint (HR: 0.65; 95% CI: 0.45–0.94; p = 0.02) driven by decreased biochemical recurrence (HR: 0.60; 95% CI: 0.40 – 0.89; p = 0.01) and men treated with external beam (HR: 0.58; 95% CI: 0.36 – 0.93; p = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes following RT (p-interaction = 0.02).
We demonstrate an association between RNASEL SNP rs12757998 and outcome after RT for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management.
prostate cancer; radiotherapy; inflammation; outcome; single nucleotide polymorphism
Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether 1) common genetic variation in CaSR was associated with PCa risk and 2) these associations varied by calcium intake or plasma 25-hydroxyvitamin D (25(OH)D) levels.
We included 1193 PCa cases and 1244 controls nested in the prospective Health Professionals Follow-up Study (1993-2004). We genotyped 18 CaSR SNPs to capture common variation. The main outcome was risk of lethal PCa (n=113); secondary outcomes were overall (n=1193) and high-grade PCa (n=225). We used the kernel machine approach to conduct a gene-level multi-marker analysis and unconditional logistic regression to compute per-allele odds ratios (OR) and 95% confidence intervals (CI) for individual SNPs.
The joint association of SNPs in CaSR was significant for lethal PCa (p=0.04); this association was stronger in those with low 25(OH)D (p=0.009). No individual SNPs were associated after considering multiple testing; 3 SNPs were nominally associated (p<0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42-0.99): rs6438705; 0.65(0.47-0.89)): rs13083990; and 1.55(1.09-2.20): rs2270916. The 3 non-synonymous SNPs (rs1801725, rs1042636, rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D (OR(95%CI): 0.54(0.31-0.95)). There were no significant associations with overall or high-grade PCa.
Our findings indicate that CaSR may be involved in PCa progression.
Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted.
molecular and genetic epidemiology; prostate cancer; vitamin D, calcium; CaSR
The number of patients in Sweden treated with radical prostatectomy for localized prostate cancer has increased exponentially. The extent to which this increase reflects treatment of non-lethal disease detected through PSA screening is unknown.
We undertook a nationwide study of all 18,837 prostate cancer patients treated with radical prostatectomy in Sweden from 1988 to 2008 with complete follow-up through 2009. We compared cumulative incidence curves, fit Cox regression and cure models and performed a simulation study to determine changes in treatment of non-lethal cancer, in cancer-specific survival over time, and effect of lead-time due to PSA screening.
The annual number of radical prostatectomies increased 25-fold during the study period. The five-year cancer-specific mortality decreased from 3.9% (95% CI 2.5 to 5.3) among patients diagnosed between 1988 and 1992 to 0.7% (95% CI 0.4–1.1) among those diagnosed between 1998 and 2002 (p for trend < 0.001). According to the cure model, the risk of not being cured declined by 13% (95% CI 12–14%) with each calendar year. The simulation study indicated that only about half of the improvement in disease-specific survival could be accounted for by lead-time.
Patients overdiagnosed with non-lethal prostate cancer appear to account for a substantial and growing part of the dramatic increase in radical prostatectomies in Sweden but increasing survival rates are likely also due to true reductions in the risk of disease-specific death over time. Because the magnitude of harm and costs due to overtreatment can be considerable, identification of men who likely benefit from radical prostatectomy is urgently needed.
Overdiagnosis; prostate cancer; PSA screening; radical prostatectomy
A growing proportion of men diagnosed with localized prostate cancer detected through prostate-specific antigen testing are dying from causes other than prostate cancer. Temporal trends in specific causes of death among prostate cancer patients have not been well described.
We analyzed causes of death among all incident prostate cancer cases recorded in the nationwide Swedish Cancer Registry (1961–2008; n = 210 112) and in the US Surveillance, Epidemiology, and End Results Program (1973–2008; n = 490 341). We calculated the cumulative incidence of death due to seven selected causes that accounted for more than 80% of the reported deaths (including ischemic heart disease and non–prostate cancer) and analyzed mortality trends by calendar year and age at diagnosis and length of follow-up.
During follow-up through 2008, prostate cancer accounted for 52% of all reported deaths in Sweden and 30% of reported deaths in the United States among men with prostate cancer; however, only 35% of Swedish men and 16% of US men diagnosed with prostate cancer died from this disease. In both populations, the cumulative incidence of prostate cancer–specific death declined during follow-up, while the cumulative incidences of death from ischemic heart disease and non–prostate cancer remained constant. The 5-year cumulative incidence of death from prostate cancer among all men was 29% in Sweden and 11% in the United States.
In Sweden and the United States, men diagnosed with prostate cancer are less likely to die from prostate cancer than from another cause. Because many of these other causes of death are preventable through changes in lifestyle, interventions that target lifestyle factors should be integrated into prostate cancer management.
Whether the genomic rearrangement TMPRSS2:ERG has prognostic value in prostate cancer is unclear.
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.
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 (HR: 0.99; 95% 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 (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).
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.
This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy.
TMPRSS2:ERG; prostate cancer; gene fusion; biomarker; prognosis
Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression1. Here,we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP–SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment con-firmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.
Although dietary fat has been associated with prostate cancer risk, the association between specific fatty acids and prostate cancer survival remains unclear. Dietary intake of 14 fatty acids was analyzed in a population-based cohort of 525 Swedish men with prostate cancer in Örebro County (1989–1994). Multivariable hazard ratios and 95% confidence intervals for time to prostate cancer death by quartile and per standard deviation increase in intake were estimated by Cox proportional hazards regression. Additional models examined the association by stage at diagnosis (localized: T0-T2/M0; advanced: T0-T4/M1, T3-T4/M0). Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer (Ptrend = 0.05 and 0.04, respectively). Among men with localized prostate cancer, hazard ratios of 2.07 (95% confidence interval: 0.93, 4.59; Ptrend = 0.03) for elevated total fat, 2.39 (95% confidence interval: 1.06, 5.38) for saturated myristic acid, and 2.88 (95% confidence interval: 1.24, 6.67) for shorter chain (C4-C10) fatty acid intakes demonstrated increased risk for disease-specific mortality for the highest quartile compared with the lowest quartile. This study suggests that high intake of total fat and certain saturated fatty acids may worsen prostate cancer survival, particularly among men with localized disease. In contrast, high marine omega-3 fatty acid intake may improve disease-specific survival for all men.
fatty acids; prostatic neoplasms; survival analysis
Recent studies suggest variation in genes along the vitamin D pathway, as well as vitamin D receptor (VDR) protein levels, may be associated with prostate cancer. As serum vitamin D levels vary by season, we sought to determine whether expression of genes on the vitamin D pathway, assessed in prostate tumor tissue, do the same.
Our study incorporates mRNA expression data from 362 men in the Swedish Watchful Waiting cohort, diagnosed between 1977 and 1999, and 106 men enrolled in the US Physicians’ Health Study (PHS) diagnosed between 1983 and 2004. We also assayed for VDR protein expression among 832 men in the PHS and Health Professionals Follow-up Study cohorts. Season was characterized by date of initial tissue specimen collection categorically and by average monthly ultraviolet radiation levels. One-way analysis of variance was used to examine variation in expression levels of six genes on the vitamin D pathway – VDR, GC, CYP27A1, CYP27B1, RXRα, CYP24A1 – and VDR protein by season, adjusted for age at diagnosis and Gleason grade. Variation was also examined separately among lethal and nonlethal cases.
Tumor expression levels of the six genes did not significantly vary by season of tissue collection. No consistent patterns emerged from subgroup analyses by lethal versus nonlethal cases.
Unlike circulating levels of 25-OH vitamin D, expression levels of genes on the vitamin D pathway and VDR protein did not vary overall by season of tissue collection. Epidemiological analyses of vitamin D gene expression may not be biased by seasonality.
Vitamin D; Vitamin D receptor; prostate cancer; gene expression; seasonality; biomarkers
Acrylamide has been designated by IARC as a “probable human carcinogen.” High levels are formed during cooking of many commonly consumed foods including French fries, potato chips, breakfast cereal, and coffee. Two prospective cohort studies and two case-control studies in Europe found no association between acrylamide intake and prostate cancer. We examined this association in a large prospective cohort of 47,896 U.S. men in the Health Professionals’ Follow-up Study, using updated dietary acrylamide intake from food frequency questionnaires in 1986, 1990, 1994, 1998, and 2002. From 1986 through 2006, we documented 5025 cases of prostate cancer, and 642 lethal cancers. We used Cox proportional hazards models to assess the association between acrylamide intake from diet and prostate cancer risk overall as well as risk of advanced or lethal cancer.
Acrylamide intake ranged from a mean of 10.5 mcg/day in the lowest quintile to 40.1 mcg/day in the highest quintile; coffee and potato products were largest contributors to intake. The multivariate-adjusted relative risk of prostate cancer was 1.02 (95% confidence interval: 0.92–1.13) for the highest versus lowest quintile of acrylamide intake (p-value for trend=0.90). Results were similar when restricted to never smokers and to men who had PSA tests. There was no significant association for dietary acrylamide and risk of lethal, advanced, or high-grade disease, or for different latency periods ranging from 0–4 years to 12–16 years. We found no evidence that acrylamide intake, within the range of U.S. diets, is associated with increased risk of prostate cancer.
Acrylamide; diet; prostate cancer
Adiponectin, an insulin-sensitizing adipokine, is inversely associated with adiposity and prostate cancer risk and progression. However, the role of genetic variation in the adiponectin (ADIPOQ) and receptor genes (ADIPOR1/R2) in prostate cancer is largely unknown.
In a nested case-control study of 1286 cases and 1267 controls within the Physicians' Health Study, we evaluated 29 common single nucleotide polymorphisms (SNPs) in ADIPOQ (n=13), ADIPOR1(n=5) and ADIPOR2(n=11) in relation to the risk of prostate cancer. In subgroups, we also evaluated the association of genotype and circulating adiponectin levels (n=951) and prostate tumor expression of insulin receptor (IR) and insulin-like growth factor 1 (IGF-1R) receptor (n=181).
Among the 12 tagging polymorphisms in ADIPOQ, four (rs266729, rs182052, rs822391, rs2082940) were significantly associated (p<0.05) with overall prostate cancer risk, with no significant difference by tumor grade or clinical stage. Two of the risk SNPs (rs266729, rs182052) plus four other SNPs (rs16861209, rs17366568, rs3774261, rs7639352) were also associated with plasma adiponectin levels and three of these (rs1686109, rs17366568, rs3774261) were also significantly associated with IR expression in prostate tumor tissue. One additional SNP was associated with IGF1-R tumor tissue expression (rs16861205). None of the 16 variants in ADIPOR1/R2 were related to cancer risk or circulating adiponectin levels.
Common variants in the adiponectin gene were associated with prostate cancer risk, plasma adiponectin levels, and IR or IGF-1R expression in the prostate tumor.
These genotype-phenotype associations support the biological relevance of adiponectin for prostate carcinogenesis, particularly in earlier stages of development.
A challenge in prostate cancer (PCa) management is identifying potentially lethal disease at diagnosis. Inflammation, focal prostatic atrophy and prostatic intraepithelial neoplasia (PIN) are common in prostate tumor specimens, but it is not clear whether these lesions have prognostic significance.
We conducted a case-control study nested in a cohort of men diagnosed with stage T1a-b PCa through transurethral resection of the prostate in Sweden. Cases are men who died of PCa (n=228). Controls are men who survived more than 10 years after PCa diagnosis without metastases (n=387). Slides were assessed for Gleason grade, inflammation, PIN, and four subtypes of focal prostatic atrophy: simple atrophy (SA), post-atrophic hyperplasia (PAH), simple atrophy with cyst formation, and partial atrophy. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for odds of lethal PCa with multivariable logistic regression.
Chronic inflammation and PIN were more frequently observed in tumors with PAH, but not SA. No specific type of atrophy or inflammation was significantly associated with lethal PCa overall, but there was a suggestion of a positive association for chronic inflammation. Independent of age, Gleason score, year of diagnosis, inflammation, and atrophy type, men with PIN were 89% more likely to die of PCa (95% CI:1.04-3.42).
Our data demonstrate that PIN, and perhaps presence of moderate or severe chronic inflammation, may have prognostic significance for PCa.
Lesions in tumor adjacent tissue, and not just the tumor itself, may aid in identification of clinically relevant disease.
Prostate adenocarcinoma; Chronic inflammation; Post-atrophic hyperplasia; Lethal prostate cancer
The association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease.
We assessed prediagnostic 25-hydroxyvitamin D [25(OH)D] levels in plasma, variation in vitamin D–related genes, and risk of lethal prostate cancer using a prospective case–control study nested within the Health Professionals Follow-up Study. We included 1260 men who were diagnosed with prostate cancer after providing a blood sample in 1993–1995 and 1331 control subjects. Men with prostate cancer were followed through March 2011 for lethal outcomes (n = 114). We selected 97 single-nucleotide polymorphisms (SNPs) in genomic regions with high linkage disequilibrium (tagSNPs) to represent common genetic variation among seven vitamin D–related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR). We used a logistic kernel machine test to assess whether multimarker SNP sets in seven vitamin D pathway–related genes were collectively associated with prostate cancer. Tests for statistical significance were two-sided.
Higher 25(OH)D levels were associated with a 57% reduction in the risk of lethal prostate cancer (highest vs lowest quartile: odds ratio = 0.43, 95% confidence interval = 0.24 to 0.76). This finding did not vary by time from blood collection to diagnosis. We found no statistically significant association of plasma 25(OH)D levels with overall prostate cancer. Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer.
In this prospective study, plasma 25(OH)D levels and common variation among several vitamin D–related genes were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer.
The safety of antioxidant supplements during radiation therapy (RT) for cancer is controversial. Antioxidants could potentially counteract the pro-oxidant effects of RT and compromise therapeutic efficacy. We performed a prospective study nested within the Physicians' Health Study (PHS) randomized trial to determine if supplemental antioxidant use during RT for prostate cancer is associated with an increased risk of prostate cancer death or metastases.
Methods and Materials
383 PHS participants received RT for prostate cancer while randomized to beta-carotene (50 mg on alternate days), or placebo. The primary endpoint was time from RT to lethal prostate cancer, defined as prostate cancer death or bone metastases. The Kaplan-Meier method was used to estimate survival probabilities, and the log-rank test to compare groups. Cox proportional hazards regression was used to estimate the effect of beta-carotene compared with placebo during RT.
With a median follow-up of 10.5 years, there was no significant difference in risk of lethal prostate cancer with use of beta-carotene during RT compared with placebo (HR=0.72; 95% CI, 0.42 to 1.24; P=0.24). After adjusting for age at RT, PSA, Gleason score, and clinical stage, the difference remained non-significant. The 10-year freedom from lethal prostate cancer was 92% (95% CI, 87-95%) in the beta-carotene group and 89% (95% CI, 84-93%) in the placebo group.
Use of the supplemental antioxidant, beta-carotene, during RT was not associated with an increased risk of prostate cancer death or metastases. This study suggests a lack of harm from supplemental beta-carotene during radiation therapy for prostate cancer.
Antioxidants; prostate cancer; vitamins; beta-carotene; outcomes