| 1. |
- Flavin, Richard, et al.
(author)
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SPINK1 protein expression and prostate cancer progression
- 2014
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In: Clinical Cancer Research. - Philadelphia, USA : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 20:18, s. 4904-11
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Journal article (peer-reviewed)abstract
- Purpose: SPINK1 overexpression has been described in prostate cancer and is linked with poor prognosis in many cancers. The objective of this study was to characterize the association between SPINK1 overexpression and prostate cancer-specific survival.Experimental design: The study included 879 participants in the U.S. Physicians' Health Study and Health Professionals Follow-Up Study, diagnosed with prostate cancer (1983-2004) and treated by radical prostatectomy. Protein tumor expression of SPINK1 was evaluated by immunohistochemistry on tumor tissue microarrays.Results: Seventy-four of 879 (8%) prostate cancer tumors were SPINK1 positive. Immunohistochemical data were available for PTEN, p-Akt, pS6, stathmin, androgen receptor (AR), and ERG (as a measure of the TMPRSS2:ERG translocation). Compared with SPINK1-negative tumors, SPINK1-positive tumors showed higher PTEN and stathmin expression, and lower expression of AR (P < 0.01). SPINK1 overexpression was seen in 47 of 427 (11%) ERG-negative samples and in 19 of 427 (4%) ERG-positive cases (P = 0.0003). We found no significant associations between SPINK1 status and Gleason grade or tumor stage. There was no association between SPINK1 expression and biochemical recurrence (P = 0.56). Moreover, there was no association between SPINK1 expression and prostate cancer mortality (there were 75 lethal cases of prostate cancer during a mean of 13.5 years follow-up; HR = 0.71; 95% confidence interval, 0.29-1.76).Conclusions: Our results suggest that SPINK1 protein expression may not be a predictor of recurrence or lethal prostate cancer amongst men treated by radical prostatectomy. SPINK1 and ERG protein expression do not seem to be entirely mutually exclusive, as some previous studies have suggested.
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| 2. |
- Dickerman, Barbra A., et al.
(author)
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Midlife metabolic factors and prostate cancer risk in later life
- 2018
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In: International Journal of Cancer. - Hoboken, USA : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 142:6, s. 1166-1173
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Journal article (peer-reviewed)abstract
- Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n = 9,097, enrolled 1967-1987) were followed for incident (n = 1,084 total; n = 378 advanced; n = 148 high-grade) and fatal (n = 340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI ≥30 kg/m2 ; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mm Hg or taking antihypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dl or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides were associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p trend = 0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer.
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| 3. |
- Epstein, Mara M, et al.
(author)
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Seasonal variation in expression of markers in the vitamin D pathway in prostate tissue
- 2012
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In: Cancer Causes and Control. - : Springer. - 0957-5243 .- 1573-7225. ; 23:8, s. 1359-1366
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Journal article (peer-reviewed)abstract
- PURPOSE: 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 the expression of genes on the vitamin D pathway, assessed in prostate tumor tissue, do the same.METHODS: 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 the 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.RESULTS: Tumor expression levels of the six genes did not vary significantly by season of tissue collection. No consistent patterns emerged from subgroup analyses by lethal versus nonlethal cases.CONCLUSIONS: 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.
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| 4. |
- Fang, Fang, et al.
(author)
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Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer
- 2011
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In: PLOS ONE. - San Fransisco, USA : Public Library Science. - 1932-6203. ; 6:4
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Journal article (peer-reviewed)abstract
- Background: Laboratory evidence suggests that vitamin D might influence prostate cancer prognosis.Methodology/principal findings: We examined the associations between prediagnostic plasma levels of 25(OH)vitamin D [25(OH)D] and 1,25(OH)(2) vitamin D [1,25(OH)(2)D] and mortality among 1822 participants of the Health Professionals Follow-up Study and Physicians' Health Study who were diagnosed with prostate cancer. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total mortality (n = 595) and lethal prostate cancer (death from prostate cancer or development of bone metastases; n = 202). In models adjusted for age at diagnosis, BMI, physical activity, and smoking, we observed a HR of 1.22 (95% CI: 0.97, 1.54) for total mortality, comparing men in the lowest to the highest quartile of 25(OH)D. There was no association between 1,25(OH)(2)D and total mortality. Men with the lowest 25(OH)D quartile were more likely to die of their cancer (HR: 1.59; 95% CI: 1.06, 2.39) compared to those in the highest quartile (P(trend) = 0.006). This association was largely explained by the association between low 25(OH)D levels and advanced cancer stage and higher Gleason score, suggesting that these variables may mediate the influence of 25(OH)D on prognosis. The association also tended to be stronger among patients with samples collected within five years of cancer diagnosis. 1,25(OH)(2)D levels were not associated with lethal prostate cancer.Conclusions/significance: Although potential bias of less advanced disease due to more screening activity among men with high 25(OH)D levels cannot be ruled out, higher prediagnostic plasma 25(OH)D might be associated with improved prostate cancer prognosis.
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| 5. |
- Fiorentino, Michelangelo, et al.
(author)
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Immunohistochemical Expression of BRCA1 and Lethal Prostate Cancer
- 2010
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In: Cancer Research. - Philadelphia, USA : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:8, s. 3136-3139
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Journal article (peer-reviewed)abstract
- 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.
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| 6. |
- Kantor, Elizabeth D., et al.
(author)
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Adolescent body mass index and erythrocyte sedimentation rate in relation to colorectal cancer risk
- 2016
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In: Gut. - London, United Kingdom : BMJ Publishing Group. - 0017-5749 .- 1468-3288. ; 65:8, s. 1289-1295
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Journal article (peer-reviewed)abstract
- Objective: Adult obesity and inflammation have been associated with risk of colorectal cancer (CRC); however, less is known about how adolescent body mass index (BMI) and inflammation, as measured by erythrocyte sedimentation rate (ESR), relate to CRC risk. We sought to evaluate these associations in a cohort of 239 658 Swedish men who underwent compulsory military enlistment examinations in late adolescence (ages 16-20 years).Design: At the time of the conscription assessment (1969-1976), height and weight were measured and ESR was assayed. By linkage to the national cancer registry, these conscripts were followed for CRC through 1 January 2010. Over an average of 35 years of follow-up, 885 cases of CRC occurred, including 501 colon cancers and 384 rectal cancers. Cox regression was used to estimate adjusted HRs and corresponding 95% CIs.Results: Compared with normal weight (BMI 18.5 to <25 kg/m(2)) in late adolescence, upper overweight (BMI 27.5 to <30 kg/m(2)) was associated with a 2.08-fold higher risk of CRC (95% CI 1.40 to 3.07) and obesity (BMI 30+ kg/m(2)) was associated with a 2.38-fold higher risk of CRC (95% CI 1.51 to 3.76) (p-trend: <0.001). Male adolescents with ESR (15+ mm/h) had a 63% higher risk of CRC (HR 1.63; 95% CI 1.08 to 2.45) than those with low ESR (<10 mm/h) (p-trend: 0.006). Associations did not significantly differ by anatomic site.Conclusions: Late-adolescent BMI and inflammation, as measured by ESR, may be independently associated with future CRC risk. Further research is needed to better understand how early-life exposures relate to CRC.
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| 7. |
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| 8. |
- Lu, Donghao, et al.
(author)
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Stress-Related Signaling Pathways in Lethal and Nonlethal Prostate Cancer
- 2016
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In: Clinical cancer research : an official journal of the American Association for Cancer Research. - Philadelphia, USA : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 22:3, s. 765-772
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Journal article (peer-reviewed)abstract
- Purpose: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and nonlethal disease.Experimental design: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n = 150; n = 82 with normal) and the Health Professionals Follow-Up Study (n = 254; n = 120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome and to biomarkers as secondary outcomes.Results: Differential mRNA expression of genes within the adrenergic (P = 0.001), glucocorticoid (P < 0.0001), serotoninergic (P = 0.0019), and muscarinic (P = 0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (P = 0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and nonlethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion.Conclusions: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies.
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| 9. |
- Meyer, Mara S., et al.
(author)
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Genetic variation in RNASEL associated with prostate cancer risk and progression
- 2010
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In: Carcinogenesis. - Oxford, United Kingdom : Oxford University Press. - 0143-3334 .- 1460-2180. ; 31:9, s. 1597-603
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Journal article (peer-reviewed)abstract
- Variation in genes contributing to the host immune response may mediate the relationship between inflammation and prostate carcinogenesis. RNASEL at chromosome 1q25 encodes ribonuclease L, part of the interferon-mediated immune response to viral infection. We therefore investigated the association between variation in RNASEL and prostate cancer risk and progression in a study of 1286 cases and 1264 controls nested within the prospective Physicians' Health Study. Eleven single-nucleotide polymorphisms (SNPs) were selected using the web-based 'Tagger' in the HapMap CEPH panel (Utah residents of Northern and Western European Ancestry). Unconditional logistic regression models assessed the relationship between each SNP and incident advanced stage (T(3)/T(4), T(0)-T(4)/M(1) and lethal disease) and high Gleason grade (>/=7) prostate cancer. Further analyses were stratified by calendar year of diagnosis. Cox proportional hazards models examined the relationship between genotype and prostate cancer-specific survival. We also explored associations between genotype and serum inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha receptor 2 using linear regression. Individuals homozygous for the variant allele of rs12757998 had an increased risk of prostate cancer [AA versus GG; odds ratio (OR): 1.63, 95% confidence interval (CI): 1.18-2.25), and more specifically, high-grade tumors (OR: 1.90, 95% CI: 1.25-2.89). The same genotype was associated with increased CRP (P = 0.02) and IL-6 (P = 0.05) levels. Missense mutations R462Q and D541E were associated with an increased risk of advanced stage disease only in the pre-prostate-specific antigen era. There were no significant associations with survival. The results of this study support a link between RNASEL and prostate cancer and suggest that the association may be mediated through inflammation. These novel findings warrant replication in future studies.
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| 10. |
- Pettersson, Andreas, et al.
(author)
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The ABC model of prostate cancer : A conceptual framework for the design and interpretation of prognostic studies
- 2017
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In: Cancer. - Hoboken, USA : John Wiley & Sons. - 0008-543X .- 1097-0142. ; 123:9, s. 1490-1496
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Research review (peer-reviewed)abstract
- There has been limited success in identifying prognostic biomarkers in prostate cancer. A partial explanation may be that insufficient emphasis has been put on clearly defining what type of marker or patient category a biomarker study aims to identify and how different cohort characteristics affect the ability to identify such a marker. In this article, the authors put forth the ABC model of prostate cancer, which defines 3 groups of patients with localized disease that an investigator may seek to identify: patients who, within a given time frame, will not develop metastases even if untreated (category A), will not develop metastases because of radical treatment (category B), or will develop metastases despite radical treatment (category C). The authors demonstrate that follow-up time and prostate-specific antigen screening intensity influence the prevalence of patients in categories A, B, and C in a study cohort, and that prognostic markers must be tested in both treated and untreated cohorts to accurately distinguish the 3 groups. The authors suggest that more emphasis should be put on considering these factors when planning, conducting, and interpreting the results from prostate cancer biomarker studies, and propose the ABC model as a framework to aid in that process.
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