| 1. |
- Brown, David A, et al.
(författare)
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Macrophage inhibitory cytokine 1 : a new prognostic marker in prostate cancer.
- 2009
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 15:21, s. 6658-6664
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: High serum levels of macrophage inhibitory cytokine 1 (MIC-1) are strongly associated with metastatic prostate cancer, suggesting MIC-1 is a biomarker for prostate cancer prognosis. EXPERIMENTAL DESIGN: We conducted a prospective cohort study of 1,442 Swedish men with a pathologically verified diagnosis of prostate cancer between 2001 and 2003. Blood was drawn either pretreatment (n = 431) or posttreatment (n = 1,011) and cases were followed for a mean time of 4.9 years (range, 0.1-6.8 years). RESULTS: MIC-1 serum levels independently predicted poor cancer-specific survival with an almost 3-fold higher cancer death rate in patients with serum levels in the highest quartile compared with men with serum levels in the lowest quartile (adjusted hazard ratio, 2.98; 95% confidence interval, 1.82-4.68). Pretreatment MIC-1 levels revealed an even stronger association with disease outcome with an 8-fold higher death rate in the highest compared with the lowest category (adjusted hazard ratio, 7.98; 95% confidence interval, 1.73-36.86). Among patients considered to have localized disease, MIC-1 significantly increased the discriminative capacity between indolent and lethal prostate cancer compared with the established prognostic markers clinical stage, pathologic grade, and prostate-specific antigen level (P = 0.016). A sequence variant in the MIC-1 gene was associated with decreased MIC-1 serum levels (P = 0.002) and decreased prostate cancer mortality (P = 0.003), suggesting a causative role of MIC-1 in prostate cancer prognosis. CONCLUSIONS: Serum MIC-1 concentration is a novel biomarker capable of predicting prostate cancer prognosis.
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| 2. |
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| 3. |
- Hedelin, Maria, et al.
(författare)
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Association of frequent consumption of fatty fish with prostate cancer risk is modified by COX-2 polymorphism
- 2007
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Ingår i: International Journal of Cancer. - Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. No Calif Canc Ctr, Fremont, CA USA. Umea Univ, Dept Radiat Sci Oncol, Umea, Sweden. Univ Milan, Dept Stat, Milan, Italy. Karolinska Univ Hosp, Ctr Oncol, CLINTEC, Stockholm, Sweden. Wake Forest Univ, Ctr Human Genet, Sch Med, Winston Salem, NC USA. Harvard Univ, Dept Epidemiol, Boston, MA 02115 USA. : WILEY-LISS. - 0020-7136 .- 1097-0215. ; 120:2, s. 398-405
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Tidskriftsartikel (refereegranskat)abstract
- Dietary intake of marine fatty acids from fish may protect against prostate cancer development. We studied this association and whether it is modified by genetic variation in cyclooxygenase (COX)-2, a key enzyme in fatty acid metabolism and inflammation. We assessed dietary intake of fish among 1,499 incident prostate cancer cases and 1,130 population controls in Sweden. Five single nucleotide polymorphisms (SNPs) were identified and genotyped in available blood samples for 1,378 cases and 782 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multivariate logistic regression. Multiplicative and additive interactions between fish intake and COX-2 SNPs on prostate cancer risk were evaluated. Eating fatty fish (e.g. salmon-type fish) once or more per week, compared to never, was associated with reduced risk of prostate cancer (OR: 0.57, 95% CI: 0.43-0.76). The OR comparing the highest to the lowest quartile of marine fatty acids intake was 0.70 (95% CI: 0.51-0.97). We found a significant interaction (p < 0.001) between salmon-type fish intake and a SNP in the COX-2 gene (rs5275: +6365 T/C), but not with the 4 other SNPs examined. We found strong inverse associations with increasing intake of salmon-type fish among carriers of the variant allele (OR for once per week or more vs. never = 0.28, 95% CI: 0.18-0.45; p(trend) < 0.01), but no association among carriers of the more common allele. Frequent consumption of fatty fish and marine fatty acids appears to reduce the risk of prostate cancer, and this association is modified by genetic variation in the COX-2 gene.
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| 4. |
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| 5. |
- Hsu, Fang-Chi, et al.
(författare)
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A novel prostate cancer susceptibility locus at 19q13.
- 2009
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Ingår i: Cancer research. - 1538-7445. ; 69:7, s. 2720-3
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Tidskriftsartikel (refereegranskat)abstract
- A two-stage genome-wide association study (GWAS) of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative identified single nucleotide polymorphisms (SNP) in 150 regions across the genome that may be associated with prostate cancer (PCa) risk. We filtered these results to identify 43 independent SNPs where the frequency of the risk allele was consistently higher in cases than in controls in each of the five CGEMS study populations. Genotype information for 22 of these 43 SNPs was obtained either directly by genotyping or indirectly by imputation in our PCa GWAS of 500 cases and 500 controls selected from a population-based case-control study in Sweden [Cancer of the Prostate in Sweden (CAPS)]. Two of these 22 SNPs were significantly associated with PCa risk (P<0.05). We then genotyped these two SNPs in the remaining cases (n=2,393) and controls (n=1,222) from CAPS and found that rs887391 at 19q13 was highly associated with PCa risk (P=9.4 x 10(-4)). A similar trend of association was found for this SNP in a case-control study from Johns Hopkins Hospital (JHH), albeit the result was not statistically significant. Altogether, the frequency of the risk allele of rs887391 was consistently higher in cases than controls among each of seven study populations examined, with an overall P=3.2 x 10(-7) from a combined allelic test. A fine-mapping study in a 110-kb region at 19q13 among CAPS and JHH study populations revealed that rs887391 was the most strongly associated SNP in the region. Additional confirmation studies of this region are warranted.
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| 6. |
- Kirchberger, Tanja, et al.
(författare)
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Cellular effects and metabolic stability of N1-cyclicinosinediphosphoribose and its derivatives
- 2006
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Ingår i: British Journal of Pharmacology. - : John Wiley & Sons. - 0007-1188 .- 1476-5381. ; 149:4
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose:Recently, a number of mimics of the second messenger cyclic ADP-ribose (cADPR) with replacement of adenosine by inosine were introduced. In addition, various alterations in the molecule ranging from substitutions at C8 of the base up to full replacement of the ribose moieties still retained biological activity. However, nothing is known about the metabolic stability and cellular effects of these novel analogues.Experimental approach:cADPR and the inosine-based analogues were incubated with CD38, ADP-ribosyl cyclase and NAD-glycohydrolase and metabolism was analysed by RP-HPLC. Furthermore, the effect of the analogues on cytokine expression and proliferation was investigated in primary T-lymphocytes and T-lymphoma cells.Key results:Incubation of cADPR with CD38 resulted in degradation to adenosine diphosphoribose. ADP-ribosyl cyclase weakly catabolised cADPR whereas NAD-glycohydrolase showed no such activity. In contrast, N1-cyclic inosine 5′-diphosphoribose (N1-cIDPR) was not hydrolyzed by CD38. Three additional N1-cIDPR analogues showed a similar stability. Proliferation of Jurkat T-lymphoma cells was inhibited by N1-cIDPR, N1-[(phosphoryl-O-ethoxy)-methyl]-N9-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthine-cyclic pyrophosphate (N1-cIDP-DE) and N1-ethoxymethyl-cIDPR (N1-cIDPRE). In contrast, in primary T cells neither proliferation nor cytokine expression was affected by these compounds.Conclusions and Implications:The metabolic stability of N1-cIDPR and its analogues provides an advantage for the development of novel pharmaceutical compounds interfering with cADPR mediated Ca2+ signalling pathways. The differential effects of N1-cIDPR and N1-cIDPRE on proliferation and cytokine expression in primary T cells versus T-lymphoma cells may constitute a starting point for novel anti-tumor drugs.
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| 7. |
- Lindstrom, Sara, et al.
(författare)
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Genetic variation in the upstream region of ERG and prostate cancer
- 2009
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Ingår i: Cancer Causes and Control. - : SPRINGER. - 0957-5243 .- 1573-7225. ; 20:7, s. 1173-1180
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Tidskriftsartikel (refereegranskat)abstract
- A considerable fraction of prostate cancers harbor a gene fusion between the androgen-regulated TMPRSS2 and ERG, one of the most frequently over-expressed proto-oncogenes in prostate cancer. Here, we investigated if inherited genetic variation upstream of ERG alters prostate cancer risk and survival. We genotyped 21 haplotype tagging SNPs (htSNPs) covering 123 kb of 5'UTR DNA including exon 3 of ERG in 2,760 incident prostate cancer cases and 1,647 controls from a population-based Swedish case-control study (CAPS). Individual SNPs and haplotypes were tested for association with prostate cancer risk and survival. One haplotype-'CTCGTATG' located 100 kb upstream of ERG-was associated with lethal prostate cancer (HR, 1.36; 95% CI, 1.2-1.9, p = 0.006). Carriers of the variant 'T' allele of rs2836626 were diagnosed with higher TNM-stage (p = 0.009) and had an increased risk of prostate cancer-specific death (HR = 1.3; 95% CI, 1.1-1.7, p = 0.009). However, this association did not remain statistically significant after adjusting for multiple testing. We found overall no association between ERG variation and prostate cancer risk. Genetic variation upstream of ERG may alter prostate cancer stage and ultimately prostate cancer-specific death but it is unlikely that it plays a role in prostate cancer development.
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| 8. |
- Lindstrom, Sara, et al.
(författare)
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Inherited variation in hormone-regulating genes and prostate cancer survival
- 2007
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Ingår i: Clinical Cancer Research. - Umea Univ, Dept Radiat Sci Oncol, SE-90185 Umea, Sweden. Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC 27109 USA. : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 13:17, s. 5156-5161
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Hormonal manipulation is the mainstay treatment of prostate cancer, notably in advanced stages. Despite initial favorably response, the cancer eventually develops hormone resistance resulting in disease progression and death. However, little is known about genetic determinants of disease progression and prostate cancer-specific death. Experimental Design: We analyzed a population-based cohort comprising 2,761 men diagnosed with prostate cancer from March 2001 to October 2003 and with complete follow-up through July 2006. During a median follow-up time of 3.8 years, a total of 300 men had died from prostate cancer. We genotyped 23 haplotype tagging single nucleoticle polymorphisms in the genes AR, CYP17, and SRD5A2 and used Cox proportional hazards analyses to quantify associations between genotype and risk of dying from prostate cancer. Results: The variant 'A': allele of an AR promoter single nucleoticle polymorphism, rs17302090, was borderline associated with a 50% increased risk of dying from prostate cancer (95% confidence interval, 1.0-2.3; P = 0.07). This finding was more pronounced in patients who received hormonal therapy as primary treatment at diagnosis (hazard ratio, 19; 95% confidence interval, 1.3-2.9; P = 0.007). We did not identify any associations between CYP17 or SRD5A2 variation and prostate cancer-specific death. Conclusions: Our results suggest that inherited genetic variation in the androgen receptor gene affects hormonal treatment response and ultimately prostate cancer death.
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| 9. |
- Lindström, Sara, et al.
(författare)
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Systematic replication study of reported genetic associations in prostate cancer : Strong support for genetic variation in the androgen pathway
- 2006
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Ingår i: The Prostate. - Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. Umea Univ, Dept Radiat Sci Oncol, Umea, Sweden. Wake Forest Univ, Sch Med, Ctr Human Genome, Winston Salem, NC USA. Karolinska Inst, Ctr Genome & Bioinformat, Stockholm, Sweden. Univ Leicester, Dept Genet, Leicester, Leics, England. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD USA. Karolinska Inst, CLINTEC, Ctr Oncol, Stockholm, Sweden. : WILEY-LISS. - 0270-4137 .- 1097-0045. ; 66:16, s. 1729-1743
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND. Association studies have become a common and popular method to identify genetic variants predisposing to complex diseases. Despite considerable efforts and initial promising findings, the field of prostate cancer genetics is characterized by inconclusive reports and no prostate cancer gene has yet been established. METHODS. We performed a literature review and identified 79 different polymorphisms reported to influence prostate cancer risk. Of these, 46 were selected and tested for association in a large Swedish population-based case-control prostate cancer population. RESULTS. We observed significant (P < 0.05) confirmation for six polymorphisms located in five different genes. Three of them coded for key enzymes in the androgen biosynthesis and response pathway; the CAG repeat in the androgen receptor (AR) gene (P = 0.03), one SNP in the CYP17 gene (P = 0.04), two SNPs in the SRD5A2 gene (P = 0.02 and 0.02, respectively), a deletion of the GSTT1. gene (P = 0.006), and one SNP in the MSR1 gene, IVS5-59C > A, (P = 0.009). CONCLUSIONS. Notwithstanding the difficulties to replicate findings in genetic association studies, our results strongly support the importance of androgen pathway genes in prostate cancer etiology.
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| 10. |
- Liu, Wennuan, et al.
(författare)
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Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer.
- 2009
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Ingår i: Cancer research. - 1538-7445. ; 69:6, s. 2176-9
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Tidskriftsartikel (refereegranskat)abstract
- We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden [CAncer of the Prostate in Sweden (CAPS)] using Affymetrix SNP arrays. By comparing allele intensities of approximately 500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06-1.48; P = 0.009]. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08-1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98-1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted.
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