| 1. |
- Johansson, Mattias, et al.
(författare)
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Combining 33 genetic variants with prostate-specific antigen for prediction of prostate cancer : longitudinal study
- 2012
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 130:1, s. 129-137
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate if a genetic risk score including 33 common genetic variants improves prediction of prostate cancer when added to measures of prostate-specific antigen (PSA). We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort (NSHDC), a prospective cohort in northern Sweden. A total of 520 cases and 988 controls matched for age, and date of blood draw were identified by linkage between the regional cancer register and the NSHDC. Receiver operating characteristic curves with area under curve (AUC) estimates were used as measures of prostate cancer prediction. The AUC for the genetic risk score was 64.3% [95% confidence interval (CI) = 61.4-67.2], and the AUC for total PSA and the ratio of free to total PSA was 86.2% (95% CI = 84.4-88.1). A model including the genetic risk score, total PSA and the ratio of free to total PSA increased the AUC to 87.2% (95% CI = 85.4-89.0, p difference = 0.002). The addition of a genetic risk score to PSA resulted in a marginal improvement in prostate cancer prediction that would not seem useful for clinical risk assessment.
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| 2. |
- Johansson, Mattias, et al.
(författare)
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Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer
- 2007
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Ingår i: International Journal of Cancer. - German Canc Res Ctr, Div Canc Epidemiol, DKFZ, D-69121 Heidelberg, Germany. Umea Univ Hosp, Dept Surg & Perioperat Sci Urol & Androl, S-90185 Umea, Sweden. Int Agcy Res Canc, F-69372 Lyon, France. Menzies Res Inst, Hobart, Tas, Australia. German Canc Inst, Genom Epidemiol Grp, DKFZ, Heidelberg, Germany. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Harvard Univ, Dept Epidemiol, Boston, MA 02115 USA. : Wiley. - 0020-7136 .- 1097-0215. ; 120:3, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-I (IGF1) stimulates cell proliferation, decreases apoptosis, and has been implicated in cancer development. Epidemiological studies have shown elevated levels of circulating IGF1 to be associated with increased risk of prostate cancer. To what extent genetic variation in the IGF1 gene is related to prostate cancer risk is largely unknown. We performed a comprehensive haplotype tagging (HT) assessment of single nucleotide polymorphisms (SNPs) representing the common haplotype variation in the IGF1 gene. We genotyped 10 SNPs (9 haplotype tagging SNPs (htSNPs)) within Cancer Prostate in Sweden (CAPS), a case–control study of 2,863 cases and 1,737 controls, in order to investigate if genetic variation in the IGF1 gene is associated with prostate cancer risk. Three haplotype blocks were identified across the IGF1 gene and 9 SNPs were selected as haplotype tagging SNPs. Common haplotypes in the block covering the 3′ region of the IGF1 gene showed significant global association with prostate cancer risk (p = 0.004), with one particular haplotype giving an odds ratio of 1.46 (95% CI = 1.15–1.84, p = 0.002). This haplotype had a prevalence of 5% in the study population. Our results indicate that common variation in the IGF1 gene, particularly in the 3′ region, may affect prostate cancer risk. Further studies on genetic variations in the IGF1 gene in relation to prostate cancer risk as well as to circulating levels of IGF1 are needed to confirm this novel finding.
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| 3. |
- Johansson, Mattias, et al.
(författare)
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Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival
- 2009
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69:12, s. 1281-1291
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Binding proteins regulate bioavailability of insulin-like growth factor-I (IGF-I) in the circulation and affect apoptosis of tumor cells in the prostate. We analyzed genetic variation within genes coding for IGF binding proteins in relation to prostate cancer incidence and survival. We also investigated if circulating IGFBP3 affects prostate cancer-specific survival. MATERIALS AND METHODS: Eleven haplotype tagging SNPs and two single SNPs in the IGFBP1, IGFBP3, and IGFALS genes were genotyped within the CAncer Prostate in Sweden (CAPS) study including 2,774 cases and 1,736 controls. Plasma samples for analyses of total- and intact IGFBP3 levels were available for 1,521 cases and 909 controls. Complete follow-up of vital status was achieved by linkage to the Swedish Cause of Death Register. RESULTS: We found no clear association between the genetic variants and prostate cancer incidence or survival. The rare allele of the IGFBP3 SNP rs2854744 was associated with elevated plasma levels of total IGFBP3 (P(trend) = 9 x 10(-8)), but not intact IGFBP3 (P(trend) = 0.16). Elevated levels of total- (P(trend) = 0.03) and intact IGFBP3 (P(trend) = 6 x 10(-14)) were associated with increased risk of prostate cancer specific death. Treatment and tumor characteristics accounted for the association with total IGFBP3, whereas the association with intact IGFBP3 was attenuated, but still statistically significant in adjusted analysis (P(trend-adjusted) = 0.0004). Elevated intact IGFBP3 was also significantly associated with increased risk of prostate cancer-specific death among patients who were chemically or surgically castrated (P(trend-adjusted) = 0.0003), and among patients who had not been treated (P(trend-adjusted) = 0.02). CONCLUSIONS: Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death.
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| 4. |
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| 5. |
- Johansson, Mattias, et al.
(författare)
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Genetic variation in the SST gene and its receptors in relation to circulating levels of insulin-like growth factor-I, IGFBP3, and prostate cancer risk
- 2009
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 18:5, s. 1644-1650
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Somatostatin (SST) and its receptors (SSTR1-5) may have a role in prostate cancer by influencing the IGFI hormone axis or through direct effects on prostate epithelia. We have investigated if genetic variation in the SST and SSTR1-5 genes influences prostate cancer risk and/or circulating IGFI and IGFBP3 hormone levels. MATERIALS AND METHODS: We analyzed 28 haplotype tagging single nucleotide polymorphisms in the SST and SSTR1-5 genes in a case-control/genetic association study to investigate the association between genetic variation and prostate cancer risk. The study included 2863 cases and 1737 controls from the Cancer Prostate in Sweden (CAPS) study. To investigate the genetic influence on circulating hormone levels, plasma concentrations of IGFI and IGFBP3 were analyzed in 874 controls of the CAPS study and 550 male subjects from the Northern Sweden Health and Disease Cohort (NSHDC). RESULTS: No clear association between prostate cancer risk and genetic variation of the SST and SSTR1-5 genes was identified. The SSTR5 missense single nucleotide polymorphism rs4988483 was associated with circulating IGFI (P = 0.002) and IGFBP3 (P = 0.0003) hormone levels in CAPS controls, with a per allele decrease of approximately 11%. This decrease was replicated in NSHDC for circulating IGFBP3 (P = 0.01) but not for IGFI (P = 0.09). Combining CAPS and NSHDC subjects indicated evidence of association between rs4988483 and both IGFBP3 (P = 2 x 10(-5)) and IGFI (P = 0.0004) hormone levels. CONCLUSIONS: Our results suggest that genetic variation in the SSTR5 gene and, particularly, the rs4988483 single nucleotide polymorphism influence circulating IGFI and IGFBP3 hormone levels with no measurable effect on prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1644-50).
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| 6. |
- Johansson, Mattias, et al.
(författare)
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Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - Umea Univ Hosp, Dept Surgical & Perioperative Sci, S-90185 Umea, Sweden. Umea Univ Hosp, Dept Urol Androl, S-90185 Umea, Sweden. Umea Univ Hosp, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. Int Agcy Res Canc, F-69372 Lyon, France. Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-85500 Utrecht, Netherlands. Harvard Univ, Dept Epidemiol, Boston, MA 02215 USA. German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. : ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 92:12, s. 4820-4826
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Tidskriftsartikel (refereegranskat)abstract
- Background: Elevated levels of circulating IGF-I have consistently been associated with increased prostate cancer risk. We recently found a haplotype in the 3 ' region of the IGF-I gene associated with increased risk of prostate cancer, and we hypothesized that the observed association is mediated by circulating IGF-I. Materials and Methods: We analyzed haplotypes and three haplotype-tagging single nucleotide polymorphisms (htSNPs) in the 3 ' region of the IGF-I gene in relation to circulating levels IGF-I in 698 control subjects from the CAncer Prostate in Sweden ( CAPS) study and 575 cases and controls from the prospective Northern Sweden Health and Disease Cohort ( NSHDC) study. We also performed a meta-analysis of these two and four other association studies on genetic variation in the 3 ' region of the IGF-I gene in relation to circulating IGF-I levels. Results: The IGF-I haplotype previously associated with prostate cancer risk, labeled "TCC," was associated with elevated levels of IGF-I in the CAPS study (P = 0.02), but not in the NSHDC study. In contrast, two of the three IGF-I htSNPs tagging this haplotype, rs6220 and rs7136446, were associated with elevated levels of IGF-I in the NSHDC ( P = 0.03 and P = 0.04, respectively), but not in the CAPS study. In the meta-analysis, the TCC haplotype and the rs6220 SNP were associated with elevated levels of circulating IGF-I ( P = 0.001 and P < 0.0001, respectively). Conclusions: Genetic variation in the 3 ' region of the IGF-I gene seems to influence circulating levels of IGF-I. This observation is consistent with the hypothesis that variation in the IGF-I gene plays a role in prostate cancer susceptibility by influencing circulating levels of IGF-I.
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| 7. |
- Johansson, Mattias, 1977-
(författare)
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Prostate cancer aetiology : epidemiological studies of the IGF- and one-carbon metabolism pathways
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate the involvement of the insulin-like growth factor- and the one-carbon metabolism pathways in prostate cancer aetiology, studying both circulating biomarkers and genetic variation. Papers included in the thesis were conducted within the case-control study CAncer Prostate in Sweden (CAPS), and the two prospective studies European Prospective Investigation into nutrition and Cancer (EPIC), and Northern Sweden Health and Disease Cohort (NSHDC).In paper I, we investigated the relation between genetic variants of the IGF1 gene and prostate cancer risk within the CAPS study. We found that a common haplotype within the 3’ region of the IGF1 gene is associated with increased prostate cancer risk.In paper II, we investigated if the variants of the IGF1 gene that were associated with prostate cancer risk in paper I, are also associated with circulating levels of IGF1. Circulating levels of IGF1 were analysed in controls from the CAPS study and three haplotype tagging SNPs (htSNPs) were genotyped in subjects from the NSHDC study in which circulating IGF1 had previously been analysed. The genetic variants previously associated with increased prostate cancer risk were now also found to be associated with elevated levels of circulating IGF1. We concluded that variation in the 3’ region of the IGF1 gene affects prostate cancer risk by influencing circulating levels of IGF1.In paper III, we investigated if variants of the IGFBP1, IGFBP3 and IGFALS genes are associated with i) prostate cancer risk, ii) circulating concentrations of total and intact IGFBP3, and iii) prostate cancer-specific survival probability. In addition, we investigated if circulating concentrations of total and intact IGFBP3 are associated with prostate cancer-specific survival probability. No association between genetic variation and overall prostate cancer risk or survival was observed, but we found a strong association between elevated levels of intact IGFBP3 and increased risk of prostate cancer-specific death. We could, however, not exclude that this association was confounded by treatment or by the tumour.In paper IV, we investigated if circulating levels of folate and vitamin B12 are associated with prostate cancer risk within the EPIC study. We observed no associations between levels of folate, vitamin B12 and overall prostate cancer risk, but elevated levels of vitamin B12 were associated with increased risk of advanced stage disease.In paper V, we investigated if circulating levels of ten B-vitamins and related metabolites within the one-carbon metabolism pathway are associated with prostate cancer risk within the NSHDC study. Overall positive associations with prostate cancer risk were observed for levels of choline, vitamin B2 and vitamin B12, and inverse associations were observed for levels of homocysteine and MMA. We also observed a biologically plausible risk modification by smoking status on the association between vitamin B12 and risk; in non-smokers vitamin B12 was positively associated with risk, whereas the association between vitamin B12 and risk was inverse or null in ever/current-smokers.In summary, our results suggest that genetic variation of the IGF1 gene affects prostate cancer risk by affecting circulating levels of IGF1. The association between circulating concentrations of intact IGFBP3 and prostate cancer-specific survival is intriguing, but further studies are needed to conclude if this association is caused by confounding. We also observed associations between several factors of one-carbon metabolism and risk, but these associations were statistically week and require confirmation in other prospective studies.
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| 8. |
- Johansson, Mattias, et al.
(författare)
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The MTHFR 677C --> T polymorphism and risk of prostate cancer : results from the CAPS study
- 2007
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Ingår i: Cancer Causes and Control. - Umea Univ Hosp, Dept Surg & Perioperat Sci, S-90185 Umea, Sweden. Univ Umea Hosp, Dept Med Biosci, S-90185 Umea, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Harvard Univ, Dept Epidemiol, Cambridge, MA 02138 USA. : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 18:10, s. 1169-1174
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Tidskriftsartikel (refereegranskat)abstract
- The methylenetetrahydrafolate reductase (MTHFR) enzyme may influence cancer development by affecting DNA methylation, synthesis and repair. The MTHFR 677C→T single nucleotide polymorphism (SNP) has been associated with decreased enzyme activity and has therefore been implicated in cancer development. We analyzed the MTHFR 677C→T SNP in 2,777 incident prostate cancer cases and 1,639 population controls from the CAncer Prostate in Sweden study (CAPS). No significant association was found overall between prostate cancer risk and the 677C→T SNP (p = 0.27) with heterozygote (CT) and homozygote (TT) allele carriers showing ORs of 1.12 (95% CI: 0.98–1.27) and 1.02 (95% CI: 0.80–1.30), respectively. In the subgroup of low risk prostate cancer, heterozygote—but not homozygote—allele carriers displayed a slight over-risk with an OR of 1.21 (95% CI: 1.03–1.41). Among men under 65 years of age, the 677C→T SNP was associated with prostate cancer risk (p = 0.007), with odds ratios of 1.33 (95% CI: 1.09–1.63) for heterozygote allele carriers and 0.86 (95% CI: 0.6–1.24) for homozygote allele carriers. However, this association was attributed to a shift in the genotype distribution in the young controls. In conclusion, our results do not provide strong support for the hypothesis that the MTHFR 677C→T polymorphism is related to prostate cancer risk.
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| 9. |
- Schumacher, Fredrick R., et al.
(författare)
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Genome-wide association study identifies new prostate cancer susceptibility loci
- 2011
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Ingår i: Human Molecular Genetics. - London : IRL Press. - 0964-6906 .- 1460-2083. ; 20:19, s. 3867-3875
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade >= 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P = 4.3 x 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P = 8.6 x 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P = 0.72 and P = 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.
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