1. |
- Garcia-Closas, Montserrat, et al.
(författare)
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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
- 2008
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 4:4, s. e1000054-
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Tidskriftsartikel (refereegranskat)abstract
- A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
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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. |
- 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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5. |
- 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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6. |
- McKay, James D, et al.
(författare)
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Haplotype-based analysis of common variation in the growth hormone receptor gene and prostate cancer risk
- 2007
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. Menzies Res Inst, Hobart, Tas, Australia. Int Agcy Res Canc, F-69372 Lyon, France. Umea Univ Hosp, Dept Surg & Perioperat Sci Urol & Androl, S-90185 Umea, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 16:1, s. 169-173
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Tidskriftsartikel (refereegranskat)abstract
- The growth hormone receptor (GHR) is potentially involved in prostate cancer through its role in stimulating insulin-like growth factor I production and its cellular effects on prostate epithelium. We have used a haplotype-based tagging approach within CAncer Prostate Sweden, a large retrospective case-control study of 2,863 cases and 1,737 controls to investigate if genetic variation in the GHR gene influences prostate cancer risk. One haplotype in the 3' region of the GHR gene was found associated with prostate cancer risk in elderly men (>65 years old at the time of diagnosis), with heterozygote haplotype carriers having an odds ratio of 1.65 (95% confidence interval, 1.21-2.16; P = 0.0009, Pcorrected = 0.03). GHR function has been implicated in the determination of body mass index. Interestingly, the same haplotype associated with risk in the 3' end of the GHR gene was also associated with a decrease in body mass index in controls (P = 0.003, Pcorrected = 0.05), possibly indicating some functionality with this haplotype. These results suggest that whereas genetic variation in the GHR gene does not seem to play a major role in prostate cancer etiology, one haplotype in the 3' region may be potentially relevant to cases with later onset of prostate cancer.
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