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Prostate cancer aetiology: epidemiological studies of the IGF- and one-carbon metabolism pathways
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Kirurgisk och perioperativ vetenskap , 2008. , 99 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1165
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:umu:diva-1645ISBN: 978-91-7264-534-9 (print)OAI: oai:DiVA.org:umu-1645DiVA: diva2:141681
Public defence
2008-05-30, E04, 6E Sut, Norrlands Universitetssjukhus, Umeå, 10:15 (English)
Opponent
Supervisors
Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2016-03-07Bibliographically approved
List of papers
1. Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer
Open this publication in new window or tab >>Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer
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2007 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 120, no 3, 539-542 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
IGF1, prostate cancer, single nucleotide polymorphism, haplotype, block
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-16411 (URN)10.1002/ijc.22344 (DOI)000242869000012 ()17096324 (PubMedID)
Available from: 2007-11-28 Created: 2007-11-28 Last updated: 2016-03-07Bibliographically approved
2. Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels.
Open this publication in new window or tab >>Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels.
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2007 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, Vol. 92, no 12, 4820-4826 p.Article in journal (Refereed) Published
Abstract [en]

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.

Identifiers
urn:nbn:se:umu:diva-22270 (URN)10.1210/jc.2007-0887 (DOI)17911177 (PubMedID)
Available from: 2009-05-04 Created: 2009-05-04 Last updated: 2009-05-15
3. Genetic and plasma variation of insuline-like growth factor binding proteins in relation to prostate cancer incidence and survival
Open this publication in new window or tab >>Genetic and plasma variation of insuline-like growth factor binding proteins in relation to prostate cancer incidence and survival
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(English)Manuscript (Other (popular science, discussion, etc.))
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3184 (URN)
Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2016-03-07Bibliographically approved
4. Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European prospective investigation into cancer and nutrition study
Open this publication in new window or tab >>Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European prospective investigation into cancer and nutrition study
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2008 (English)In: Cancer Epidemiol Biomarkers Prev, ISSN 1055-9965, Vol. 17, no 2, 279-285 p.Article in journal (Refereed) Published
Abstract [en]

Background: Determinants of one-carbon metabolism, such as folate and vitamin B12, have been implicated in cancer development. Previous studies have not provided conclusive evidence for the importance of circulating concentrations of folate and vitamin B12 in prostate cancer etiology. The aim of the present study was to investigate the relationship between prostate cancer risk and circulating concentrations of folate and vitamin B12 in a large prospective cohort. Methods: We analyzed circulating concentrations of folate and vitamin B12 in 869 cases and 1,174 controls, individually matched on center, age, and date of recruitment, nested within the European Prospective Investigation into Cancer and Nutrition cohort. Relative risks (RR) for prostate cancer were estimated using conditional logistic regression models. Results: Overall, no significant associations were observed for circulating concentrations of folate (Ptrend = 0.62) or vitamin B12 (Ptrend = 0.21) with prostate cancer risk. RRs for a doubling in folate and vitamin B12 concentrations were 1.03 [95% confidence interval (95% CI), 0.92-1.16] and 1.12 (95% CI, 0.94-1.35), respectively. In the subgroup of cases diagnosed with advanced stage prostate cancer, elevated concentrations of vitamin B12 were associated with increased risk (RR for a doubling in concentration, 1.69; 95% CI, 1.05-2.72, Ptrend = 0.03). No other subgroup analyses resulted in a statistically significant association. Conclusion: This study does not provide strong support for an association between prostate cancer risk and circulating concentrations of folate or vitamin B12. Elevated concentrations of vitamin B12 may be associated with an increased risk for advanced stage prostate cancer, but this association requires examination in other large prospective studies. (Cancer Epidemiol Biomarkers Prev 2007;17(2):279–85)

National Category
Public Health, Global Health, Social Medicine and Epidemiology Nutrition and Dietetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-9273 (URN)10.1158/1055-9965.EPI-07-0657 (DOI)000253255500004 ()18268110 (PubMedID)
Available from: 2008-12-16 Created: 2008-12-16 Last updated: 2016-03-07Bibliographically approved
5. Prospective investigation of one-carbon metabolism in relation to prostate cancer risk: results from the NSHDC study
Open this publication in new window or tab >>Prospective investigation of one-carbon metabolism in relation to prostate cancer risk: results from the NSHDC study
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(English)Manuscript (Other academic)
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-3186 (URN)
Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2016-03-07Bibliographically approved

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