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Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels.
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
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2007 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, 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.

Place, publisher, year, edition, pages
2007. Vol. 92, no 12, 4820-4826 p.
Identifiers
URN: urn:nbn:se:umu:diva-22270DOI: 10.1210/jc.2007-0887PubMedID: 17911177OAI: oai:DiVA.org:umu-22270DiVA: diva2:214218
Available from: 2009-05-04 Created: 2009-05-04 Last updated: 2017-12-13
In thesis
1. Prostate cancer aetiology: epidemiological studies of the IGF- and one-carbon metabolism pathways
Open this publication in new window or tab >>Prostate cancer aetiology: epidemiological studies of the IGF- and one-carbon metabolism pathways
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:nbn:se:umu:diva-1645 (URN)978-91-7264-534-9 (ISBN)
Public defence
2008-05-30, E04, 6E Sut, Norrlands Universitetssjukhus, Umeå, 10:15 (English)
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Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2016-03-07Bibliographically approved

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