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H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer
Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
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2004 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, Vol. 96, no 16, 1248-1254 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer. METHODS: The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A statistically significant difference (P =.006) in genotype frequency was observed for the nonsynonymous change H6D (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer. CONCLUSION: This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.

Place, publisher, year, edition, pages
2004. Vol. 96, no 16, 1248-1254 p.
URN: urn:nbn:se:umu:diva-15412DOI: 10.1093/jnci/djh227PubMedID: 15316060OAI: diva2:155084
Available from: 2007-04-25 Created: 2007-04-25 Last updated: 2009-11-23Bibliographically approved
In thesis
1. Prostate cancer and inflammatory genes
Open this publication in new window or tab >>Prostate cancer and inflammatory genes
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostate cancer remains a significant health concern for men throughout the world. Accumulating epidemiologic and molecular evidence suggests that inflammation is an important component in the aetiology of prostate cancer. Supporting this hypothesis, population studies have found an increased risk of prostate cancer in men with a prior history of certain sexually transmitted infections or prostatitis. More general evidence of a relationship between inflammation and prostate cancer has been provided by reports indicating that daily use of non steroidal anti-inflammatory drugs (NSAIDs) may be associated with a lower incidence of prostate cancer. The exact mechanism whereby inflammation might act in tumour development and progression remains to be elucidated, but is likely to be complex. The genetic contribution to inflammatory responses involved in the development of prostate cancer has not yet been extensively or systematically studied.

However, this thesis evaluates the role of various inflammation-related genes in the pathogenesis of prostate cancer. The macrophage scavenger receptor 1 (MSR1) is a transmembrane protein that is mainly expressed by macrophages. This receptor mediates the binding, internalization and processing of a wide range of macromolecules, and is suggested to play a major role in the recognition and clearance of pathogenic and damaged cells. Recent reports have suggested MSR1 to be a candidate gene for hereditary prostate cancer. Therefore, we screened the MSR1 gene among men with hereditary prostate cancer and identified 18 sequence variants. One previously reported truncation mutation was found more frequently in men with prostate cancer than in unaffected men, in accordance with previously published results. However, the difference in frequencies we found between these groups was not statistically significant. In addition, we genotyped five common polymorphisms in MSR1 in 215 men with unselected prostate cancer and 425 controls. No association between any of the five common variants and prostate cancer were found.

We then performed a comprehensive genetic study using extensive populationbased case-control material to evaluate possible associations between sequence variants in inflammation-related genes and prostate cancer. The first gene to be examined was interleukin-1 receptor antagonist (IL-1-RN), encoding a cytokine that plays an important role in regulation of the inflammatory response by binding to the IL-1 receptor and thus inhibiting the binding of the pro-inflammatory cytokines IL-1α and IL-1β. Collectively, these three cytokines exert a central role in the protection against diverse lesions, ranging from microbial colonisation to infection and malignant transformation. The genetic analysis of IL-1RN revealed that the most common haplotype was significantly associated with prostate cancer risk for patients with prostate cancer, and further this association appears to be stronger in cases with advanced disease.

The macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth-factor-β superfamily has been shown to exert diverse biological functions, including regulation of macrophage activity in the inflammatory response and both growth inhibition and induction of apoptosis in epithelial and other tumour cell lines. The genetic analysis of MIC-1 revealed that a seuqence variant (H6D) appears to be associated with a decreased prostate cancer risk. We also performed measurements of MIC-1 serum levels among patients with prostate cancer and healthy controls. These data indicate that serum MIC-1 levels are associated with an increased risk for prostate cancer. Further, the clear relation between clinical stage and MIC-1 level also suggest that MIC-1 may be useful as a prognostic factor, where high serum concentration is associated with a poor prognosis.

In summary, our results provide further support for the assumption that polymorphisms in inflammatory genes play critical roles in prostate cancer susceptibility. Additional studies are needed to elucidate the mechanisms whereby the demonstrated variations contribute to prostate cancer development.

Place, publisher, year, edition, pages
Umeå: Strålningsvetenskaper, 2005. 76 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 991
Prostate cancer, inflammation, association studies, epidemiology, MSR1, MIC-1, IL1-RN
National Category
Cancer and Oncology
Research subject
urn:nbn:se:umu:diva-667 (URN)91-7305-962-5 (ISBN)
Public defence
2006-01-20, 244 Lionssalen, 7, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Available from: 2005-12-28 Created: 2005-12-28 Last updated: 2009-11-23Bibliographically approved

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