Carcinogenesis Advance Access originally published online on April 10, 2006
Carcinogenesis 2006 27(9):1867-1875; doi:10.1093/carcin/bgl036
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Polymorphisms in genes involved in GH1 release and their association with breast cancer risk
1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany
2 Department of Biosciences at Novum, Karolinska Institute Huddinge, Sweden
3 Department of Molecular Biology, Centre of Oncology, Maria Sklodowska-Curie Institute Gliwice, Poland
4 Institute of Human Genetics, University of Heidelberg Heidelberg, Germany
5 Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessia, University of Heidelberg, Faculty of Clinical Medicine Mannheim, Germany
6 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics Clinical Center University of Cologne, Germany
7 Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne Germany
*To whom correspondence should be addressed at: Kerstin Wagner, Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Tel: +49 6221 421811; Fax: +49 6221 421810; Email: K.Wagner{at}dkfz.de
The regulation of growth hormone 1 (GH1) and insulin-like-growth factor-1 (IGF-1) release is under the influence of three pituitary hormones [growth hormone releasing hormone (GHRH), ghrelin (GHRL) and somatostatin (SST)], which act in an autocrine/paracrine fashion in the breast. By binding to their respective receptors, they control cell proliferation, differentiation and apoptosis in a GH1/IGF-1-dependent manner. We investigated single nucleotide polymorphisms (SNPs) in the GHRH, GHRHR, GHRL, GHSR, SST and SSTR2 gene regions in a Polish and a German cohort of 798 breast cancer cases and 1011 controls. Our study revealed an association of a novel TC repeat polymorphism in the SST promoter with a decreased breast cancer risk in the Polish study population [odds ratio (OR), 0.65; 95% confidence interval (CI), 0.44–0.96]. The closely linked SNP IVS1 A+46G showed the same trend. For both polymorphisms the association was stronger in women above the age of 50 (OR, 0.33; 95% CI, 0.14–0.76 and OR, 0.39; 95% CI, 0.18–0.87, respectively). The protective effect of these polymorphisms was confirmed in a haplotype analysis among women above 50 years of age and carrying the two variant alleles (OR, 0.37; 95% CI, 0.17–0.80). In the independent German population, we observed slightly decreased ORs among women above the age of 50 years. In the SSTR2 gene, carriers of the promoter 21/21 TG repeat genotype were at a decreased breast cancer risk (OR, 0.62; 95% CI, 0.41–0.94) compared to carriers of the other genotypes in the Polish population. Furthermore, we identified a protective effect of the GHRHR C-261T SNP in both populations (joint analysis CT+TT versus CC: OR, 0.80; 95% CI, 0.65–0.99). This effect was carried by a haplotype containing the protective allele. Thus, our study concludes a possible protective influence of distinct polymorphisms in genes involved in GH1 release on breast cancer risk.
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