Polymorphisms in genes involved in GH1 release and their association with breast cancer risk.
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.
Wagner
Kerstin
K
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. K.Wagner@dkfz.de
Hemminki
Kari
K
Grzybowska
Ewa
E
Klaes
Rüdiger
R
Burwinkel
Barbara
B
Bugert
Peter
P
Schmutzler
Rita K
RK
Wappenschmidt
Barbara
B
Butkiewicz
Dorota
D
Pamula
Jolanta
J
Pekala
Wioletta
W
Försti
Asta
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D054439:Ghrelin; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D036361:Peptide Hormones / Q000378:metabolism; D011110:Polymorphism, Genetic; D017481:Receptors, Somatostatin / Q000378:metabolism; D012306:Risk; D013004:Somatostatin / Q000378:metabolism
D054439:Ghrelin; D036361:Peptide Hormones; D017481:Receptors, Somatostatin; D013004:Somatostatin; D013006:Growth Hormone; C093733:somatostatin receptor 2