Carcinogenesis Advance Access originally published online on August 12, 2004
Carcinogenesis 2004 25(12):2473-2478; doi:10.1093/carcin/bgh263
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Carcinogenesis vol.25 no.12 © Oxford University Press 2004; all rights reserved.
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The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer
1 Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, 2 Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden, 3 Department of Tumor Biology, Centre of Oncology, Maria Sklodowska-Curie Institue, Gliwice, Poland, 4 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany and 5 Department of Genetic Toxicology, Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland
6 To whom correspondence should be addressed. Tel: +49 6221 421811; Fax: +49 6221 421810; Email: k.wagner{at}dkfz.de
The insulin-like growth factor 1 (IGF-1) pathway plays an important role in regulating cell proliferation, differentiation and apoptosis. IRS1, IRS2 and SHC1 are the key mediators for the downstream pathway processes. Genetic variation within these genes may lead to altered signalling. We screened IRS1, IRS2 and SHC1 for published coding region polymorphisms and choose five of them, IRS1 Ala804Ala and Gly972Arg, IRS2 Cys816Cys and Gly1057Asp and SHC1 Met300Val, for further analysis. We studied the association of the polymorphisms with breast cancer risk using a case–control design with Polish familial breast cancer cases and respective controls. For the polymorphisms in IRS1 and IRS2 no differences in the allele, genotype or haplotype distributions could be detected between the case and control subjects. Carriers of the variant allele of the SHC1 polymorphism were at decreased risk of breast cancer (OR 0.54, 95% CI 0.32–0.90, P = 0.016). A non-significant trend for a protective effect of the SHC1 Val300 allele was also seen in an independent population consisting of German familial breast cancer cases and matched controls. The joint analysis after Mantel–Haenzsel adjustment of the two populations gave an OR of 0.62 (95% CI 0.41–0.93, P = 0.02) for the SHC1 Val300 carriers. A stronger effect was detected in women diagnosed below the age of 50 (OR 0.54, 95% CI 0.32–0.89, P = 0.01). A genotype combination analysis of the non-synonymous polymorphisms in the IRS1, IRS2 and SHC1 genes did not show any effect on breast cancer risk.
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