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Carcinogenesis Advance Access published online on August 12, 2004
Carcinogenesis, doi:10.1093/carcin/bgh263
© 2004 by Oxford University Press
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Received June 17, 2004
Revised June 27, 2004
Accepted August 2, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer

Kerstin Wagner 1*, Kari Hemminki 2, Ewa Grzybowska 3, Rüdiger Klaes 4, Dorota Butkiewicz 3, Jolanta Pamula 3, Wioletta Pekala 3, Helena Zientek 3, Danuta Mielzynska 5, Ewa Siwinska 5, Asta Försti 2

1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 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
5 Department of Genetic Toxikology, Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland

* To whom correspondence should be addressed. E-mail: K.Wagner{at}dkfz.de.


  Abstract

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 an altered signalling. We screened IRS1, IRS2 and SHC1 for published coding region polymorphisms and choose five of them, IRS1 (Ala804Ala, Gly972Arg), IRS2 (Cys816Cys, Gly1057Asp) and SHC1(Met300Val), for a further analysis. We studied the association of the polymorphisms to 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 of 0.41-0.93, p = 0.02) for the SHC1 300Val 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 nonsynonymous polymorphisms in the IRS1, IRS2 and SHC1 genes did not show any effect on breast cancer risk.


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