The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer.
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.
Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. k.wagner@dkfz.de
Kerstin
K
Wagner
Kari
K
Hemminki
Ewa
E
Grzybowska
Rüdiger
R
Klaes
Dorota
D
Butkiewicz
Jolanta
J
Pamula
Wioletta
W
Pekala
Helena
H
Zientek
Danuta
D
Mielzynska
Ewa
E
Siwinska
Asta
A
Försti
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008875:Middle Aged; D011044:Poland; D011110:Polymorphism, Genetic / Q000235:genetics*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D048868:Adaptor Proteins, Signal Transducing; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II