Association of Insulin Receptor Substrate-1 G972R Variant with Non-small Cell Lung Cancer Risk

  • Lee, Chang Youl (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Ahn, Chul Min (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Jeon, Jeong Hee (Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Kim, Hyung Jung (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kim, Se Kyu (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Chang, Joon (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kim, Sung Kyu (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Chang, Yoon Soo (Department of Internal Medicine, Yonsei University College of Medicine)
  • Received : 2006.06.13
  • Accepted : 2006.09.07
  • Published : 2009.07.30


Background: The insulin receptor substrate-1 (IRS-1) is the primary docking molecule for the insulin-like growth factor I receptor (IGF-IR), and is required for activation of the phosphatidylinositol 3'-kinase (PI3K) pathway. IRS-1 activation of the (PI3K) pathway regulates IGF-mediated survival, enhancement of cellular motility and apoptosis. Therefore, we attempted to ascertain whether IRS-1 genetic variations affect an individual's risk for non-small cell lung cancer (NSCLC). Methods: Two-hundred and eighteen subjects, either diagnosed with NSCLC or control subjects, were matched by age, gender and smoking status. Genomic DNA from each subject was amplified by PCR and analyzed according to the restriction fragment length polymorphism (RFLP) profile to detect the IRS-1 G972R polymorphism. Results: The frequencies of each polymorphic variation, in the control population, were as follows: GG=103 (94.5%) and GR=6 (5.5%); for the NSCLC subjects, the genotypic frequencies were as follows: GG=106 (97.2%) and GR=3 (2.8%). We could not demonstrate statistically significant differences in the genotypic distribution between the NSCLC and the control subjects (p=0.499, Fisher's Exact test). The relative risk of NSCLC, associated with the IRS-1 G972R polymorphic variation, was 1.028 (95% CI; 0.63~9.90). In addition, we found no differences between polymorphic variants with regard to the histological subtype of NSCLC. Conclusion: We did not observe any noteworthy differences in the frequency of the IRS-1 G972R polymorphism in NSCLC patients, compared to control subjects. These results suggest suggesting that, in our study population, the IRS-1 G972R polymorphism does may not appear to be associated with an increased risk of NSCLC.


  1. Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center: insulin-like growth factors. N Engl J Med 1997;336:633-40
  2. Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 1999;91:151-6
  3. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563-6
  4. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998;351:1393-6
  5. Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999;91:620-5
  6. Tsuruzoe K, Emkey R, Kriauciunas KM, Ueki K, Kahn CR. Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol Cell Biol 2001;21:26-38
  7. Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995;16:117-42
  8. Smith RM, Harada S, Jarett L. Insulin internalization and other signaling pathways in the pleiotropic effects of insulin. Int Rev Cytol 1997;173:243-80
  9. White MF, Maron R, Kahn CR. Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells. Nature 1985;318:183-6
  10. White MF, Kahn CR. The insulin signaling system. J Biol Chem 1994;269:1-4
  11. Esposito DL, Li Y, Cama A, Quon MJ. Tyr (612) and Tyr (632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells. Endocrinology 2001;142:2833-40
  12. Kim B, van Golen CM, Feldman EL. Insulin-like growth factor I induces preferential degradation of insulin receptor substrate-2 through the phosphatidylinositol 3-kinase pathway in human neuroblastoma cells. Endocrinology 2005;146:5350-7
  13. Delafontaine P, Song YH, Li Y. Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arterioscler Thromb Vasc Biol 2004;24:435-44
  14. McGettrick AJ, Feener EP, Kahn CR. Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation. J Biol Chem 2005;280: 6441-6
  15. Slattery ML, Samowitz W, Curtin K, Ma KN, Hoffman M, Caan B, et al. Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. Cancer Epidemiol Biomarkers Prev 2004;13: 1206-14
  16. Hsing AW, Gao YT, Chua S Jr, Deng J, Stanczyk FZ. Insulin resistance and prostate cancer risk. J Natl Cancer Inst 2003;95:67-71
  17. Stumvoll M, Fritsche A, Volk A, Stefan N, Madaus A, Maerker E, et al. The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose-tolerant humans. Diabetes 2001;50:882-5
  18. Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate- 1 (IRS) system in human metabolic disorders. FASEB J 2001;15:2099-111
  19. Almind K, Inoue G, Pedersen O, Kahn CR. A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. J Clin Invest 1996;97:2569-75
  20. Rosen CJ, Glowacki J, Craig W. Sex steroids, the insulin- like growth factor regulatory system, and aging: implications for the management of older postmenopausal women. J Nutr Health Aging 1998;2:39-44
  21. Kido Y, Nakae J, Hribal ML, Xuan S, Efstratiadis A, Accili D. Effects of mutations in the insulin-like growth factor signaling system on embryonic pancreas development and $\beta$-cell compensation to insulin resistance. J Biol Chem 2002;277:36740-7