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A Prospective Study of Plasma Insulin-like Growth Factor-1 and Binding Protein-3 and Risk of Colorectal Neoplasia in Women¹

Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 [E. G., W. C. W., M. J. S., G. A. C., F. E. S., S. E. H.]; Departments of Nutrition [E. G., E. A. P., W. C. W., M. J. S.] and Epidemiology [E. G., E. A. P., W. C. W., M. J. S., G. A. C. S. E. H.], Harvard School of Public Health, Boston, Massachusetts 02115; and Cancer Prevention Research Unit, Departments of Medicine and Oncology, Jewish General Hospital and McGill University, Montreal, Quebec, H3T 1E2 Canada [M. N. P., N. M.]

Insulin-like growth factor-1 (IGF-1) is an important mitogen, and IGF binding protein-3 (IGFBP-3) has opposing effects. Acromegalics, who have abnormally elevated levels of IGF-1, are at increased risk of colorectal tumors. Recent studies have found that IGF-1 levels correlate with risk of prostate cancer and colorectal cancer in men, premenopausal breast cancer in women, and lung cancer in men and women. We examined whether prediagnostic plasma levels of IGF-1 and IGFBP-3 influence risk of colorectal cancer and adenoma in women. From 1989 to 1990, a total of 32,826 women from the Nurses’ Health Study provided blood specimens that were archived in liquid nitrogen. During 6 years of follow-up from 1989 to 1994, we documented 79 new cases of colorectal cancer, 90 cases of intermediate/late-stage adenoma (1 cm or tubulovillous/villous histology), and 107 cases of early-stage adenoma (<1 cm and tubular histology). After matching controls (2:1 for cancers and 1:1 for adenomas) to cases by age, month of blood draw, fasting status, and indication for endoscopy (for adenoma controls), plasma IGF-1 and IGFBP-3 levels were measured. Controlling for IGFBP-3 level, relative to women in the low tertile of IGF-1, those in the high tertile were at elevated risk of intermediate/late-stage colorectal neoplasia adenoma [multivariate relative risk (RR), 2.78; 95% confidence interval (CI), 0.76–9.76] and cancer (RR, 2.18; 95% CI, 0.94–5.08). Controlling for IGF-1 level, relative to women in the low tertile of IGFBP-3, women in the high tertile of IGFBP-3 were at lower risk of intermediate/late-stage colorectal adenoma (RR, 0.28; 95% CI, 0.09–0.85) and cancer (RR, 0.28; 95% CI, 0.10–0.83). Neither IGF-1 nor IGFBP-3 had any appreciable relation with early-stage adenoma. These analyses indicate that high levels of circulating IGF-1 and particularly low levels of IGFBP-3 are associated independently with an elevated risk of large or tubulovillous/villous colorectal adenoma and cancer.

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				R. E. Schoen, J. Schragin, J. L. Weissfeld, F. L. Thaete, R. W. Evans, C. J. Rosen, and L. H. Kuller Lack of Association between Adipose Tissue Distribution and IGF-1 and IGFBP-3 in Men and Women Cancer Epidemiol. Biomarkers Prev., June 1, 2002; 11(6): 581 - 586. [Abstract] [Full Text] [PDF]

				S. J. London, J.-M. Yuan, G. S. Travlos, Y.-T. Gao, R. E. Wilson, R. K. Ross, and M. C. Yu Insulin-Like Growth Factor I, IGF-Binding Protein 3, and Lung Cancer Risk in a Prospective Study of Men in China J Natl Cancer Inst, May 15, 2002; 94(10): 749 - 754. [Abstract] [Full Text] [PDF]

				R Palmqvist, G Hallmans, S Rinaldi, C Biessy, R Stenling, E Riboli, and R Kaaks Plasma insulin-like growth factor 1, insulin-like growth factor binding protein 3, and risk of colorectal cancer: a prospective study in northern Sweden Gut, May 1, 2002; 50(5): 642 - 646. [Abstract] [Full Text] [PDF]

				C. S. Carter, M. M. Ramsey, R. L. Ingram, A. B. Cashion, W. T. Cefalu, Z.Q. Wang, and W. E. Sonntag Models of Growth Hormone and IGF-1 Deficiency: Applications to Studies of Aging Processes and Life-Span Determination J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2002; 57(5): B177 - 188. [Abstract] [Full Text]

				L. Le Marchand, T. Donlon, A. Seifried, R. Kaaks, S. Rinaldi, and L. R. Wilkens Association of a Common Polymorphism in the Human GH1 Gene with Colorectal Neoplasia J Natl Cancer Inst, March 20, 2002; 94(6): 454 - 460. [Abstract] [Full Text] [PDF]

				M. J. Borugian, S. B. Sheps, A. S. Whittemore, A. H. Wu, J. D. Potter, and R. P. Gallagher Carbohydrates and Colorectal Cancer Risk among Chinese in North America Cancer Epidemiol. Biomarkers Prev., February 1, 2002; 11(2): 187 - 193. [Abstract] [Full Text] [PDF]

				E. Giovannucci Insulin, Insulin-Like Growth Factors and Colon Cancer: A Review of the Evidence J. Nutr., November 1, 2001; 131(11): 3109S - 3120. [Abstract] [Full Text] [PDF]

				A. Decensi, H. Johansson, R. Miceli, L. Mariani, T. Camerini, E. Cavadini, M. G. Di Mauro, A. Barreca, A. G. Gonzaga, S. Diani, et al. Long-Term Effects of Fenretinide, a Retinoic Acid Derivative, on the Insulin-like Growth Factor System in Women with Early Breast Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2001; 10(10): 1047 - 1053. [Abstract] [Full Text] [PDF]

				J. Ma, E. Giovannucci, M. Pollak, J. M. Chan, J. M. Gaziano, W. Willett, and M. J. Stampfer Milk Intake, Circulating Levels of Insulin-Like Growth Factor-I, and Risk of Colorectal Cancer in Men J Natl Cancer Inst, September 5, 2001; 93(17): 1330 - 1336. [Abstract] [Full Text] [PDF]

				C. Deal, J. Ma, F. Wilkin, J. Paquette, F. Rozen, B. Ge, T. Hudson, M. Stampfer, and M. Pollak Novel Promoter Polymorphism in Insulin-Like Growth Factor-Binding Protein-3: Correlation with Serum Levels and Interaction with Known Regulators J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1274 - 1280. [Abstract] [Full Text]

				J. Ma, M. Stampfer, and M. Pollak RESPONSE: More About: 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, December 6, 2000; 92(23): 1949 - 1949. [Full Text] [PDF]

				A. G. Renehan, S. T. O'Dwyer, and S. M. Shalet RESPONSE: More About: 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, December 6, 2000; 92(23): 1949a - 1949a. [Full Text] [PDF]