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Longitudinal Study of Insulin-like Growth Factor, Insulin-like Growth Factor Binding Protein-3, and their Polymorphisms: Risk of Neoplastic Progression in Barrett's Esophagus

¹ Public Health Sciences Division and ² Human Biology Division, Fred Hutchinson Cancer Research Center; Departments of ³ Epidemiology, ⁴ Medicine, ⁵ Pathology, ⁶ Genome Sciences, ⁷ Otolaryngology-Head and Neck Surgery, University of Washington; ⁸ Department of Gastroenterology, Virginia Mason Medical Center, Seattle, Washington and ⁹ Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts

Requests for reprints: Thomas L. Vaughan, Program in Epidemiology (M4-874), Fred Hutchinson Cancer Research Center, P.O. Box 19024, Seattle, WA 98109. E-mail: tvaughan{at}u.washington.edu

Background: Insulin-like growth factor-I (IGF-I) is a potent mitogen. IGF-I and its main binding protein, IGF binding protein-3 (IGFBP-3), and their polymorphisms have been investigated in relation to risk of many cancers, but not esophageal adenocarcinoma.

Materials and Methods: We used data and specimens from a longitudinal study of persons with Barrett's esophagus (n = 344; median, 5.4 years follow up) to determine whether baseline serum concentrations of IGF-I and IGFBP-3 and associated polymorphisms were related to the risk of developing esophageal adenocarcinoma or flow cytometric abnormalities.

Results: Overall, circulating concentrations of IGF-I and IGBP-3 were not associated with risk of esophageal adenocarcinoma or flow cytometric abnormalities, with the exception of an approximate tripling of risk of aneuploidy among participants with higher IGFBP-3 levels [above median; adjusted hazard ratio (HR) comparing subjects with levels lower than median versus higher of equal to median, 2.7; 95% confidence interval (95% CI), 1.2-6.0; P = 0.01]. Genotypic analyses revealed that persons with the IGF-I [cytosine-adenine (CA)]₁₉ or the IGFBP-3 A-202C C allele were associated with lower circulating concentrations of IGF-I (P_trend = 0.01) and IGFBP-3 (P_trend = 0.002), respectively. Persons with two copies of the IGF-I receptors 2-bp deletion allele had a nonsignificant 2-fold increased risk of tetraploidy (HR, 2.3; 95% CI, 0.9-5.9; P_trend = 0.11). After adjustment for IGFBP-3 levels, participants carrying two IGFBP-3 C alleles had a significantly higher risk of developing aneuploidy (HR, 3.8; 95% CI, 1.0-14.0; P_trend = 0.04) than carriers of A alleles; whereas no associations were observed between the outcomes studied and the IGF-I receptors AGG trinucleotide repeat polymorphism at position 97.

Conclusion: Our findings, although based on a relatively small number of outcomes and subject to several limitations, indicate a potential role of the complex IGF system in neoplastic progression among persons with Barrett's esophagus. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2387–96)