Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer

Cancer Epidemiol Biomarkers Prev. 2010 Nov;19(11):2877-87. doi: 10.1158/1055-9965.EPI-10-0507. Epub 2010 Sep 1.

Abstract

Background: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins.

Methods: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium.

Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10(-4)); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R(2) = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers.

Conclusion: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women.

Impact: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Aged
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / blood
  • Breast Neoplasms / genetics*
  • Carrier Proteins / genetics*
  • Cohort Studies
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Glycoproteins / genetics*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor Binding Proteins / blood
  • Insulin-Like Growth Factor Binding Proteins / genetics*
  • Insulin-Like Growth Factor I / genetics*
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / genetics*
  • Receptors, Somatostatin / genetics*
  • Risk Factors
  • Signal Transduction / genetics

Substances

  • Biomarkers, Tumor
  • Carrier Proteins
  • Glycoproteins
  • IGFBP3 protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor Binding Proteins
  • Receptors, Somatostatin
  • insulin-like growth factor binding protein, acid labile subunit
  • Insulin-Like Growth Factor I
  • somatostatin receptor 5