Insulin-like growth factor pathway genetic polymorphisms, circulating igf1 and IGFBP3, and prostate cancer survival

Yin Cao, Sara Lindström, Fredrick Schumacher, Victoria L. Stevens, Demetrius Albanes, Sonja I. Berndt, Heiner Boeing, H. Bas Bueno-De-Mesquita, Federico Canzian, Saioa Chamosa, Stephen J. Chanock, W. Ryan Diver, Susan M. Gapstur, J. Michael Gaziano, Edward L. Giovannucci, Christopher A. Haiman, Brian Henderson, Mattias Johansson, Loïc Le Marchand, Domenico PalliBernard Rosner, Afshan Siddiq, Meir Stampfer, Daniel O. Stram, Rulla Tamimi, Ruth C. Travis, Dimitrios Trichopoulos, Walter C. Willett, Meredith Yeager, Peter Kraft, Ann W. Hsing, Michael Pollak, Xihong Lin, Jing Ma

Research output: Contribution to journalArticlepeer-review


Background The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown. Methods Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided. Results The IGF signaling pathway was associated with PCa mortality (P =. 03), and IGF2-AS and SSTR2 were the main contributors (both P =. 04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than. 05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend =. 003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend trend.corr =. 04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality. Conclusions The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

Original languageEnglish (US)
Article numberdju218
JournalJournal of the National Cancer Institute
Issue number5
StatePublished - May 14 2014
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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