title: Insulin-like growth factor axis gene polymorphisms modify risk of pancreatic cancer.
abstract: OBJECTIVE
  Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways. We hypothesized that IGF-axis genetic variants modify individual susceptibility to pancreatic cancer.
  
  
  METHODS
  We retrospectively genotyped 41 single-nucleotide polymorphisms of 10 IGF-axis genes (IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP3, IGFBP5, IRS1, IRS2, and IRS4) in 706 pancreatic cancer patients and 706 cancer-free controls using Sequenom and TaqMan technology. The association between genotype and pancreatic cancer risk was evaluated using multivariate logistic regression. A P value ≤.007 at a false discovery rate of 10% was set as the significance level.
  
  
  RESULTS
  We observed that the IGF1 *10212C>A and Ex4+2776G>A and IGF1R IVS2-70184A>G and IVS2+46329T>C variant genotypes were significantly associated with decreased pancreatic cancer risk (odds ratio [OR] range, 0.60-0.75) and that IGFBP1 Ex4+111A>G (I253M) was significantly associated with increased pancreatic cancer risk (OR=1.46) after adjusted for other risk factors and multiple comparisons (P≤.007). IGF2R and IGFBP3 variant haplotypes were associated with increased and decreased pancreatic cancer risk, respectively (P<.001). We also observed a weak interaction of the IGF1R IVS2+46329T>C and IGF2R Ex45+11C>T (L2222L) genotypes with diabetes (P(interaction)=.05) and interaction of IGF2R and IRS1 genotypes with alcohol consumption (P(interaction)=.03 and .019, respectively) on increased pancreatic cancer risk.
  
  
  CONCLUSIONS
  These findings support our hypothesis that polymorphic variants of IGF-axis genes act alone or jointly with other risk factors to affect susceptibility to pancreatic cancer.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States. xqundong@mdanderson.org
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Dong
authors.forename: Yanan
authors.initials: Y
authors.lastname: Li
authors.forename: Hongwei
authors.initials: H
authors.lastname: Tang
authors.forename: Ping
authors.initials: P
authors.lastname: Chang
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Donghui
authors.initials: D
authors.lastname: Li
mesh_terms: D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D013002:Somatomedins / Q000235:genetics*
chemical_list: D013002:Somatomedins