title: Relaxed imprinting of IGF2 in peripheral blood cells of patients with a history of prostate cancer.
abstract: BACKGROUND
  Insulin-like growth factor 2 (IGF2) is the predominant IGF in adults and regulates cell growth. In contrast to normal tissues, where IGF2 is imprinted and only expressed from the paternal allele, loss of imprinting (LOI) and biallelic IGF2 expression are observed in many cancers including prostate cancer (PCa). We here studied whether LOI of IGF2 in normal circulating peripheral blood lymphocytes can predict increased PCa risk.
  
  
  METHODS
  We analyzed IGF2 protein levels, IGF2 820G/A genotype and imprinting status, as well as methylation status of the IGF2 imprinting control region (ICR) in 113 blood samples of patients with a history of radical prostatectomy (RPE) for PCa by ELISA, restriction-fragment length polymorphism, and bisulfite-DNA sequencing. Results were compared to 249 male blood donors with unknown prostate specific antigen (PSA) status.
  
  
  RESULTS
  The 820G/A genotype was enriched in the RPE group and was associated with younger age at cancer diagnosis. LOI in patients was only slightly more frequent than in controls, but IGF2 levels were significantly higher and uncoupled from the imprinting status. Analysis of the IGF2/H19 ICR revealed marked hypermethylation.
  
  
  CONCLUSIONS
  The IGF 820G/A genotype is associated with PCa diagnosis at younger age. Increased IGF2 in patients with PCa appears to be the result of impaired imprinting in non-neoplastic cells rather than a paracrine tumor product. Uncoupling of IGF2 protein levels from imprinting status (not LOI alone) and hypermethylation of the ICR characterized PCa patients and could have the potential to indicate persons at risk in screening programs.
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, University of Heidelberg Theodor-Kutzer-Ufer 1-368135, Mannheim Germany.
authors.forename: Djeda
authors.initials: D
authors.lastname: Belharazem
authors.forename: Matthias
authors.initials: M
authors.lastname: Kirchner
authors.forename: Franziska
authors.initials: F
authors.lastname: Geissler
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.forename: Martin
authors.initials: M
authors.lastname: Spahn
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kneitz
authors.forename: Hubertus
authors.initials: H
authors.lastname: Riedmiller
authors.forename: Christian
authors.initials: C
authors.lastname: Sauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Küffer
authors.forename: Lutz
authors.initials: L
authors.lastname: Trojan
authors.forename: Christian
authors.initials: C
authors.lastname: Bolenz
authors.forename: Maurice Stephan
authors.initials: MS
authors.lastname: Michel
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
keywords: cancer; imprinting; insulin-like growth factor 2; prostate; screening