title: Carcinoma of the colon and rectum with deregulation of insulin-like growth factor 2 signaling: clinical and molecular implications.
abstract: BACKGROUND
  Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) is an early event in the development of colorectal cancer (CRC). Whether LOI of IGF2 denotes a molecular or clinical cancer subgroup is currently unknown.
  
  
  METHODS
  Tumor biopsies and paired normal mucosa from 399 patients with extensive clinical annotations were analyzed for LOI and IGF2 expression. LOI status in 140 informative cases was correlated with clinicopathologic parameters and outcome.
  
  
  RESULTS
  LOI was frequent in normal mucosa and tumors and occurred throughout the large intestine. LOI was unrelated to microsatellite instability, KRAS mutation status, stage, and survival. However, CRC with LOI showed increased IGF2 protein levels and activation of AKT1. Gene expression analysis of tumors with and without LOI and knockdown of IGF2 in cell lines revealed that IGF2 induced distinct sets of activated and repressed genes, including Wnt5a, CEACAM6, IGF2BP3, KPN2A, BRCA2, and CDK1. Inhibition of AKT1 in IGF2-stimulated cells showed that the downstream effects of IGF2 on cell proliferation and gene expression were strictly AKT1-dependent.
  
  
  CONCLUSIONS
  LOI of IGF2 is a frequent and early event in CRC that occurs both in the adenomatous polyposis coli (APC) gene-mutated and serrated route of carcinogenesis. LOI leads to overexpression of IGF2, activates IGF1R and AKT1, and is a powerful driver of cell proliferation. Moreover, our results suggest that IGF2 via AKT1 also contributes to non-canonical wnt signaling. Although LOI had no significant impact on major clinical parameters and outcome, its potential as a target for preventive and therapeutic interventions merits further investigation.
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Djeda
authors.initials: D
authors.lastname: Belharazem
authors.affiliation: Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Magdeburg
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Berton
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Str 40, 37075, Göttingen, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Beissbarth
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Sauer
authors.affiliation: Medical Research Center (ZMF), University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
authors.affiliation: Medical Clinic, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Hofheinz
authors.affiliation: Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Post
authors.affiliation: Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kienle
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Str 40, 37075, Göttingen, Germany. philipp.stroebel@med.uni-goettingen.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D016203:CDC2 Protein Kinase; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011110:Polymorphism, Genetic; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D015996:Survival Rate; D060449:Wnt Signaling Pathway / Q000235:genetics*; D000071818:Wnt-5a Protein / Q000235:genetics
chemical_list: D015703:Antigens, CD; D024682:BRCA2 Protein; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; C498780:IGF2BP3 protein, human; C117307:KRAS protein, human; D016601:RNA-Binding Proteins; D017451:Receptors, Somatomedin; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: AKT1; Colon cancer; IGF2; Imprinting; Wnt5a