title: Tumor phosphatidylinositol-3-kinase signaling and development of metastatic disease in locally advanced rectal cancer.
abstract: BACKGROUND
  Recognizing EGFR as key orchestrator of the metastatic process in colorectal cancer, but also the substantial heterogeneity of responses to anti-EGFR therapy, we examined the pattern of composite tumor kinase activities governed by EGFR-mediated signaling that might be implicated in development of metastatic disease.
  
  
  METHODS
  Point mutations in KRAS, BRAF, and PIK3CA and ERBB2 amplification were determined in primary tumors from 63 patients with locally advanced rectal cancer scheduled for radical treatment. Using peptide arrays with tyrosine kinase substrates, ex vivo phosphopeptide profiles were generated from the same baseline tumor samples and correlated to metastasis-free survival.
  
  
  RESULTS
  Unsupervised clustering analysis of the resulting phosphorylation of 102 array substrates defined two tumor classes, both consisting of cases with and without KRAS/BRAF mutations. The smaller cluster group of patients, with tumors generating high ex vivo phosphorylation of phosphatidylinositol-3-kinase-related substrates, had a particularly aggressive disease course, with almost a half of patients developing metastatic disease within one year of follow-up.
  
  
  CONCLUSIONS
  High phosphatidylinositol-3-kinase-mediated signaling activity of the primary tumor, rather than KRAS/BRAF mutation status, was identified as a hallmark of poor metastasis-free survival in patients with locally advanced rectal cancer undergoing radical treatment of the pelvic cavity.
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway. a.h.ree@medisin.uio.no
authors.forename: Anne Hansen
authors.initials: AH
authors.lastname: Ree
authors.forename: Annette Torgunrud
authors.initials: AT
authors.lastname: Kristensen
authors.forename: Marie Grøn
authors.initials: MG
authors.lastname: Saelen
authors.forename: Rik
authors.initials: R
authors.lastname: de Wijn
authors.forename: Hege
authors.initials: H
authors.lastname: Edvardsen
authors.forename: Jovana
authors.initials: J
authors.lastname: Jovanovic
authors.forename: Torveig Weum
authors.initials: TW
authors.lastname: Abrahamsen
authors.forename: Svein
authors.initials: S
authors.lastname: Dueland
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
mesh_terms: D000595:Amino Acid Sequence; D018572:Disease-Free Survival; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012004:Rectal Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases