title: Microsatellite instability, KRAS mutations and cellular distribution of TRAIL-receptors in early stage colorectal cancer.
abstract: BACKGROUND
  The fact that the receptors for the TNF-related apoptosis inducing ligand (TRAIL) are almost invariably expressed in colorectal cancer (CRC) represents the rationale for the employment of TRAIL-receptors targeting compounds for the therapy of patients affected by this tumor. Yet, first reports on the use of these bioactive agents provided disappointing results. We therefore hypothesized that loss of membrane-bound TRAIL-R might be a feature of some CRC and that the evaluation of membrane staining rather than that of the overall expression of TRAIL-R might predict the response to TRAIL-R targeting compounds in this tumor.
  
  
  OBJECTIVE
  Thus, we evaluated the immunofluorescence pattern of TRAIL-receptors and E-cadherin to assess the fraction of membrane-bound TRAIL-receptors in 231 selected patients with early-stage CRC undergoing surgical treatment only. Moreover, we investigated whether membrane staining for TRAIL-receptors as well as the presence of KRAS mutations or of microsatellite instability (MSI) had an effect on survival and thus a prognostic effect.
  
  
  RESULTS
  As expected, almost all CRC samples stained positive for TRAIL-R1 and 2. Instead, membrane staining for these receptors was positive in only 71% and 16% of samples respectively. No correlation between KRAS mutation status or MSI-phenotype and prognosis could be detected. TRAIL-R1 staining intensity correlated with survival in univariate analysis, but only membranous staining of TRAIL-R1 and TRAIL-R2 on cell membranes was an independent predictor of survival (cox multivariate analysis: TRAIL-R1: p = 0.019, RR 2.06[1.12-3.77]; TRAIL-R2: p = 0.033, RR 3.63[1.11-11.84]).
  
  
  CONCLUSIONS
  In contrast to the current assumptions, loss of membrane staining for TRAIL-receptors is a common feature of early stage CRC which supersedes the prognostic significance of their staining intensity. Failure to achieve therapeutic effects in recent clinical trials using TRAIL-receptors targeting compounds might be due to insufficient selection of patients bearing tumors with membrane-bound TRAIL-receptors.
authors.affiliation: Institute of Pathology, University of Munich, Munich, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kriegl
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.forename: David
authors.initials: D
authors.lastname: Horst
authors.forename: Antonia
authors.initials: A
authors.lastname: Rizzani
authors.forename: Rene
authors.initials: R
authors.lastname: Jackstadt
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
authors.forename: Eike
authors.initials: E
authors.lastname: Gallmeier
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerbes
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Enrico N
authors.initials: EN
authors.lastname: De Toni
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000368:Aged; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D060888:Real-Time Polymerase Chain Reaction; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015996:Survival Rate; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015820:Cadherins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D004247:DNA; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins