title: LGR5 and CD133 as prognostic and predictive markers for fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer.
abstract: BACKGROUND
  Expression of leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) gene is associated with a metastatic phenotype and poor prognosis in colorectal cancer (CRC). CD133 expression is a putative cancer stem cell marker and a proposed prognostic marker in CRC, whereas the predictive value of CD133 expression for effect of adjuvant chemotherapy in CRC is unclear.
  
  
  METHODS
  For the study of LGR5 mRNA and CD133 expression, tissue microarrays from 409 primary CRC stage II and III tumors, where patients had been randomized to adjuvant chemotherapy or surgery only, were available. LGR5 mRNA and CD133 expression were assessed by in situ hybridization (ISH) and immunohistochemistry (IHC), respectively. LGR5 mRNA and CD133 expression as prognostic and predictive markers were evaluated by univariate and multivariate analyses.
  
  
  RESULTS
  For all CRC patients, positive LGR5 mRNA and CD133 expression were associated with classic adenocarcinoma histology type (p = 0.001 and p = 0.014, respectively). Positive LGR5 mRNA expression was also associated with smaller tumor diameter for CRC stage II (p = 0.005), but not for CRC stage III (p = 0.054). For CRC stage II, lack of LGR5 mRNA expression was associated with longer time to recurrence (TTR) in Kaplan-Meier (p = 0.045) and in multivariate Cox analysis (HR 0.27, 95% CI 0.08-0.95, p = 0.041). For colon cancer stage III patients, lack of CD133 expression was associated with better effect of adjuvant chemotherapy (p = 0.016) in Kaplan-Meier univariate analysis, but the interaction between CD133 and adjuvant chemotherapy was not statistically significant in multivariate analysis (HR 0.59, 95% CI 0.18-1.89, p = 0.374).
  
  
  CONCLUSIONS
  LGR5 mRNA expression is a prognostic factor for CRC stage II patients, whereas the value of CD133 expression as prognostic and predictive biomarker is inconclusive.
authors.affiliation: a Department of Clinical Science , University of Bergen , Bergen , Norway.
authors.forename: Luka
authors.initials: L
authors.lastname: Stanisavljević
authors.affiliation: b Department of Oncology and Medical Physics , Haukeland University Hospital , Bergen , Norway.
authors.forename: Mette P
authors.initials: MP
authors.lastname: Myklebust
authors.affiliation: c Department of Pathology , Haukeland University Hospital , Bergen , Norway.|d Department of Clinical Medicine , University of Bergen , Bergen , Norway.
authors.forename: Sabine
authors.initials: S
authors.lastname: Leh
authors.affiliation: a Department of Clinical Science , University of Bergen , Bergen , Norway.|b Department of Oncology and Medical Physics , Haukeland University Hospital , Bergen , Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Dahl
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D007978:Levamisole; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D000071916:AC133 Antigen; D014408:Biomarkers, Tumor; C116884:LGR5 protein, human; C000606023:PROM1 protein, human; D043562:Receptors, G-Protein-Coupled; D007978:Levamisole; D005472:Fluorouracil