title: REG4 independently predicts better prognosis in non-mucinous colorectal cancer.
abstract: BACKGROUND
  Colorectal cancer (CRC) is one of the world's three most common cancers and its incidence is rising. To identify patients who benefit from adjuvant therapy requires novel biomarkers. The regenerating islet-derived gene (REG) 4 belongs to a group of small secretory proteins involved in cell proliferation and regeneration. Its up-regulated expression occurs in inflammatory bowel diseases also in gastrointestinal cancers. Reports on the association of REG4 expression with CRC prognosis have been mixed. Our aim was to investigate tumor REG4 expression in CRC patients and its coexpression with other intestinal markers.
  
  
  METHODS
  Tumor expression of REG4 was evaluated by immunohistochemistry in 840 consecutive surgically treated CRC patients at Helsinki University Central Hospital. Expression of MUC1, MUC2, MUC5AC, synapthophysin, and chromogranin was evaluated in a subgroup of 220 consecutively operated CRC patients. REG4 expression with clinicopathological parameters, other intestinal markers, and the impact of REG4 expression on survival were assessed.
  
  
  RESULTS
  REG4 expression associated with favorable clinicopathological parameters and with higher overall survival from non-mucinous CRC (p = 0.019). For such patients under 65, its expression was an independent marker of lower risk of death within 5 years that cancer; univariable hazard ratio (HR) = 0.57; 95% confidence interval (CI) (0.34-0.94); multivariable HR = 0.55; 95% CI (0.33-0.92). In non-mucinous CRC, REG4 associated with positive MUC2, MUC4, and MUC5AC expression.
  
  
  CONCLUSIONS
  We show, to our knowledge for the first time, that REG4 IHC expression to be an independent marker of favorable prognosis in non-mucinous CRC. Our results contradict those from studies based on quantification of REG4 mRNA levels, a discrepancy warranting further studies.
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Kaprio
authors.affiliation: Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland; Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Hagström
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Mustonen
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Selja
authors.initials: S
authors.lastname: Koskensalo
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland.
authors.forename: Leif C
authors.initials: LC
authors.lastname: Andersson
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
authors.forename: Caj
authors.initials: C
authors.lastname: Haglund
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002864:Chromogranins / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D009077:Mucins / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D010641:Phenotype; D011379:Prognosis; D016019:Survival Analysis; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002864:Chromogranins; D037181:Lectins, C-Type; D009077:Mucins; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human; D016708:Synaptophysin