title: A survival-stratification model of human colorectal carcinomas with beta-catenin and p27kip1.
abstract: BACKGROUND
  The stabilization and nuclear translocation of beta-catenin are early events in the majority of sporadic colorectal carcinomas (CRC). beta-catenin up-regulates c-Myc and cyclin D1, which antagonize the association of the cyclin-dependent kinase (Cdk) inhibitor, p27(kip1), with Cdk2, thus allowing cell cycle progression through G1 to S-phase. Lack of p27 is a significant predictor of poor survival in a series of 136 CRC specimens. A combination of molecules in the same pathway may be a better prognostic factor.
  
  
  METHODS
  The expression of beta-catenin, c-Myc, and cyclin D1 in relation to patients' survival and clinicopathologic parameters in the same series was evaluated by immunohistochemistry.
  
  
  RESULTS
  Intense nuclear overexpression of beta-catenin, but not a lack of cell membrane or cytoplasmic expression, is a significant predictor of poor survival by both univariate (P = 0.0029) and multivariate analyses (P = 0.004, risk ratio =3.8), suggesting that beta-catenin is retained in the nucleus to function as an oncogene. None of the patients with high nuclear beta-catenin and low p27 expression survived 5 years or more whereas 65% of patients with all other combinations of the two markers survived (P < 0.0001). This combination is also a significant and independent prognostic factor (P = 0.001; risk ratio = 9.7). Overexpression of c-Myc is associated with higher mortality rates, but the expression of cyclin D1 has no prognostic significance.
  
  
  CONCLUSIONS
  The combined expression of beta-catenin and p27 can stratify patients into markedly different survival groups, possibly via their antagonistic effects on metastasis promotion.
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore. gcscpy@sgh.com.sg
authors.forename: Peh Yean
authors.initials: PY
authors.lastname: Cheah
authors.forename: Poh Heok
authors.initials: PH
authors.lastname: Choo
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Yao
authors.forename: Kong Weng
authors.initials: KW
authors.lastname: Eu
authors.forename: Francis
authors.initials: F
authors.lastname: Seow-Choen
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012189:Retrospective Studies; D015996:Survival Rate; D015534:Trans-Activators / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051176:beta Catenin
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27