A survival-stratification model of human colorectal carcinomas with beta-catenin and p27kip1

Cancer. 2002 Dec 15;95(12):2479-86. doi: 10.1002/cncr.10986.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Biomarkers, Tumor / metabolism
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cytoskeletal Proteins / metabolism*
  • Enzyme Inhibitors / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Proto-Oncogene Proteins c-myc / metabolism
  • Retrospective Studies
  • Survival Rate
  • Trans-Activators / metabolism*
  • Tumor Suppressor Proteins / metabolism*
  • beta Catenin


  • Biomarkers, Tumor
  • CTNNB1 protein, human
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Trans-Activators
  • Tumor Suppressor Proteins
  • beta Catenin
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27