A survival–stratification model of human colorectal carcinomas with β‐catenin and p27kip1

• Published in: Cancer 2002-12, Vol.95 (12), p.2479-2486
• Main Authors: Cheah, Peh Yean, Choo, Poh Heok, Yao, Jocelyn, Eu, Kong Weng, Seow‐Choen, Francis
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Adenocarcinoma - pathology; beta Catenin; Biomarkers, Tumor - metabolism; Cell Cycle Proteins - metabolism; Cell Differentiation; colorectal carcinoma; 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; p27kip1; Prognosis; Proto-Oncogene Proteins c-myc - metabolism; Retrospective Studies; risk stratification; Survival Rate; Trans-Activators - metabolism; Tumor Suppressor Proteins - metabolism; β‐catenin
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.10986

BACKGROUND The stabilization and nuclear translocation of β‐catenin are early events in the majority of sporadic colorectal carcinomas (CRC). β‐catenin up‐regulates c‐Myc and cyclin D1, which antagonize the association of the cyclin‐dependent kinase (Cdk) inhibitor, p27kip1, 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 β‐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 β‐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 β‐catenin is retained in the nucleus to function as an oncogene. None of the patients with high nuclear β‐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 β‐catenin and p27 can stratify patients into markedly different survival groups, possibly via their antagonistic effects on metastasis promotion. Cancer 2002;95:2479–86. © 2002 American Cancer Society. DOI 10.1002/cncr.10986 A combination of β‐catenin and p27 expression stratifies patients into markedly different survival groups for human colorectal carcinomas. Five‐year disease‐specific survival rates ranged from 0% for patients with high nuclear β‐catenin and low p27 expression to 65% for patients with all other combinations of the two markers (P < 0.0001).