P21^WAF1/CIP1 expression in colorectal carcinomas is related to Kras mutations and prognosis

Abstract

Background/aim 

P21^WAF1/CIP1 is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest. A consensus has not been reached concerning the prognostic value of p21^WAF1/CIP1 expression in colorectal cancers.

Patients/methods 

P21^WAF1/CIP1 expression was determined immunohistochemically in a series of 211 cases of colorectal carcinomas, together with its relation to p53, bcl-2, cell turnover (as assessed by Ki67 expression and apoptotic counts) and the Kras gene status. The expression of p21^WAF1/CIP1 was also compared with reference to clinicopathological parameters and patient survival.

Results 

The median value for nuclear p21^WAF1/CIP1 expression was 31% (interquartile range, 13–47%) and the fraction of cases considered to be high expressers (>20%) was 66%. Expression of p21^WAF1/CIP1 was not associated with immunoreactivity for p53 or bcl-2, or cell turnover. P21^WAF1/CIP1 high-expressing tumors were more often well differentiated (P<0.001), node-negative (P=0.037), Dukes' B (P=0.027) and Kras gene-mutated cases (P=0.04). On univariate analysis, low p21^WAF1/CIP1 expressers (≤20%) had lower cancer-related survival as compared with high expressers (5-year survival, 56 vs. 70%; P=0.042). Lymph node status, liver metastasis and tumor size were also significant predictors. Multivariate analysis revealed lymph node-positive (P<0.001), liver metastasis (P<0.001), and low p21^WAF1/CIP1 expression (P=0.017) to be independent predictors of short survival.

Conclusion 

The regulation of p21^WAF1/CIP1, independent of p53 or bcl-2 expression, appears to be associated with Kras mutations. The immunohistochemical detection of p21^WAF1/CIP1 might thus be used to predict more precise outcome in colorectal cancer patients.