p21(WAF1/CIP1) expression in colorectal carcinoma correlates with advanceddisease stage and p53 mutations

Defects in the mechanisms controlling the cell cycle are crucial in cell tr ansformation and/or tumour progression. p21(WAF1/CIP1) is an inhibitor of c yclin-dependent kinases, induced by p53-dependent and p53-independent pathw ays, which can block progression through the cell cycle, p21(WAF1/CIP1) exp ression has been investigated immunohistochemically in a series of 191 pati ents with colorectal cancer of known p53 status. The purpose of the study w as two-fold: to assess the relationship between p21(WAF1/CIP1) immunoreacti vity and p53 alterations, and to evaluate the prognostic significance of p2 1(WAF1/CIP1) expression, In 96 carcinomas (51 per cent), p21(WAF1/CIP1) was expressed in over 10 per cent of tumour cells, whereas in 26, p21(WAF1/CIP 1) was detected in under 10 per cent of neoplastic cells; 69 tumours lacked p21(WAF1/CIP1) expression. Immunoreactivity was more frequent in tumours o f the right colon (p<0.003) and was inversely correlated with tumour stage (p<0.03), p53 gene mutations (p<0.0007), p53 protein accumulation (p<0.019) , and Bcl-2 expression (p<0.0005). In univariate analysis, down-regulation of p21(WAF1/CIP1) expression was associated with poor overall (p=0.0022) an d disease-free survival (p=0.0009). Multivariate analysis, however, did not confirm any independent prognostic significance of p21(WAF1/CIP1) expressi on. The results indicate that p21(WAF1/CIP1), associated with abnormal accu mulation of p53 protein and the occurrence of p53 gene mutations in colorec tal cancer and that lack of p21(WAF1/CIP1) expression is correlated with re duced patient survival in univariate analysis. These data underline the cru cial pathogenetic role of the p53-p21(WAF1/CIP1) pathway in carcinomas of t he large bowel. Copyright (C) 1999 John Wiley & Sons, Ltd.