p21WAF1/CIP1 expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations

Defects in the mechanisms controlling the cell cycle are crucial in cell transformation and/or tumour progression. p21WAF1/CIP1 is an inhibitor of cyclin-dependent kinases, induced by p53-dependent and p53-independent pathways, which can block progression through the cell cycle. p21WAF1/CIP1 expression has been investigated immunohistochemically in a series of 191 patients with colorectal cancer of known p53 status. The purpose of the study was two-fold: to assess the relationship between p21WAF1/CIP1 immunoreactivity and p53 alterations, and to evaluate the prognostic significance of p21WAF1/CIP1 expression. In 96 carcinomas (51 per cent), p21WAF1/CIP1 was expressed in over 10 per cent of tumour cells, whereas in 26, p21WAF1/CIP1 was detected in under 10 per cent of neoplastic cells; 69 tumours lacked p21WAF1/CIP1 expression. Immunoreactivity was more frequent in tumours of 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 p21WAF1/CIP1 expression was associated with poor overall (p = 0.0022) and disease-free survival (p = 0.0009). Multivariate analysis, however, did not confirm any independent prognostic significance of p21WAF1/CIP1 expression. The results indicate that p21WAF1/CIP1 is associated with abnormal accumulation of p53 protein and the occurrence of p53 gene mutations in colorectal cancer and that lack of p21WAF1/CIP1 expression is correlated with reduced patient survival in univariate analysis. These data underline the crucial pathogenetic role of the p53-p21WAF1/CIP1 pathway in carcinomas of the large bowel.