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

J Pathol. 1999 Feb;187(3):302-7. doi: 10.1002/(SICI)1096-9896(199902)187:3<302::AID-PATH243>3.0.CO;2-U.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Biomarkers, Tumor / metabolism*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism*
  • Female
  • Follow-Up Studies
  • Genes, p53*
  • Humans
  • Immunoenzyme Techniques
  • Intestinal Mucosa / metabolism
  • Male
  • Mutation
  • Neoplasm Proteins / metabolism
  • Neoplasm Staging
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Survival Rate


  • Biomarkers, Tumor
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2