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Dynamic expression profile of p21 WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy

Official URL:https://doi.org/10.1200/JCO.2003.07.077
PubMed:View item in PubMed
Creators Name:Rau, B. and Sturm, I. and Lage, H. and Berger, S. and Schneider, U. and Haupfmann, S. and Wust, P. and Riess, H. and Schlag, P.M. and Doerken, B. and Daniel, P.T.
Journal Title:Journal of Clinical Oncology
Journal Abbreviation:J Clin Oncol
Volume:21
Number:18
Page Range:3391-3401
Date:15 September 2003
Keywords:Base Pair Mismatch, bcl-2-Associated X Protein, Cell Cycle Proteins, Cell Division, Combined Modality Therapy, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, DNA Mutational Analysis, DNA Repair, DNA-Binding Proteins, Disease-Free Survival, Immunohistochemistry, Ki-67 Antigen, Longitudinal Studies, MutS Homolog 2 Protein, Neoadjuvant Therapy, p53 Genes, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Rectal Neoplasms, Single-Stranded Conformational Polymorphism, Survival Rate
Abstract:Purpose: We investigated p53 and its downstream effectors p21(WAF1/CIP1), BAX, and hMSH2 as well as the proliferation marker Ki-67 (mki-67/MIB-1) in patients undergoing preoperative radiochemotherapy for rectal carcinoma to identify prognostic and predictive factors. The focus of this study was on the dynamics of these genetic markers in a longitudinal study—that is, before and after radiochemotherapy. Patients and Methods: Expression of p53, BAX, p21(WAF1/CIP1), Ki-67, and hMSH2 was investigated by immunohistochemistry in pre- and posttherapeutic tumor samples in 66 patients. Tumor DNA was screened for p53 mutations by single-strand conformation polymorphism–polymerase chain reaction (SSCP-PCR). Paired tumor samples (pretherapy and posttherapy) were collected prospectively. Results: Patients with a decrease in p21 expression following radiochemotherapy had better disease-free survival (P = .03). Similarly, patients with an increase in proliferative activity as measured by increased Ki-67 expression posttherapy had better disease-free survival (P < .005). In addition, we observed a significantly better prognosis for patients with high hMSH2 expression. In contrast, pretherapeutic levels of p53, BAX, or p21 expression and p53 mutation had no prognostic value, indicating that the combination of radiotherapy and chemotherapy might override defects in these genes. Conclusion: These findings are novel and support the clinical relevance of p21 in the suppression of both proliferation and apoptosis. Thus, the dynamic induction of p21(WAF1/CIP1) was associated with a lower proliferative activity but an ultimately worse treatment outcome following neoadjuvant radiochemotherapy and tumor resection. Induction of p21, therefore, represents a novel resistance mechanism in rectal cancer undergoing preoperative radiochemotherapy.
ISSN:0732-183X
Item Type:Article

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