Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy.
OBJECTIVE
We investigated p53 and its downstream effectors p21WAF1/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.


METHODS
Expression of p53, BAX, p21WAF1/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.


CONCLUSIONS
These findings are novel and support the clinical relevance of p21 in the suppression of both proliferation and apoptosis. Thus, the dynamic induction of p21WAF1/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.
Rau
Beate
B
Charité Medical School, Campus Berlin-Buch, Humboldt University, Department of Surgery and Surgical Oncology, Robert-Roessle Klinik, Lindenberger Weg 80, 13125 Berlin, Germany. rau@rrk-berlin.de
Sturm
Isrid
I
Lage
Hermann
H
Berger
Stefan
S
Schneider
Ulrike
U
Hauptmann
Steffen
S
Wust
Peter
P
Riess
Hanno
H
Schlag
Peter M
PM
Dörken
Bernd
B
Daniel
Peter T
PT
D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein; D020360:Neoadjuvant Therapy; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012004:Rectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000628:therapy*; D015996:Survival Rate; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein