p21 expression predicts outcome in p53-null ovarian carcinoma.
OBJECTIVE
p21 is a direct p53 response gene. Although several studies have correlated p21 and p53 expression, only one has evaluated p21 expression as a function of sequenced p53 gene mutation. We hypothesize that such an analysis may be useful in prognosticating outcome for individuals diagnosed with epithelial ovarian cancer.


METHODS
DNA from the primary ovarian cancers of 267 patients was studied. p53 mutations were directly sequenced. Two percent or greater nuclear staining with WAF1/CIP1 monoclonal antibody was determined by a hazard ratio analysis to constitute positive p21 expression.


RESULTS
Positive p21 nuclear staining occurred more frequently in p53 wild-type ovarian tumors than tumors found to have a p53 mutation (P = 0.001). Positive p21 staining conferred an overall survival advantage (P = 0.02). p21 expression in cancers with p53 missense mutations was not prognostic but did show a strong trend toward significance in the wild-type p53 subset (P = 0.056). Surprisingly, positive p21 staining reflected compromised survival for individuals with p53-null ovarian cancers (P = 0.005). The mean expression level for p21-positive stains in the wild-type group was greater than in null p53 cancers (23 versus 11%; P = 0.001). A Cox multivariable analysis revealed p21 to be a strong independent prognostic factor in p53-null ovarian cancer (P = 0.02).


CONCLUSIONS
p21 expression is closely related to sequenced p53 mutations. This is the first study of positive p21 staining as an independent poor prognostic factor in p53-null ovarian cancer. A dual role for p21 activity, dependent on levels of expression, appears to explain these paradoxical results and is consistent with a complex model for regulation of p21.
Rose
Stephen L
SL
Holden Comprehensive Cancer Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.
Goodheart
Michael J
MJ
DeYoung
Barry R
BR
Smith
Brian J
BJ
Buller
Richard E
RE
D000911:Antibodies, Monoclonal; D002453:Cell Cycle; D002455:Cell Division; D005260:Female; D016158:Genes, p53; D006801:Humans; D015999:Multivariate Analysis; D009154:Mutation; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis* / Q000502:physiology*; D013997:Time Factors; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D016283:Proto-Oncogene Proteins p21(ras)