Prognostic significance of p53 mutation and p53 overexpression in advanced epithelial ovarian cancer: a Gynecologic Oncology Group Study.
OBJECTIVE
The prognostic significance of p53 mutations and overexpression in advanced epithelial ovarian cancers was examined in primary tumors from 125 patients participating in a Gynecologic Oncology Group randomized phase III treatment protocol.


METHODS
Mutational analysis of p53 was performed in RNA or genomic DNA extracted from frozen tumor. An immunohistochemistry assay was used to detect p53 overexpression in fixed tumor.


RESULTS
There were 81 patients (74%) with a single mutation, three patients (3%) with two mutations, and 25 patients (23%) lacking a mutation in exons 2 to 11 of p53. Although most mutations occurred within exons 5 to 8, mutations outside this region were observed in 11% of patients. A mutation in exons 2 to 11 of p53 was associated with a short-term improvement in overall survival and progression-free survival. Adjusted Cox modeling demonstrated a 70% reduction in risk of death (P =.014) and a 60% reduction in risk of disease progression (P =.014) for women with such mutations. However, these striking risk reductions increased over time (P <.02) and eventually disappeared with longer follow-up. Overexpression of p53 was observed in 55 patients (100%) with only missense mutation(s), seven patients (32%) with truncation mutations, and eight patients (40%) lacking a mutation in exons 2 to 11. Overexpression of p53 was associated with tumor grade but not with patient outcome.


CONCLUSIONS
Alterations in p53 are a common event in advanced epithelial ovarian cancer. A mutation in p53, but not overexpression of p53, is associated with a short-term survival benefit. Additional studies are required to define the roles that p53 plays in regulating therapeutic responsiveness and patient outcome.
Havrilesky
Laura
L
Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
Darcy
kathleen M
kM
Hamdan
Hasnah
H
Priore
Roger L
RL
Leon
Jorge
J
Bell
Jeffrey
J
Berchuck
Andrew
A
D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53