TP53 oncomorphic mutations predict resistance to platinum‑ and taxane‑based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma.
Individual mutations in the tumor suppressor TP53 alter p53 protein function. Some mutations create a non-functional protein, whereas others confer oncogenic activity, which we term 'oncomorphic'. Since mutations in TP53 occur in nearly all ovarian tumors, the objective of this study was to determine the relationship of oncomorphic TP53 mutations with patient outcomes in advanced serous ovarian cancer patients. Clinical and molecular data from 264 high-grade serous ovarian cancer patients uniformly treated with standard platinum- and taxane-based adjuvant chemotherapy were downloaded from The Cancer Genome Atlas (TCGA) portal. Additionally, patient samples were obtained from the University of Iowa and individual mutations were analyzed in ovarian cancer cell lines. Mutations in the TP53 were annotated and categorized as oncomorphic, loss of function (LOF), or unclassified. Associations between mutation types, chemoresistance, recurrence, and progression-free survival (PFS) were calculated. Oncomorphic TP53 mutations were present in 21.3% of ovarian cancers in the TCGA dataset. Patients with oncomorphic TP53 mutations demonstrated significantly worse PFS, a 60% higher risk of recurrence (HR=1.60, 95% confidence intervals 1.09, 2.33, p=0.015), and higher rates of platinum resistance (χ(2) test p=0.0024) when compared with single nucleotide mutations not categorized as oncomorphic. Furthermore, tumors containing oncomorphic TP53 mutations displayed unique protein expression profiles, and some mutations conferred increased clonogenic capacity in ovarian cancer cell models. Our study reveals that oncomorphic TP53 mutations are associated with worse patient outcome. These data suggest that future studies should take into consideration the functional consequences of TP53 mutations when determining treatment options.
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Pavla
P
Brachova
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Samuel R
SR
Mueting
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Matthew J
MJ
Carlson
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Michael J
MJ
Goodheart
Holden Comprehensive Cancer Center and Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242, USA.
Anna M
AM
Button
Holden Comprehensive Cancer Center and Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242, USA.
Sarah L
SL
Mott
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Donghai
D
Dai
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Kristina W
KW
Thiel
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Eric J
EJ
Devor
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Kimberly K
KK
Leslie
D000328:Adult; D000368:Aged; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage; D011379:Prognosis; D043823:Taxoids / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D001952:Bridged-Ring Compounds; C495901:TP53 protein, human; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; C080625:taxane; D010984:Platinum