Journal article
TP53 oncomorphic mutations predict resistance to platinum- and taxane- based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma
International Journal of Oncology, Vol.46(2), pp.607-618
2015
DOI: 10.3892/ijo.2014.2747
PMCID: PMC4277253
PMID: 25385265
Abstract
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.
Details
- Title: Subtitle
- TP53 oncomorphic mutations predict resistance to platinum- and taxane- based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma
- Creators
- Pavla BrachovaSamuel R MuetingMatthew J CarlsonMichael J Goodheart - University of Iowa, Obstetrics and GynecologyAnna M ButtonSarah L MottDonghai Dai - University of Iowa, Obstetrics and GynecologyKristina W Thiel - University of Iowa, Obstetrics and GynecologyEric J Devor - University of Iowa, Obstetrics and GynecologyKimberly K Leslie - University of Iowa, Obstetrics and Gynecology
- Resource Type
- Journal article
- Publication Details
- International Journal of Oncology, Vol.46(2), pp.607-618
- Publisher
- Spandidos Publications; ATHENS
- DOI
- 10.3892/ijo.2014.2747
- PMID
- 25385265
- PMCID
- PMC4277253
- ISSN
- 1019-6439
- eISSN
- 1791-2423
- Number of pages
- 12
- Grant note
- R01 CA099908 / NCI NIH HHS NI H R01CA 99908 / NCI NIH HHS 5R01CA099908-12 / National Institutes of Health (nih_________::NIH)
- Language
- English
- Date published
- 2015
- Description audience
- Academic
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9983930396402771
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