期刊
GYNECOLOGIC ONCOLOGY
卷 138, 期 1, 页码 159-164出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ygyno.2015.04.039
关键词
TP53 genes; Ovarian neoplasms; Drug therapy; Survival
资金
- National Foundation for Cancer Research
- Roswell Park Cancer Institute Alliance Foundation Award
- National Cancer Institute Cancer Center Support Grant [NIH 2P30 CA016056-36, NIH 1R01CA158318-01A1]
- RPCI-UPCI Ovarian Cancer SPORE [NIH P50CA159981-01A1, NIH K01LM012100, NIH P30CA016056]
Objective. To test if TP53 hot spot mutations (HSMs) confer differential chemotherapy resistance or survival outcomes, the effects of microtubule stabilizers on human ovarian carcinoma cells (OCCs) expressing TP53 HSMs were studied in vitro. Survival outcomes of patients with high grade serous epithelial ovarian carcinoma (HGS EOC) expressing matched HSMs were compared using The Cancer Genome Atlas (TCGA) data. Methods. Growth inhibition of OCCs transfected with a HSM (m175, m248 or m273) was measured during treatment with paclitaxel, epothilone B (epoB), or ixabepilone. Effects of epoB on p53 expression, phosphorylation, and acetylation, as well as p53-regulated expression of p21 and mdm2 proteins, were determined by Western blot analysis. Expression of p53 target genes P21, GADD45, BAX, P1DD, NF-kB2, PAI-1, and MDR1 was measured by RT-PCR. cBioPortal.org identified patients with codon R175, R248 or R273 HSMs from TCGA data. Survival outcomes were characterized. Results. p53-m248 confers chemoresistance and is not acetylated during epoB treatment.m273 demonstrated high MDR1 expression and resistance to paclitaxel. P21, GADD45 and PAI-1 expression were down-regulated in mutant OCCs. Optimally cytoreduced patients with codon R273 (n = 17), R248 (n = 13), R175 (n = 7) HSMs, or any other TP53 imitation demonstrated median 14.9, 17.6, 17.8 and 16.9 months (p = 0.806) progression free survival and 84.1, 33.6, 62.1 and 44.5 months (p = 0.040) overall survival, respectively. Conclusions. Human OCCs harboring different TP53 HSMs were selectively resistant to microtubule stabilizers. Patients with different HSMs had significantly different overall survival. Both in vitro data and clinical experience support further studying the outcomes of particular TP53 HSMs. (C) 2015 Elsevier Inc. All rights reserved.
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