TY - JOUR
T1 - TP53 hot spot mutations in ovarian cancer
T2 - Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from the Cancer Genome Atlas
AU - Seagle, Brandon Luke L.
AU - Yang, Chia Ping Huang
AU - Eng, Kevin H.
AU - Dandapani, Monica
AU - Odunsi-Akanji, Oluwatosin
AU - Goldberg, Gary L.
AU - Odunsi, Kunle
AU - Horwitz, Susan Band
AU - Shahabi, Shohreh
N1 - Funding Information:
The results published here are in part based upon the data generated by the TCGA Research Network: http://cancergenome.nih.gov/ . We thank Dr. Elisabeth de Vries, MD/PhD, Professor of Medical Oncology, University Medical Center Groningen, Netherlands, for providing the cell lines used in this study, and Dr. Gerda Hofstetter, MD for performing the RT-PCR experiments. This study is funded in part by the National Foundation for Cancer Research (SBH), Roswell Park Cancer Institute Alliance Foundation Award (KO), National Cancer Institute Cancer Center Support Grant NIH 2P30 CA016056-36 (KO), NIH 1R01CA158318-01A1 (KO), and RPCI-UPCI Ovarian Cancer SPORE NIH P50CA159981-01A1 (KO), NIH K01LM012100 (KE), and NIH P30CA016056 (RPCI).
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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, PIDD, 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 mutation 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.
AB - 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, PIDD, 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 mutation 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.
KW - Drug therapy
KW - Ovarian neoplasms
KW - Survival
KW - TP53 genes
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U2 - 10.1016/j.ygyno.2015.04.039
DO - 10.1016/j.ygyno.2015.04.039
M3 - Article
C2 - 25958320
AN - SCOPUS:84931560283
VL - 138
SP - 159
EP - 164
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
IS - 1
ER -