TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from the Cancer Genome Atlas

Brandon Luke L. Seagle; Chia Ping Huang Yang; Kevin H. Eng; Monica Dandapani; Oluwatosin Odunsi-Akanji; Gary L. Goldberg; Kunle Odunsi; Susan Band Horwitz; Shohreh Shahabi

doi:10.1016/j.ygyno.2015.04.039

TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from the Cancer Genome Atlas

Brandon Luke L. Seagle, Chia Ping Huang Yang, Kevin H. Eng, Monica Dandapani, Oluwatosin Odunsi-Akanji, Gary L. Goldberg, Kunle Odunsi, Susan Band Horwitz, Shohreh Shahabi^*

^*Corresponding author for this work

Medical Social Sciences

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	159-164
Number of pages	6
Journal	Gynecologic oncology
Volume	138
Issue number	1
DOIs	https://doi.org/10.1016/j.ygyno.2015.04.039
State	Published - Jul 1 2015

Funding

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).

Keywords

Drug therapy
Ovarian neoplasms
Survival
TP53 genes

ASJC Scopus subject areas

Obstetrics and Gynecology
Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ygyno.2015.04.039

Cite this

Seagle, B. L. L., Yang, C. P. H., Eng, K. H., Dandapani, M., Odunsi-Akanji, O., Goldberg, G. L., Odunsi, K., Horwitz, S. B., & Shahabi, S. (2015). TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from the Cancer Genome Atlas. Gynecologic oncology, 138(1), 159-164. https://doi.org/10.1016/j.ygyno.2015.04.039

@article{be853cd036b3440fb1570a789e14a99d,

title = "TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from the Cancer Genome Atlas",

abstract = "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.",

keywords = "Drug therapy, Ovarian neoplasms, Survival, TP53 genes",

author = "Seagle, \{Brandon Luke L.\} and Yang, \{Chia Ping Huang\} and Eng, \{Kevin H.\} and Monica Dandapani and Oluwatosin Odunsi-Akanji and Goldberg, \{Gary L.\} and Kunle Odunsi and Horwitz, \{Susan Band\} and Shohreh Shahabi",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = jul,

day = "1",

doi = "10.1016/j.ygyno.2015.04.039",

language = "English (US)",

volume = "138",

pages = "159--164",

journal = "Gynecologic oncology",

issn = "0090-8258",

publisher = "Academic Press Inc.",

number = "1",

}

Seagle, BLL, Yang, CPH, Eng, KH, Dandapani, M, Odunsi-Akanji, O, Goldberg, GL, Odunsi, K, Horwitz, SB & Shahabi, S 2015, 'TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from the Cancer Genome Atlas', Gynecologic oncology, vol. 138, no. 1, pp. 159-164. https://doi.org/10.1016/j.ygyno.2015.04.039

TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from the Cancer Genome Atlas. / Seagle, Brandon Luke L.; Yang, Chia Ping Huang; Eng, Kevin H. et al.
In: Gynecologic oncology, Vol. 138, No. 1, 01.07.2015, p. 159-164.

Research output: Contribution to journal › Article › peer-review

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

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

UR - http://www.scopus.com/inward/record.url?scp=84931560283&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931560283&partnerID=8YFLogxK

U2 - 10.1016/j.ygyno.2015.04.039

DO - 10.1016/j.ygyno.2015.04.039

M3 - Article

C2 - 25958320

AN - SCOPUS:84931560283

SN - 0090-8258

VL - 138

SP - 159

EP - 164

JO - Gynecologic oncology

JF - Gynecologic oncology

IS - 1

ER -

TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from the Cancer Genome Atlas

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this