TP53 oncomorphic mutations predict resistance to platinum‑ and taxane‑based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma

Brachova,Pavla; Mueting,Samuel R.; Carlson,Matthew J.; Goodheart,Michael J.; Button,Anna M.; Mott,Sarah L.; Dai,Donghai; Thiel,Kristina W.; Devor,Eric J.; Leslie,Kimberly K.

doi:10.3892/ijo.2014.2747

TP53 oncomorphic mutations predict resistance to platinum‑ and taxane‑based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma

Authors:
- Pavla Brachova
- Samuel R. Mueting
- Matthew J. Carlson
- Michael J. Goodheart
- Anna M. Button
- Sarah L. Mott
- Donghai Dai
- Kristina W. Thiel
- Eric J. Devor
- Kimberly K. Leslie
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA, Holden Comprehensive Cancer Center and Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242, USA
Published online on: November 11, 2014 https://doi.org/10.3892/ijo.2014.2747
Pages: 607-618

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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 (χ2 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.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
2	Cannistra SA: Cancer of the ovary. N Engl J Med. 351:2519–2529. 2004. View Article : Google Scholar : PubMed/NCBI
3	Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar : PubMed/NCBI
4	Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P and Olivier M: Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 28:622–629. 2007. View Article : Google Scholar : PubMed/NCBI
5	Freed-Pastor WA and Prives C: Mutant p53: one name, many proteins. Genes Dev. 26:1268–1286. 2012. View Article : Google Scholar : PubMed/NCBI
6	Brachova P, Thiel KW and Leslie KK: The consequence of oncomorphic TP53 mutations in ovarian cancer. Int J Mol Sci. 14:19257–19275. 2013. View Article : Google Scholar : PubMed/NCBI
7	Hall J, Paul J and Brown R: Critical evaluation of p53 as a prognostic marker in ovarian cancer. Expert Rev Mol Med. 6:1–20. 2004. View Article : Google Scholar : PubMed/NCBI
8	Meng X, Dizon DS, Yang S, et al: Strategies for molecularly enhanced chemotherapy to achieve synthetic lethality in endometrial tumors with mutant p53. Obstet Gynecol Int. 2013:8281652013. View Article : Google Scholar
9	Meng X, Laidler LL, Kosmacek EA, et al: Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53. Gynecol Oncol. 128:461–469. 2013. View Article : Google Scholar :
10	Hanel W, Marchenko N, Xu S, Xiaofeng Yu S, Weng W and Moll U: Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. Cell Death Differ. 20:898–909. 2013. View Article : Google Scholar : PubMed/NCBI
11	Gaiddon C, Lokshin M, Ahn J, Zhang T and Prives C: A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol. 21:1874–1887. 2001. View Article : Google Scholar : PubMed/NCBI
12	Xie TX, Zhou G, Zhao M, et al: Serine substitution of proline at codon 151 of TP53 confers gain of function activity leading to anoikis resistance and tumor progression of head and neck cancer cells. Laryngoscope. 123:1416–1423. 2013. View Article : Google Scholar : PubMed/NCBI
13	Scian MJ, Stagliano KE, Deb D, et al: Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes. Oncogene. 23:4430–4443. 2004. View Article : Google Scholar : PubMed/NCBI
14	Lang GA, Iwakuma T, Suh YA, et al: Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 119:861–872. 2004. View Article : Google Scholar : PubMed/NCBI
15	Olive KP, Tuveson DA, Ruhe ZC, et al: Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 119:847–860. 2004. View Article : Google Scholar : PubMed/NCBI
16	Wang YX and Kotlikoff MI: Inactivation of calcium-activated chloride channels in smooth muscle by calcium/calmodulin-dependent protein kinase. Proc Natl Acad Sci USA. 94:14918–14923. 1997. View Article : Google Scholar
17	Ko JL, Chiao MC, Chang SL, et al: A novel p53 mutant retained functional activity in lung carcinomas. DNA Repair (Amst). 1:755–762. 2002. View Article : Google Scholar
18	Sproston AR, Boyle JM, Heighway J, Birch JM and Scott D: Fibroblasts from Li-Fraumeni patients are resistant to low dose-rate irradiation. Int J Radiat Biol. 70:145–150. 1996. View Article : Google Scholar : PubMed/NCBI
19	Song H, Hollstein M and Xu Y: p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nat Cell Biol. 9:573–580. 2007. View Article : Google Scholar : PubMed/NCBI
20	Krepulat F, Löhler J, Heinlein C, Hermannstädter A, Tolstonog GV and Deppert W: Epigenetic mechanisms affect mutant p53 transgene expression in WAP-mutp53 transgenic mice. Oncogene. 24:4645–4659. 2005. View Article : Google Scholar : PubMed/NCBI
21	Bergamaschi D, Gasco M, Hiller L, et al: p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer cell. 3:387–402. 2003. View Article : Google Scholar : PubMed/NCBI
22	Irwin MS, Kondo K, Marin MC, Cheng LS, Hahn WC and Kaelin WG Jr: Chemosensitivity linked to p73 function. Cancer cell. 3:403–410. 2003. View Article : Google Scholar : PubMed/NCBI
23	Duan W, Ding H, Subler MA, et al: Lung-specific expression of human mutant p53-273H is associated with a high frequency of lung adenocarcinoma in transgenic mice. Oncogene. 21:7831–7838. 2002. View Article : Google Scholar : PubMed/NCBI
24	Morselli E, Tasdemir E, Maiuri MC, et al: Mutant p53 protein localized in the cytoplasm inhibits autophagy. Cell cycle. 7:3056–3061. 2008. View Article : Google Scholar : PubMed/NCBI
25	Bourdon JC, Fernandes K, Murray-Zmijewski F, et al: p53 isoforms can regulate p53 transcriptional activity. Genes Dev. 19:2122–2137. 2005. View Article : Google Scholar : PubMed/NCBI
26	Hofstetter G, Berger A, Fiegl H, et al: Alternative splicing of p53 and p73: the novel p53 splice variant p53delta is an independent prognostic marker in ovarian cancer. Oncogene. 29:1997–2004. 2010. View Article : Google Scholar : PubMed/NCBI
27	Holmila R, Fouquet C, Cadranel J, Zalcman G and Soussi T: Splice mutations in the p53 gene: case report and review of the literature. Hum Mutat. 21:101–102. 2003. View Article : Google Scholar
28	Sameshima Y, Akiyama T, Mori N, et al: Point mutation of the p53 gene resulting in splicing inhibition in small cell lung carcinoma. Biochem Biophys Res Commun. 173:697–703. 1990. View Article : Google Scholar : PubMed/NCBI
29	Bodnar L, Stanczak A, Cierniak S, et al: Wnt/β-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer. J Ovarian Res. 7:162014. View Article : Google Scholar
30	Kang HJ, Chun SM, Kim KR, Sohn I and Sung CO: Clinical relevance of gain-of-function mutations of p53 in high-grade serous ovarian carcinoma. PloS One. 8:e726092013. View Article : Google Scholar : PubMed/NCBI
31	Monti P, Campomenosi P, Ciribilli Y, et al: Characterization of the p53 mutants ability to inhibit p73 beta transactivation using a yeast-based functional assay. Oncogene. 22:5252–5260. 2003. View Article : Google Scholar : PubMed/NCBI
32	Liu G, McDonnell TJ, Montes de Oca Luna R, et al: High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci USA. 97:4174–4179. 2000. View Article : Google Scholar : PubMed/NCBI
33	Rose SL, Goodheart MJ, DeYoung BR, Smith BJ and Buller RE: p21 expression predicts outcome in p53-null ovarian carcinoma. Clin Cancer Res. 9:1028–1032. 2003.PubMed/NCBI
34	Schmider A, Gee C, Friedmann W, et al: p21 (WAF1/CIP1) protein expression is associated with prolonged survival but not with p53 expression in epithelial ovarian carcinoma. Gynecol Oncol. 77:237–242. 2000. View Article : Google Scholar : PubMed/NCBI
35	Rojas M, Yao S and Lin YZ: Controlling epidermal growth factor (EGF)-stimulated Ras activation in intact cells by a cell-permeable peptide mimicking phosphorylated EGF receptor. J Biol Chem. 271:27456–27461. 1996. View Article : Google Scholar : PubMed/NCBI
36	Ludes-Meyers JH, Subler MA, Shivakumar CV, et al: Transcriptional activation of the human epidermal growth factor receptor promoter by human p53. Mol Cell Biol. 16:6009–6019. 1996.PubMed/NCBI
37	Di Agostino S, Strano S, Emiliozzi V, et al: Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer cell. 10:191–202. 2006. View Article : Google Scholar : PubMed/NCBI
38	Wong KK, Izaguirre DI, Kwan SY, et al: Poor survival with wild-type TP53 ovarian cancer? Gynecol Oncol. 130:565–569. 2013. View Article : Google Scholar : PubMed/NCBI
39	Willis A, Jung EJ, Wakefield T and Chen X: Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. Oncogene. 23:2330–2338. 2004. View Article : Google Scholar : PubMed/NCBI
40	Xu J, Qian J, Hu Y, et al: Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations. Sci Rep. 4:42232014.PubMed/NCBI