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Open Access 01-12-2018 | Research article

High expression of the p53 isoform γ is associated with reduced progression-free survival in uterine serous carcinoma

Authors: Katharina Bischof, Stian Knappskog, Ingunn Stefansson, Emmet Martin McCormack, Jone Trovik, Henrica Maria Johanna Werner, Kathrine Woie, Bjorn Tore Gjertsen, Line Bjorge

Published in: BMC Cancer | Issue 1/2018

Abstract

Background

Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial carcinoma. Large-scale comprehensive efforts have resulted in an improved molecular understanding of its pathogenesis, and the p53 pathway has been proposed as a key player and is potentially targetable. Here we attempt to further portray the p53 pathway in USC by assessing p53 isoform expression.

Methods

We applied quantitative Real-Time PCRs (RT-qPCR) for expression analyses of total p53 mRNA as well as quantitative distinction of p53β, p53γ, and the total mRNA of amino-terminal truncated Δ40p53 and Δ133p53 in a retrospective cohort of 37 patients with USC. TP53 mutation status was assessed by targeted massive parallel sequencing. Findings were correlated with clinical data.

Results

The p53 isoform expression landscape in USCs was heterogeneous and dominated by total Δ133p53, while the distinct p53β and p53γ variants were found at much lower levels. The isoform expression profiles varied between samples, while their expression was independent of TP53 mutation status. We found high relative p53γ expression to be associated with reduced progression-free survival (PFS).

Conclusions

This is the first indication that elevated p53γ expression is associated with reduced PFS in USC. This single-center study may offer some insight in the landscape of p53 isoform expression in USC, but further validation studies are crucial to understand the context-dependent and tissue-specific role of the p53 isoform network in gynecological cancer.

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Wright JD, Medel NIB, Sehouli J, Fujiwara K, Herzog TJ. Contemporary management of endometrial cancer. Lancet. 2012;379(9823):1352–60. https://doi.org/10.1016/S0140-6736(12)60442-5.CrossRefPubMed

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. https://doi.org/10.3322/caac.20107.CrossRefPubMed

Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global cancer in women: burden and trends. Cancer Epidemiol Biomark Prev. 2017;26(4):444–57. https://doi.org/10.1158/1055-9965.EPI-16-0858.CrossRef

Kurman RJ, Visvanathan K, Shih Ie M. Bokhman’s dualistic model of endometrial carcinoma. Revisited. Gynecol Oncol. 2013;129(2):271–2. https://doi.org/10.1016/j.ygyno.2013.03.029.CrossRefPubMed

Black JD, English DP, Roque DM, Santin AD. Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer. Women’s Health. 2014;10(1):45–57. https://doi.org/10.2217/whe.13.72.CrossRefPubMedPubMedCentral

Goff BA. Uterine papillary serous carcinoma: what have we learned over the past quarter century? Gynecol Oncol. 2005;98(3):341–3. https://doi.org/10.1016/j.ygyno.2005.07.006.CrossRefPubMed

Cancer Genome Atlas Research N. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73. https://doi.org/10.1038/nature12113.CrossRef

Meng X, Dizon DS, Yang S, Wang X, Zhu D, Thiel KW, Leslie KK. Strategies for molecularly enhanced chemotherapy to achieve synthetic lethality in endometrial tumors with mutant p53. Obstet Gynecol Int 2013; 2013:828165. DOI: https://doi.org/10.1155/2013/828165.

Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9(10):701–13. https://doi.org/10.1038/nrc2693.CrossRefPubMed

10.

Marcel V, Fernandes K, Terrier O, Lane DP, Bourdon JC. Modulation of p53beta and p53gamma expression by regulating the alternative splicing of TP53 gene modifies cellular response. Cell Death Differ. 2014;21(9):1377–87. https://doi.org/10.1038/cdd.2014.73.CrossRefPubMedPubMedCentral

11.

Fujita K, Mondal AM, Horikawa I, Nguyen GH, Kumamoto K, Sohn JJ, Bowman ED, Mathe EA, Schetter AJ, Pine SR, Ji H, Vojtesek B, Bourdon JC, Lane DP, Harris CC. p53 isoforms Delta133p53 and p53beta are endogenous regulators of replicative cellular senescence. Nat Cell Biol. 2009;11(9):1135–42. https://doi.org/10.1038/ncb1928.CrossRefPubMedPubMedCentral

12.

Scotti MM, Swanson MS. RNA mis-splicing in disease. Nat Rev Genet. 2016;17(1):19–32. https://doi.org/10.1038/nrg.2015.3.CrossRefPubMed

13.

Sibley CR, Blazquez L, Ule J. Lessons from non-canonical splicing. Nat Rev Genet. 2016;17(7):407–21. https://doi.org/10.1038/nrg.2016.46.CrossRefPubMedPubMedCentral

14.

Surget S, Khoury MP, Bourdon JC. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective. Onco Targets Ther. 2013;7:57–68. https://doi.org/10.2147/OTT.S53876.PubMedPubMedCentralCrossRef

15.

Bourdon JC, Khoury MP, Diot A, Baker L, Fernandes K, Aoubala M, Quinlan P, Purdie CA, Jordan LB, Prats AC, Lane DP, Thompson AM. p53 mutant breast cancer patients expressing p53gamma have as good a prognosis as wild-type p53 breast cancer patients. Breast Cancer Res. 2011;13(1):R7. https://doi.org/10.1186/bcr2811.CrossRefPubMedPubMedCentral

16.

Avery-Kiejda KA, Morten B, Wong-Brown MW, Mathe A, Scott RJ. The relative mRNA expression of p53 isoforms in breast cancer is associated with clinical features and outcome. Carcinogenesis. 2014;35(3):586–96. https://doi.org/10.1093/carcin/bgt411.CrossRefPubMed

17.

Gadea G, Arsic N, Fernandes K, Diot A, Joruiz SM, Abdallah S, Meuray V, Vinot S, Anguille C, Remenyi J, Khoury MP, Quinlan PR, Purdie CA, Jordan LB, Fuller-Pace FV, de Toledo M, Cren M, Thompson AM, Bourdon JC, Roux P. TP53 drives invasion through expression of its Delta133p53beta variant. elife. 2016;5 https://doi.org/10.7554/eLife.14734.

18.

Hofstetter G, Berger A, Fiegl H, Slade N, Zoric A, Holzer B, Schuster E, Mobus VJ, Reimer D, Daxenbichler G, Marth C, Zeimet AG, Concin N, Zeillinger R. Alternative splicing of p53 and p73: the novel p53 splice variant p53delta is an independent prognostic marker in ovarian cancer. Oncogene. 2010;29(13):1997–2004. https://doi.org/10.1038/onc.2009.482.CrossRefPubMed

19.

Hofstetter G, Berger A, Schuster E, Wolf A, Hager G, Vergote I, Cadron I, Sehouli J, Braicu EI, Mahner S, Speiser P, Marth C, Zeimet AG, Ulmer H, Zeillinger R, Concin N. Delta133p53 is an independent prognostic marker in p53 mutant advanced serous ovarian cancer. Br J Cancer. 2011;105(10):1593–9. https://doi.org/10.1038/bjc.2011.433.CrossRefPubMedPubMedCentral

20.

Hofstetter G, Berger A, Berger R, Zoric A, Braicu EI, Reimer D, Fiegl H, Marth C, Zeimet AG, Ulmer H, Moll U, Zeillinger R, Concin N. The N-terminally truncated p53 isoform Delta40p53 influences prognosis in mucinous ovarian cancer. Int J Gynecol Cancer. 2012;22(3):372–9. https://doi.org/10.1097/IGC.0b013e31823ca031.CrossRefPubMed

21.

Marabese M, Marchini S, Marrazzo E, Mariani P, Cattaneo D, Fossati R, Compagnoni A, Signorelli M, Moll UM, Codegoni AM, Broggini M. Expression levels of p53 and p73 isoforms in stage I and stage III ovarian cancer. Eur J Cancer. 2008;44(1):131–41. https://doi.org/10.1016/j.ejca.2007.10.011.CrossRefPubMed

22.

van den Berg L, Segun AD, Mersch S, Blasberg N, Grinstein E, Wai D, Anlauf M, Gabbert HE, Mahotka C, Heikaus S. Regulation of p53 isoform expression in renal cell carcinoma. Front Biosci. 2010;2:1042–53. PMID: 20515774

23.

Ji W, Zhang N, Zhang H, Ma J, Zhong H, Jiao J, Gao Z. Expression of p53β and Δ133p53 isoforms in different gastric tissues. Int J Clin Exp Pathol. 2015;8(9):10468–74. PMCID: PMC4637571 PubMedPubMedCentral

24.

Anensen N, Hjelle SM, Van Belle W, Haaland I, Silden E, Bourdon JC, Hovland R, Tasken K, Knappskog S, Lonning PE, Bruserud O, Gjertsen BT. Correlation analysis of p53 protein isoforms with NPM1/FLT3 mutations and therapy response in acute myeloid leukemia. Oncogene. 2012;31(12):1533–45. https://doi.org/10.1038/onc.2011.348.CrossRefPubMed

25.

Edmondson RJ, Crosbie EJ, Nickkho-Amiry M, Kaufmann A, Stelloo E, Nijman HW, Leary A, Auguste A, Mileshkin L, Pollock P, MacKay HJ, Powell ME, Bosse T, Creutzberg CL, Kitchener HC. Markers of the p53 pathway further refine molecular profiling in high-risk endometrial cancer: a TransPORTEC initiative. Gynecol Oncol. 2017;146(2):327–33. https://doi.org/10.1016/j.ygyno.2017.05.014.CrossRefPubMed

26.

Fransson A, Glaessgen D, Alfredsson J, Wiman KG, Bajalica-Lagercrantz S, Mohell N. Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant high-grade serous ovarian cancer. J Ovarian Res. 2016;9(1):27. https://doi.org/10.1186/s13048-016-0239-6.CrossRefPubMedPubMedCentral

27.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.CrossRefPubMed

28.

Stefansson IM, Raeder M, Wik E, Mannelqvist M, Kusonmano K, Knutsvik G, Haldorsen I, Trovik J, Øyan AM, Kalland KH, Staff AC, Salvesen HB, Akslen LA. Increased angiogenesis is associated with a 32-gene expression signature and 6p21 amplification in aggressive endometrial cancer. Oncotarget. 2015;6(12):10634–45. https://doi.org/10.18632/oncotarget.3521.CrossRefPubMedPubMedCentral

29.

Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24–6. https://doi.org/10.1038/nbt.1754.CrossRefPubMedPubMedCentral

30.

Mehta S, Tsai P, Lasham A, Campbell H, Reddel R, Braithwaite A, Print CA. Study of TP53 RNA splicing illustrates pitfalls of RNA-seq methodology. Cancer Res. 2016;76(24):7151–9.CrossRefPubMed

31.

Shen S, Wang Y, Wang C, Wu YN, Xing Y. SURVIV for survival analysis of mRNA isoform variation. Nat Commun. 2016;7:11548. https://doi.org/10.1038/ncomms11548.CrossRefPubMedPubMedCentral

32.

Silden E, Hjelle SM, Wergeland L, Sulen A, Andresen V, Bourdon JC, Micklem DR, McCormack E, Gjertsen BT. Expression of TP53 isoforms p53beta and p53gamma enhances chemosensitivity in TP53(null) cell lines. PLoS One. 2013;8(2):e56276. https://doi.org/10.1371/journal.pone.0056276.CrossRefPubMedPubMedCentral

33.

Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J, Olivier M. TP53 variations in human cancers: new lessons from the IARC TP53 database and genomics data. Hum Mutat. 2016;37(9):865–7. https://doi.org/10.1002/humu.23035.CrossRefPubMed

Title: High expression of the p53 isoform γ is associated with reduced progression-free survival in uterine serous carcinoma
Authors: Katharina Bischof
Stian Knappskog
Ingunn Stefansson
Emmet Martin McCormack
Jone Trovik
Henrica Maria Johanna Werner
Kathrine Woie
Bjorn Tore Gjertsen
Line Bjorge
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-018-4591-3

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