Complex analysis of the TP53 tumor suppressor in mantle cell and diffuse large B-cell lymphomas

Zlamalikova,Lenka; Moulis,Mojmir; Ravcukova,Barbora; Liskova,Kvetoslava; Malcikova,Jitka; Salek,David; Jarkovsky,Jiri; Svitakova,Miluse; Hrabalkova,Renata; Smarda,Jan; Smardova,Jana

doi:10.3892/or.2017.5891

Complex analysis of the TP53 tumor suppressor in mantle cell and diffuse large B-cell lymphomas

Authors:
- Lenka Zlamalikova
- Mojmir Moulis
- Barbora Ravcukova
- Kvetoslava Liskova
- Jitka Malcikova
- David Salek
- Jiri Jarkovsky
- Miluse Svitakova
- Renata Hrabalkova
- Jan Smarda
- Jana Smardova
View Affiliations

Affiliations: Department of Pathology, University Hospital, Brno, Czech Republic, Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic, Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic, Department of Internal Medicine - Hematology and Oncology, University Hospital, Brno, Czech Republic, Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
Published online on: August 8, 2017 https://doi.org/10.3892/or.2017.5891
Pages: 2535-2542

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

Mutations and deletions of the tumor suppressor TP53 gene are the most frequent genetic alterations detected in human tumors, though they are rather less frequent in lymphomas. However, acquisition of the TP53 mutation was demonstrated to be one of the characteristic markers in mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) and prognostic value of the TP53 status has been recognized for these diseases. We present the complex analysis of the TP53 aberrations in 57 cases of MCL and 131 cases of DLBCL. The TP53 status was determined by functional analyses in yeast (FASAY) followed by cDNA and gDNA sequencing. The level of the p53 protein was assessed by immunoblotting and loss of the TP53-specific locus 17p13.3 was detected by FISH. Altogether, we detected 13 TP53 mutations among MCL cases (22.8%) and 29 TP53 mutations in 26 from 131 DLBCL cases (19.8%). The ratio of missense TP53 mutations was 76.9% in MCL and 82.8% in DLBCL. The frequency of TP53 locus deletion was rather low in both diseases, reaching 9.3% in MCL and 15.3% in DLBCL. The presence of TP53 mutation was associated with shorter overall survival (OS) and progression-free survival (PFS) in MCL. Among DLBCL cases, the TP53 mutations shortened both OS and PFS of patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and decreased both OS and PFS of patients with secondary DLBCL disease.

View Figures

View References

1	Harris SL and Levine AJ: The p53 pathway: Positive and negative feedback loops. Oncogene. 24:2899–2908. 2005. View Article : Google Scholar : PubMed/NCBI
2	Sherr CJ: Principles of tumor suppression. Cell. 116:235–246. 2004. View Article : Google Scholar : PubMed/NCBI
3	Xu-Monette ZY, Medeiros LJ, Li Y, Orlowski RZ, Andreeff M, Bueso-Ramos CE, Greiner TC, McDonnell TJ and Young KH: Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood. 119:3668–3683. 2012. View Article : Google Scholar : PubMed/NCBI
4	Leroy B, Anderson M and Soussi T: TP53 mutations in human cancer: Database reassessment and prospects for the next decade. Hum Mutat. 35:672–688. 2014. View Article : Google Scholar : PubMed/NCBI
5	Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, et al: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 127:2375–2390. 2016. View Article : Google Scholar : PubMed/NCBI
6	Rosenquist R, Rosenwald A, Du MQ, Gaidano G, Groenen P, Wotherspoon A, Ghia P, Gaulard P, Campo E and Stamatopoulos K: European Research Initiative on CLL (ERIC) and the European Association for Haematopathology (EAHP): Clinical impact of recurrently mutated genes on lymphoma diagnostics: State-of-the-art and beyond. Haematologica. 101:1002–1009. 2016. View Article : Google Scholar : PubMed/NCBI
7	Iqbal J, Naushad H, Bi C, Yu J, Bouska A, Rohr J, Chao W, Fu K, Chan WC and Vose JM: Genomic signatures in B-cell lymphoma: How can these improve precision in diagnosis and inform prognosis? Blood Rev. 30:73–88. 2016. View Article : Google Scholar : PubMed/NCBI
8	Stefancikova L, Moulis M, Fabian P, Ravcukova B, Vasova I, Muzik J, Malcikova J, Falkova I, Slovackova J and Smardova J: Loss of the p53 tumor suppressor activity is associated with negative prognosis of mantle cell lymphoma. Int J Oncol. 36:699–706. 2010.PubMed/NCBI
9	Stefancikova L, Moulis M, Fabian P, Vasova I, Zedek F, Ravcukova B, Muzik J, Kuglik P, Vranova V, Falkova I, et al: Prognostic impact of p53 aberrations for R-CHOP-treated patients with diffuse large B-cell lymphoma. Int J Oncol. 39:1413–1420. 2011.PubMed/NCBI
10	Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Chappuis P, Sappino AP, Limacher IM, Bron L and Benhattar J: A simple p53 functional assay for screening cell lines, blood, and tumors. Proc Natl Acad Sci USA. 92:3963–3967. 1995. View Article : Google Scholar : PubMed/NCBI
11	Smardová J, Nemajerová A, Trbusek M, Vagunda V and Kovarík J: Rare somatic p53 mutation identified in breast cancer: A case report. Tumour Biol. 22:59–66. 2001. View Article : Google Scholar : PubMed/NCBI
12	Ishioka C, Frebourg T, Yan YX, Vidal M, Friend SH, Schmidt S and Iggo R: Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nat Genet. 5:124–129. 1993. View Article : Google Scholar : PubMed/NCBI
13	Waridel F, Estreicher A, Bron L, Flaman JM, Fontolliet C, Monnier P, Frebourg T and Iggo R: Field cancerisation and polyclonal p53 mutation in the upper aero-digestive tract. Oncogene. 14:163–169. 1997. View Article : Google Scholar : PubMed/NCBI
14	Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J and Olivier M: TP53 variations in human cancers: New lessons from the IARC TP53 database and genomics Data. Hum Mutat. 37:865–876. 2016. View Article : Google Scholar : PubMed/NCBI
15	Grochova D, Vankova J, Damborsky J, Ravcukova B, Smarda J, Vojtesek B and Smardova J: Analysis of transactivation capability and conformation of p53 temperature-dependent mutants and their reactivation by amifostine in yeast. Oncogene. 27:1243–1252. 2008. View Article : Google Scholar : PubMed/NCBI
16	Halldórsdóttir AM, Lundin A, Murray F, Mansouri L, Knuutila S, Sundström C, Laurell A, Ehrencrona H, Sander B and Rosenquist R: Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia. 25:1904–1908. 2011. View Article : Google Scholar : PubMed/NCBI
17	Slotta-Huspenina J, Koch I, de Leval L, Keller G, Klier M, Bink K, Kremer M, Raffeld M, Fend F and Quintanilla-Martinez L: The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index. Haematologica. 97:1422–1430. 2012. View Article : Google Scholar : PubMed/NCBI
18	Beà S, Valdés-Mas R, Navarro A, Salaverria I, Martín-Garcia D, Jares P, Giné E, Pinyol M, Royo C, Nadeu F, et al: Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA. 110:18250–18255. 2013. View Article : Google Scholar : PubMed/NCBI
19	Meissner B, Kridel R, Lim RS, Rogic S, Tse K, Scott DW, Moore R, Mungall AJ, Marra MA, Connors JM, et al: The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma. Blood. 121:3161–3164. 2013. View Article : Google Scholar : PubMed/NCBI
20	Zhang J, Jima D, Moffitt AB, Liu Q, Czader M, Hsi ED, Fedoriw Y, Dunphy CH, Richards KL, Gill JI, et al: The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 123:2988–2996. 2014. View Article : Google Scholar : PubMed/NCBI
21	Nordström L, Sernbo S, Eden P, Grønbaek K, Kolstad A, Räty R, Karjalainen ML, Geisler C, Ralfkiaer E, Sundström C, et al: SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma: a Nordic Lymphoma Group study. Br J Haematol. 166:98–108. 2014. View Article : Google Scholar : PubMed/NCBI
22	Delfau-Larue MH, Klapper W, Berger F, Jardin F, Briere J, Salles G, Casasnovas O, Feugier P, Haioun C, Ribrag V, et al: European Mantle Cell Lymphoma Network: High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 126:604–611. 2015. View Article : Google Scholar : PubMed/NCBI
23	Stöcklein H, Hutter G, Kalla J, Hartmann E, Zimmermann Y, Katzenberger T, Adam P, Leich E, Höller S, Müller-Hermelink HK, et al: Genomic deletion and promoter methylation status of Hypermethylated in Cancer 1 (HIC1) in mantle cell lymphoma. J Hematop. 1:85–95. 2008. View Article : Google Scholar : PubMed/NCBI
24	Xu-Monette ZY, Wu L, Visco C, Tai YC, Tzankov A, Liu WM, Montes-Moreno S, Dybkaer K, Chiu A, Orazi A, et al: Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: Report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 120:3986–3996. 2012. View Article : Google Scholar : PubMed/NCBI
25	Lu TX, Young KH, Xu W and Li JY: TP53 dysfunction in diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 97:47–55. 2016. View Article : Google Scholar : PubMed/NCBI