TP53 deletion in patients with multiple myeloma and monoclonal gammopathy of undetermined significance - molecular cytogenetic analysis of 84 patients

Czech version

Authors: P. Mičková ¹; J. Balcárková ¹; T. Pika ²; V. Ščudla ²; J. Bačovský ²; J. Minařík ²; K. Nevimová ¹; M. Jarošová ¹
Authors‘ workplace: Hemato-onkologická klinika, LF UP a FN Olomouc ¹; III. interní klinika – NRE, LF UP a FN Olomouc ²
Published in: Transfuze Hematol. dnes,20, 2014, No. 1, p. 32-38.
Category: Comprehensive Reports, Original Papers, Case Reports

Overview

In the pathogenesis of multiple myeloma (MM), both primary and secondary genetic changes play an important role. The latter includes deletion of TP53 gene, which belongs among a group of high-risk changes associated with significantly shorter progression-free survival as well as overall survival.

Our objective was to determine the frequency and type of deletion of TP53 gene (17p13) in a group of 84 patients with MM or monoclonal gammopathy of undetermined significance (MGUS), comprising 41 males and 43 females with a median age of 61 years. In 45 patients, two distinct bone marrow samples were available, therefore we compared the results from these two collections, too. Bone marrow samples obtained from all patients were analysed using both conventional and molecular cytogenetic methods. To detect deletion of the TP53 gene, the FICTION technique with the LSI TP53/CEP 17 probe (Abbott Molecular) was used. The cut-off was set at 20%.

The analysis of 84 patients with MM revealed deletion of TP53 gene in 12 (14%) patients; one patient had chromosome 17 monosomy. Deletion of TP53 gene was not observed in any of the six individuals with MGUS. Most frequently, the deletion was observed in more advanced stages of multiple myeloma. In 10 out 12 patients, the deletion of TP53 gene was a part of a complex karyotype changes. All deletions in our cohort were monoallelic. The study also confirmed a correlation between the deletion of TP53 gene and the deletion of RB1 gene. Our results support the recommendations of the European Myeloma Network supporting the role of routine examination of MM patients for TP53 gene deletion.

Key words:
multiple myeloma, chromosomal changes, deletion of the TP53 gene, FICTION

Sources

1. Adam Z, Hájek R, Mayer J, Ščudla V, Vorlíček J, a kol. Mnohočetný myelom a další monoklonální gamapatie. Brno, 1999. 19-21.

2. Nahi H, Sutlu T, Jansson M, et al. Clinical impact of chromosomal aberrations in multiple myeloma. J Intern med 2011; 269(2): 137-47.

3. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991; 253(5015): 49-53.

4. Lodé L, Eveillard M, Trichet V, et al. Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma. Haematologica 2010; 95(11): 1973-6.

5. Strachan T, Read A. Human molecular genetics. 4th edition. New York, 2010; 556.

6. Liebisch P, Döhner H. Cytogenetics and molecular cytogenetics in multiple myeloma. Eur J Cancer 2006; 42(11): 1520-9.

7. Bacher U, Haferlach T, Wolfgang K, et al. Correlation of cytomorphology, immunophenotyping, and interphase fluorescence in situ hybridization in 381 patients with monoclonal gammopathy of undetermined significance and 301 patients with plasma cell myeloma. Cancer Genet Cytogenet 2010; 203(2): 169-75.

8. Chiecchio L, Dagrada GP, Ibrahim AH, et al. Timing of acquisition of deletion 13 in plasma cell dyscrasias is dependent on genetic context. Haematologica 2009; 94(12): 1708-13.

9. Chang H, Qi C, Yi QL, et al. p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood 2005; 105(1): 358-60.

10. Ortega MM, Melo MB, De Souza CA, et al. A possible role of the p53 gene deletion as a prognostic factor in multiple myeloma. Ann hematol 2003; 82(7): 405-9.

11. Drach J, Ackerman J, Kaufmann H, et al. Deletions of the p53 gene in multiple myeloma. Br J Haematol 2000; 108(4): 886.

12. Carlebach M, Amiel A, Gaber E, et al. Multiple myeloma: monoallelic deletions of the tumor suppressor genes TP53 and RB1 in long-term follow-up. Cancer Genet Cytogenet 2000; 117(1): 57-60.

13. Avet-Loiseau H, Li JY, Godon C, et al. p53 deletion is not a frequent event in multiple myeloma. Br J Haematol. 1999; 106(3): 717-9.

14. Drach J, Ackermann J, Fritz E, et al. Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood 1998; 92(3): 802-9.

15. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003; 101(11): 4569-75.

16. Liebisch P, Wendl C, Wellmann A, et al. High incidence of trisomies 1q, 9q, and 11q in multiple myeloma: results from a comprehensive molecular cytogenetic analysis. Leukemia 2003; 17: 2535-7.

17. Tiedemann RE, Gonzales-Paz N, Kyle RA, et al. Genetic aberrations and survival in plasma cell leukemia. Leukemia 2008; 22(5):1044-52.

18. Chang H, Sloan S, Li D, Keith Stewart A. Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions.

19. Stewart AK, Fonseca R. Prognostic and therapeutic significance of myeloma genetics and gene expression profilig. J Clin Oncol 2005; 23(26): 6339-44.

20. Kapoor P, Rajkumar SV. Update on risk stratification and treatment of newly diagnosed multiple myeloma. Int J Hematol 2011; 94(4): 310-20.

21. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 2007; 109(8): 3489-95.

22. Balcárková J, Procházková K, Ščudla V, a kol. Molekulárně cytogenetická analýza plazmatických buněk u pacientů s mnohočetným myelomem. Transfuze a hematol dnes 2007; 4: 176 -182.

23. Xiong W, Wu X, Starnes S, et al. An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Blood 2008; 112(10): 4235-46.

24. Malcikova J, Smardova J, Rocnova L, et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood 2009; 114(26): 5307-14.

25. Smith EM, Boyd K, Davies FE. The potential role of epigenetic therapy in multiple myeloma. Br J Haematol 2010; 148(5): 702-13.

26. Pichiorri F, Suh SS, Rocci A, et al. Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell 2010; 18(4): 367-81.

27. Avet-Loiseau H, Caillot D, Marit G, et al. Long-term maintenance with lenalidomide improves progression free survival in myeloma patients with high-risk cytogenetics: An IFM study. ASH Annual Meeting Abstracts 2010; 116(21):1944.

28. Reece D, Song KW, Fu T, et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood 2009; 114(3): 522-5.

29. Bahlis NJ, Song K, Trieu Y, et al. Lenalidomide overcomes poor prognosis conferred by del 13q and t(4;14) but not del 17p13 in multiple myeloma: results of the Canadian MM016 trial. Blood 2007; 110: 1052A (ABSTRACT).

30. Hodge DR, Peng B, Cherry JC, et al. Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer res 2005; 65(11): 4673-82.

31. Jones RJ, Bjorklund CC, Baladanadayuthapani V, et al. Drug resistance to inhibitors of the human double minute-2 E3 ligase is mediated by point mutations of p53, but can be overcome with the p53 targeting agent RITA. Mol Cancer Ther 2012; 11(10): 2243-53.

32. Saha MN, Jiang H, Mukai A, et al. RITA inhibits multiple myeloma cell growth through induction of p53-mediated caspase-dependent apoptosis and synergistically enhances nutlin-induced cytotoxic responses Mol Cancer Ther 2010; 9(11): 3041-51.

33. Zhang Q, Lu H. Nutlin’s two roads toward apoptosis. Cancer Biol Ther 2010; 10(6): 579-81.

34. Saha MN, Jiang H, Jayakar J, et al. MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 2010; 9(11): 936-44.

35. Saha MN, Micallef J, Qiu L, et al. Pharmacological activation of the p53 pathway in haematological malignancies. J Clin Pathol 2010; 63(3): 204-9.

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Article was published in

Transfusion and Haematology Today

2014 Issue 1