P53 and Molecular Genetics of Multiple Myeloma

Mini Review

J Blood Disord. 2014;1(1): 3.

P53 and Molecular Genetics of Multiple Myeloma

Benedetta Lucani, Giulia Papini, Monica Bocchia and Alessandro Gozzetti*

Department of Hematology, University of Siena, Italy

*Corresponding author: Alessandro Gozzetti, Hematology, Policlinico "Santa Maria alle Scotte", VialeBracci 16, 53100, University of Siena, Italy.

Received: September 15, 2014; Accepted: September 16, 2014; Published: September 17, 2014


Myeloma; FISH; TP53


Multiple Myeloma (MM) is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated B cells, accounting for 1% of all cancers and ~10% of all hematologic malignancies [1,2]. The median Overall Survival (OS) ranges from a few months to several years, a large fraction of disease heterogeneity can be determined by host factors (age, performance status, and comorbidities), stage, disease aggressiveness, response to therapy and myeloma cell biology [3,4]. Staging of myeloma using the Durie- Salmon staging [5] or the International Staging System [4,6] provides prognostic information but it is not helpful to guide treatment, while a risk stratification model could be useful for therapeutic decisionmaking [7]. In terms of survival, patients with standard risk myeloma have a median OS of 6-7 years, while those with high risk disease have a median OS of less than 2-3 years despite tandem Autologous Stem-Cell Transplantation (ASCT), being suitable for novel drugs in clinical trials [1]. This suggests the importance to discriminate cytogenetic and molecular characteristics of these patients. Genetic aberrations can be classified as primary events, contributing to plasma cell immortalization, or secondary events, contributing to disease progression. Overall MM is broadly divided into two majorcategories, hyperdiploid MM (h-MM) and non-hyperdiploid MM (nh-MM). Nonhyperdiploidy myeloma involves the translocation of Immunoglobulin Heavy chain alleles (IGH) at 14q32 with various partner chromosomes including 4, 6, 11, 16, and 20. Hyperdiploidy myeloma involves trisomies of the odd numbered chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 coupled to a low prevalence of IGH translocations, has a tendency towards a more favorable outcome and is generally associated with better survival [8,9]. The t (4; 14) is observed in 15% of myeloma cases and has been associated with an adverse prognosis and poor survival [10-13], irrespective of the treatment choice [14,15]. The consequence of the translocation is increased expression of FGFR3 and Multiple Myeloma SET domain (MMSET) [16,17]. The t (11; 14) is more common, occurring in approximately 17% of myeloma patients and it directly up regulates a cyclin D gene in the form CCND1 [10,18]. In most series tested, t (11;14) (q13;q32) seems to be associated with a trend toward a favorable outcome, yet not statistically significant [8]. The t (14;16) involving maf genes has been described in 5-7% of all MM cases, it has been associated with a higherfrequency of chromosome 13 deletion and a more aggressive clinical outcome [12]. The t (6;14) and t (14;20) are the rarest translocations observed, resulting in a up regulation of the CCND3 and MAFB genes, respectively [10,19]. The secondary genetic events include loss of Chromosome 13/13q, Chromosome 1 abnormalities and Loss of 17p. The first is the most common cytogenetic alteration, observed in 50% of myeloma cases, resulting mainly from a constitute monosomy (85%) or less frequently form interstitial deletions (15%) [20-23]. To establish the prognostic impact of del (13/13q) is challenging due to its frequent association with other high risk lesions, such as t (4;14) whit whom it is concurrently present in approximately 90%of cases [8]. Regarding chromosome 1 we can find both 1q gain and 1p loss observed respectively in 35% and 30% of cases, both associated with ashorter survival [24-30].

The most important negative molecular cytogenetic factor for prognostication is the deletion of 17p13 [14,15,31]. This alteration is detected in 11% of newly diagnosed patients and in all series tested, 17p13 deletion, impacted very negatively on survival, with a median OS of 22 months [16,32]. Recently more detailed studies have analyzed the association between the percentage of plasma cells affected by this deletion and its prognostic value, demonstrating a short survival only in those in patients that have at least 60% of plasma cells with 17p13 deletion..

At the level of the band 17p13 is present the gene locus p53 tumor suppressor, which is lost in the case of deletion [14,15,31].

The p53 tumor suppressor is a critical regulator of tissue homeostasis, and its inactivation at the gene or protein level confers cellular properties conducive for oncogenesis and cancer progression [33]. The functional loss of the p53 protein (TP53) may take place with the deletion but also with the mutation. TP53 mutations are rare in multiple myeloma, only 3% of newly diagnosed patients while their prevalence increases with more advanced disease [34,35]. In particular this aspect was elaborated Chng et al. that showed that the presence of TP53 mutations was significantly associated with 17p13 deletion (56% of cases) and for the first time in 2007 reported the extremely negative prognostic significance of TP53 mutations, as the presence of TP53 mutations was associated with a survival of only one and half year [35]. Conversely, in 2011 Lode et al. demonstrated that the mutations in TP53 are exclusively associated with del (17p) and survival analyses did not reveal any difference, in patients with del (17p), between patients presenting additionally a TP53 mutation and those with a germ line TP53. However, the numbers are too small to draw any definitive inference [32].

In conclusion, the concomitance of TP53 mutations and del (17p) is relatively rare, being found at most in 13% of newly diagnosed MM [33], whereas the functional loss of the gene is found in a definitely higher percentage of cases; in addition according to the work of Lodè the vast majority (63%) of del (17p) are hemizygous patients, suggesting that in these non-mutated patients, normal and functional p53 protein is still present, potentially overcoming the poor effect ofdel (17p), albeit without clinical impact. So we can think that other modifications may occur and alter p53 pathway. The p53 pathway silencing might pass also through changes in the expression level or in the activation of p53 itself, regulated by several specific inhibitors and/or activators, such as MDM2, MDM4 has showed in a recent work [34]. Moreover other recent studies have shown epigenetic mechanisms, as well as deregulation of microRNA involved in the pathobiology of MM; Picchiorri et al. identified two related microRNA clusters located in regions considered important for MM (miR-194- 2-192 at 11q13.1 and miR-194-1215 at 1q41.1) [5] associated with activation of the p53 pathway. Furthermore this work showed that the expression of these miRNAs changed during transition from normal PC, via MGUS to intramedullary MM resulting significantly down regulated in a cohort of newly diagnosed MMs; these result have defined a mechanism of p53 regulation through miRNAs acting on MDM2 expression. We believe that miRNAs in MM should be investigated in the future as potential mechanisms of resistance. This data could give information's not only about disease development and prognosis, but can also provide potential therapeutic targets.


  1. Rajkumar SV. Treatment of multiple myeloma. Nat Rev Clin Oncol. 2011; 8: 479-491.
  2. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood. 2011; 118: 3205-3211.
  3. Russell SJ, Rajkumar SV. Multiple myeloma and the road to personalised medicine. Lancet Oncol. 2011; 12: 617-619.
  4. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005; 23: 3412-3420.
  5. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23: 2210-2221.
  6. Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C. Groupe Français de Cytogénétique Hématologique. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood. 2001; 98: 2229-2238.
  7. Dewald GW, Kyle RA, Hicks GA, Greipp PR. The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis. Blood. 1985; 66: 380-390.
  8. Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006; 108: 2020-2028.
  9. Keats JJ, Reiman T, Maxwell CA, Taylor BJ, Larratt LM, Mant MJ, et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003; 101: 1520-1529.
  10. Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003; 101: 4569-4575.
  11. Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI, et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol. 2004; 125: 64-68.
  12. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007; 109: 3489-3495.
  13. Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003; 101: 4569-4575.
  14. Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM, et al. Frequent translocation t(4;14) (p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet. 1997; 16: 260-264.
  15. Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood. 1998; 92: 3025-3034.
  16. Chesi M, Bergsagel PL, Brents LA, Smith CM, Gerhard DS, Kuehl WM. Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood. 1996; 88: 674-681.
  17. Shaughnessy J, Gabrea A, Qi Y, Brents L, Zhan F, Tian E, et al. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood. 2001; 98: 217-223.
  18. Fonseca R, Oken MM, Harrington D, Bailey RJ, Van Wier SA, Henderson KJ, et al. Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia. 2001; 15: 981-986.
  19. Fonseca R, Harrington D, Oken MM, Dewald GW, Bailey RJ, Van Wier SA, et al. Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an eastern cooperative oncology group study. Cancer Res. 2002; 62: 715-720.
  20. Avet-Loiseau H, Li JY, Morineau N, Facon T, Brigaudeau C, Harousseau JL, et al. Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myélome. Blood. 1999; 94: 2583-2589.
  21. Avet-Louseau H, Daviet A, Sauner S, Bataille R. Intergroupe Francophone du Myélome. Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol. 2000; 111: 1116-1117.
  22. Boyd KD, Ross FM, Chiecchio L, Dagrada GP, Konn ZJ, Tapper WJ, et al. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia. 2012; 26: 349-355.
  23. Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010; 116: 56-65.
  24. Chang H, Qi X, Jiang A, Xu W, Young T, Reece D. 1p21 deletions are strongly associated with 1q21 gains and are an independent adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma. Bone Marrow Transplantation. 2010; 45: 117-121.
  25. Shaughnessy J. Amplification and over expression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. Hematology. 2005; 10: 117-126.
  26. Shaughnessy JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007; 109: 2276-2284.
  27. Boyd KD, Ross FM, Walker BA, Wardell CP, Tapper WJ, Chiecchio L, et al. Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival. Clin Cancer Res. 2011; 17: 7776-7784.
  28. Chang H, Jiang A, Qi C, Trieu Y, Chen C, Reece D. Impact of genomic aberrations including chromosome 1 abnormalities on the outcome of patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone. Leuk Lymphoma. 2010; 51: 2084-2091.
  29. Drach J, Ackermann J, Fritz E, Krömer E, Schuster R, Gisslinger H, et al. Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood. 1998; 92: 802-809.
  30. Lode L, Eveillard M, Trichet V, Soussi T, Wuillème S, Richebourg S, et al. Mutations in TP53 are exclusively associated with del (17p) in multiple myeloma. Haematologica. 2010; 95: 1973-1976.
  31. 31. Vousden KH, Lu X. Live or let die: the cell's response to p53. Nat Rev Cancer. 2002; 2: 594-604.
  32. Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004; 64: 1546-1558.
  33. Chng WJ, Price-Troska T, Gonzalez-Paz N, Van Wier S, Jacobus S, Blood E, et al. Clinical significance of TP53 mutation in myeloma. Leukemia. 2007; 21: 582-584.
  34. 34. Terragna C, Martello M, Testoni N, Angelucci E, Brioli A, Ballanti S, et al. The poor outcome of multiple Myeloma (MM) patients carrying at diagnosis deleted TP53 and/or amplified MDM4 might be related to the deregulation of genes involved in cell cycle control and DNA damage repair. American Society of Hematology. 2012; 120.
  35. Pichiorri F, Suh SS, Rocci A, De Luca L, Taccioli C, Santhanam R, 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: 367-381.

Download PDF

Citation: Lucani B, Papini G, Bocchia M and Gozzetti A. P53 and Molecular Genetics of Multiple Myeloma. J Blood Disord. 2014;1(1): 1005. ISSN 2379-8009

Journal Scope
Online First
Current Issue
Editorial Board
Instruction for Authors
Submit Your Article
Contact Us