A possible role of the P53 gene deletion as a prognostic factor in multiple myeloma

Abstract In multiple myeloma (MM), previous studies showed that mutations of the p53 gene are rare events in patients with newly diagnosed disease, but it is not known whether deletions of p53 are of any significance in MM. To address this question, we used interphase fluorescence in situ hybridization (FISH) with a DNA probe specific for the p53 locus at 17p13 and investigated bone marrow plasma cells from 72 patients with MM (59 patients = 81.9% before therapy). By FISH, deletions of p53, which were found to be predominantly monoallelic, were detected in 32.8% and 54.5% of patients with newly diagnosed and relapsed MM, respectively. Karyotypes from six of the patients with a p53 deletion by FISH showed a structural abnormality of 17p in only one of them. Additional FISH studies including a distal-17p probe (specific for theD17S34 locus) provided evidence for an interstitial deletion on 17p resulting in loss of p53 hybridization signals in myeloma cells. Among all 59 patients with newly diagnosed MM, presence of a p53 deletion was associated with stage III (P = .054), but not with other laboratory and clinical parameters. Patients with a p53 deletion had significantly shorter survival time compared with those without a deletion, both from the time of diagnosis (median 13.9v 38.7 months; P < .0001) and from the time of initiation of induction treatment consisting of conventional dose chemotherapy (median 15.9 months v median not reached at 38 months; P < .0002). On stepwise multivariate regression analysis, presence of a p53 deletion was the most significant independent parameter predicting for shortened survival (P = .002). We conclude that a p53 gene deletion, which can be identified by interphase FISH in almost a third of patients with newly diagnosed MM, is a novel prognostic factor predicting for short survival of MM patients treated with conventional-dose chemotherapy. © 1998 by The American Society of Hematology.

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P53 gene deletion in multiple myeloma

Revista Brasileira de Hematologia e Hemoterapia ◽

10.1590/s1516-84842003000200014 ◽

2003 ◽

Vol 25 (2) ◽

Author(s):

Manoela M. Ortega ◽

Mônica B. Melo ◽

Cármino A. de Souza ◽

Irene Lorand-Metze ◽

Fernando F. Costa ◽

...

Keyword(s):

Multiple Myeloma ◽

Gene Deletion ◽

P53 Gene ◽

P53 Gene Deletion

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Presence of a p53 Gene Deletion in Patients With Multiple Myeloma Predicts for Short Survival After Conventional-Dose Chemotherapy

Blood ◽

10.1182/blood.v92.3.802.415a17_802_809 ◽

1998 ◽

Vol 92 (3) ◽

pp. 802-809 ◽

Cited By ~ 2

Author(s):

Johannes Drach ◽

Jutta Ackermann ◽

Elke Fritz ◽

Elisabeth Krömer ◽

Rudolf Schuster ◽

...

Keyword(s):

Multiple Myeloma ◽

Gene Deletion ◽

P53 Gene ◽

Induction Treatment ◽

Structural Abnormality ◽

Newly Diagnosed ◽

Short Survival ◽

Conventional Dose ◽

P53 Gene Deletion ◽

Conventional Dose Chemotherapy

In multiple myeloma (MM), previous studies showed that mutations of the p53 gene are rare events in patients with newly diagnosed disease, but it is not known whether deletions of p53 are of any significance in MM. To address this question, we used interphase fluorescence in situ hybridization (FISH) with a DNA probe specific for the p53 locus at 17p13 and investigated bone marrow plasma cells from 72 patients with MM (59 patients = 81.9% before therapy). By FISH, deletions of p53, which were found to be predominantly monoallelic, were detected in 32.8% and 54.5% of patients with newly diagnosed and relapsed MM, respectively. Karyotypes from six of the patients with a p53 deletion by FISH showed a structural abnormality of 17p in only one of them. Additional FISH studies including a distal-17p probe (specific for theD17S34 locus) provided evidence for an interstitial deletion on 17p resulting in loss of p53 hybridization signals in myeloma cells. Among all 59 patients with newly diagnosed MM, presence of a p53 deletion was associated with stage III (P = .054), but not with other laboratory and clinical parameters. Patients with a p53 deletion had significantly shorter survival time compared with those without a deletion, both from the time of diagnosis (median 13.9v 38.7 months; P < .0001) and from the time of initiation of induction treatment consisting of conventional dose chemotherapy (median 15.9 months v median not reached at 38 months; P < .0002). On stepwise multivariate regression analysis, presence of a p53 deletion was the most significant independent parameter predicting for shortened survival (P = .002). We conclude that a p53 gene deletion, which can be identified by interphase FISH in almost a third of patients with newly diagnosed MM, is a novel prognostic factor predicting for short survival of MM patients treated with conventional-dose chemotherapy. © 1998 by The American Society of Hematology.

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PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion

British Journal of Haematology ◽

10.1111/j.1365-2141.2005.05851.x ◽

2006 ◽

Vol 132 (2) ◽

pp. 230-236 ◽

Cited By ~ 42

Author(s):

H. Nahi ◽

M. Merup ◽

S. Lehmann ◽

S. Bengtzen ◽

L. Mollgard ◽

...

Keyword(s):

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Gene Deletion ◽

P53 Gene ◽

P53 Gene Deletion ◽

Acute Myeloid

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P54 Controversial role of age as a prognostic factor in multiple myeloma

Controlled Clinical Trials ◽

10.1016/s0197-2456(97)91149-1 ◽

1997 ◽

Vol 18 (3) ◽

pp. S143

Author(s):

Catherine Klersy ◽

Alessandro Corso ◽

Donatella De Amici ◽

Angela Pistorio ◽

Carmine Tinelli ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factor

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A Functional Promoter Polymorphism (−8C>G) of the Proteasome Subunit α6 Gene Is Associated with Multiple Myeloma and Poor Outcome Independent of Circulating Proteasome Serum Levels.

Blood ◽

10.1182/blood.v112.11.1668.1668 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1668-1668

Author(s):

Hagen S Bachmann ◽

Juergen Novotny ◽

Stephan Sixt ◽

Peter Liebisch ◽

Ulrich Frey ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factor ◽

Genetic Model ◽

University Hospital ◽

20S Proteasome ◽

Genotype Distribution ◽

Healthy Controls ◽

Α Subunit ◽

Dominant Genetic Model

Abstract Introduction: The proteasome system plays a crucial role in several malignant diseases, especially in multiple myeloma (MM). Recently, the serum 20S circulating proteasome level (CPL) was shown to be an independent prognostic factor in MM. A single nucleotide polymorphism (SNP) −8C>G in PSMA6, one of seven α-subunit genes of the 20S proteasome, was currently demonstrated to be associated with myocardial infarction. Additionally, it has been shown that PSMA6 expression is genotype-dependently altered e.g. in human B cells, whereas the G allele is associated with a 1.8 fold higher expression. Demonstrating the extensive role of the proteasome system in MM we investigated the role of the novel SNP in our cohort of 116 patients with MM. Methods: DNA-samples of 116 patients with MM, all treated at the University Hospital Essen, and 125 healthy controls were genotyped for PSMA6 −8C>G. CPL of 70 patients were studied by an anti-20S proteasome enzyme-linked immunoabsorbant assay (ELISA). PSMA6 −8C>G genotypes were correlated with patients’ survival and CPL. Results: Patients’ genotype distribution (69 CC, 44 CG, 3 GG) and genotype distribution of healthy controls (90 CC, 31 CG, 4 GG) were consistent with Hardy-Weinberg equilibrium. Genotypes were significantly associated with MM in a dominant genetic model (CC vs. CG+GG), with an odds ratio of 1.75 (95% confidence interval (CI): 1.02–3.00, p=0.043). Kaplan-Meier curves revealed a significant association of PSMA6 −8C>G with 5-year survival (p=0.014). Median survival time was 43 months for the GG genotype and 50 months for the CG genotype. It was not reached within follow-up by the CC genotype (CC 5-year survival rate 61.2%). Following hazard ratios (HR) were calculated: CC vs. CG: 2.007, 95%CI 1.11–3.63, p=0.022; CC vs. GG: 2.515, 95%CI 0.58–10.86, p=0.217 and in the dominant genetic model CC vs. CG+GG: 2.038, 95%CI 1.14–3.65, p=0.017. In multivariate analysis the GG/GC genotypes were independent prognostic factors (HR 2.1, p=0.014). To proove if the detected effect of individual PSMA6 genotypes was dependent or independent from CPL, ELISA experiments were performed. There was no detectable difference in CPL between the genotypes. Mean CPL was 255 ng/mL for CC homozygous and 205 ng/mL for G allele carriers (p=0.718). Conclusions: These results suggest the PSMA6 −8C>A polymorphism as a survival prognosticator as well as indicator of a high risk group within patients with MM. PSMA6 genotypes were not associated with CPL. Therefore, the SNP is independent of this known prognostic factor and could lead to additional prognostic information for MM patients.

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