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p53 and RAS gene mutations in multiple myeloma
M Portier1, J P Molès, G R Mazars
1INSERM U291, Immunopathologie des Maladies Tumorales et Autoimmunes, Montpellier, France.
Abstract:
We analysed genomic DNA from 30 patients with multiple myeloma (MM), searching for alterations in the p53 and RAS genes by a combination of polymerase chain reaction and single-strand conformation polymorphism techniques. Mutations in the p53 gene were observed in 20% (6 out of 30) of the patients, and were located in conserved sequence blocks within exons 5 and 7. These were single-nucleotide substitutions and consisted predominantly (4/6) of G:C to A:T transitions. Of the six patients with a mutated p53 gene, four were in the terminal phase of the disease. RAS gene mutations were found more frequently since they occurred in 47% (14 out of 30) of the patients. Mutations consisted of single-nucleotide substitutions, located in codons 12, 13 and 61 of either K- or N-RAS, to the exclusion of H-RAS. Moreover, one patient bore two simultaneous mutations, affecting simultaneously the K- and the N-RAS genes. RAS gene mutations were more frequently observed in patients with fulminating disease (10/15, 67%) than in patients with less aggressive forms of the disease (4/15, 26%). We also analysed genomic DNAs from 10 human myeloma cell lines, of which two bore mutations affecting codon 12 of the K-RAS gene, and one codon 12 of the N-RAS gene. The first two cell lines were obtained from freshly explanted tumor cells in which we observed identical mutations. Results presented here show that activating mutations in the RAS genes are, in MM, more frequent than those affecting the p53 gene and suggest that both events are related to terminal phases of the disease.
Insights
Activating mutations in RAS genes are more common than p53 gene mutations in multiple myeloma (MM). Both RAS and p53 alterations are linked to advanced stages of this blood cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Multiple myeloma (MM) is a cancer of plasma cells.
- Understanding genetic alterations in MM is crucial for prognosis and treatment.
Purpose of the Study:
- To investigate the frequency and types of mutations in the p53 and RAS genes in multiple myeloma patients.
- To correlate these genetic alterations with disease phase and aggressiveness.
Main Methods:
- Genomic DNA analysis from 30 MM patients and 10 MM cell lines.
- Polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) techniques were employed.
- Specific analysis focused on exons 5 and 7 of the p53 gene and codons 12, 13, and 61 of RAS genes (K-RAS, N-RAS, H-RAS).
Main Results:
- p53 gene mutations were found in 20% of patients, primarily G:C to A:T transitions in conserved regions, and were associated with the terminal disease phase.
- RAS gene mutations occurred in 47% of patients, affecting K-RAS or N-RAS at codons 12, 13, or 61. One patient had simultaneous K-RAS and N-RAS mutations.
- RAS mutations were more prevalent in fulminating disease (67%) compared to less aggressive forms (26%).
- Analysis of myeloma cell lines revealed mutations in K-RAS and N-RAS.
Conclusions:
- Activating RAS gene mutations are more frequent than p53 mutations in multiple myeloma.
- Both p53 and RAS gene mutations appear to be associated with the terminal phases of multiple myeloma.
- These findings highlight the role of RAS and p53 alterations in MM progression.