TP53 Gene Alterations including Codon 72 Polymorphism in Patients with Multiple Myeloma

Abstract

Introduction: Multiple Myeloma (MM) is a cytogenetically heterogeneous haematologic malignancy characterised by uncontrolled proliferation of clonal plasma cells within the bone marrow. TP53 gene inactivation is considered as an independent prognostic marker and patients harbouring these mutations are usually resistant to standard therapy. Aim: To determine the frequency of TP53 gene mutations in exons 4 to 9 and the distribution of Arg72Pro polymorphism in exon 4 in newly diagnosed multiple myeloma patients. Materials and Methods: Mutation analysis of genomic DNA from unsorted bone marrow aspirates of 30 patients (10 showed TP53 deletion by interphase FISH) and from peripheral blood lymphocytes of 30 healthy control individuals was performed by direct sequencing of amplified products using self-designed primers. The codon 72 polymorphism was studied using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique in an additional 108 MM patients and 70 healthy controls. Results: TP53 gene alterations were recorded in six patients (20%) and three of them showed two or more changes. No alterations were observed in exons 5, 7 and 9 in myeloma patients. Four mutations in codons c.284C>T (exon 4), c.641A>G (exon 6), c.787A>G and c.808T>G (exon 8) and three intronic variants c.672+48G>A (intron 6), c.782+72C>T and c.782+92T>G (intron 7) were seen only in the patient group. The variants c.108G>A (exon 4), c.672+62A>G (intron 6) and c.993+12T>C (intron 9) were observed in both groups. Three patients died within six months of diagnosis. The genotype and allele frequencies for Arg72Pro polymorphism were similar in the patient and in the control groups. Conclusion: The presence of TP53 mutations denoted a poor prognosis while the TP53 Pro72Arg polymorphism is not associated with increased risk for MM.

Keywords

• arg72pro polymorphism
• del(17p)
• tp53 mutations