Biological and Clinical Implications of Exon 8 P53 (R282W) Gene Mutation in Relation to Development and Progression of Chronic Myeloid Leukaemia Patients in India Population

Abstract

Background: TP53, located on chromosome 17p13, is one of the most mutated genes affecting many types of human cancers .To establish an association between the incidence of exon 8 p53 (R282W) gene and progression of the disease in CML and also to correlate the presence of mutation with the clinicopathological features of the disease.Methods: p53 status was investigated by studying mutations in the p53 gene at exon 8 region after confirming the diagnosis by BCR-ABL. 100 CML samples were analyzed using the Allele-Specific Oligonucleotide PCR assay. Mutations occurred in 58% of the cases in exon 8 codon 282 region of the p53 gene. C : T transitions occurred at a high frequency with a statistically significant result (p=0.03).Results: Of the 100 clinically confirmed specimens, 58% tested positive for the mutation. Also, the mutation was found to be higher in the progressed stages (88.2% in accelerated phase and 60.0% in blast crisis) of CML compared to the chronic stage (35.2%). A statistically significant association (p=0.001) was found between the occurrence of p53 R282W mutation and the clinical phase of CML with chronic, accelerated and blast crisis phases. The mutation was detected in a vast majority (88.2%) of patients in the accelerated and the blast crisis phase (60.0%) indicating that this mutation might play a critical role in predicting the progression of disease in CML. Clinicopathological correlation with TLC, platelet count and the haematological response elicited a significant association with patients harboring the mutation with (p=0.01), (p=0.001) and (p=0.01) respectively. Conclusion:Our study suggests that p53 mutations in the exon 8 region might have a strong influence on disease progression and poor response of imatiib (Tyrosine kinase inhibitor) in CML patients.

Breast Cancer Patient with Li-Fraumeni Syndrome: A Case Report Highlighting the Importance of Multidisciplinary Management

“…TP53 mutations cause not only the loss of their suppressor function acquiring a dominant negative activity, but also a gain in oncogenic properties that are independent of the function of the wild-type gene. Missense mutations promote tumorigenesis through mechanisms that interrupt response pathways to DNA damage [20]. The R282W mutant is associated with an earlier onset of familial cancers and poorer outcomes of cancer patients.…”

Multidrug resistance in chronic myeloid leukemia

“…CML patients whose exon 8 region of the Tp53 gene is mutated have higher accelerated phase and blast crisis values. In addition, the molecular response is decreased during treatment with imatinib, thus increasing the influence of the mutation on CML (Mir et al, 2013). Stabilization of p53 also triggers apoptosis in CML.…”

Detection of R282w P53 Gene Mutation on Exon 8 in Gastric Cancer Patients in Southwest Iran

“…Codon 282 encodes arginine amino acid on the P53 binding site in the central domain during gene expression and makes the minor groove contact (20)(21)(22). Mutation in the aforementioned site leads to the exclusion of arginine and breaking the conjunction of central domain with DNA major groove and following a decrease in P53 gene expression (R282W designates an arginine mutated to tryptophan at position 282) (18,23). R282W P53 mutant can alter the behavior and fate of the tumor cell and is thought to promote the progression of many types of cancer (18).…”