Sailaja K

TP53 Codon 72 Polymorphism and Risk of Acute Leukemia

TP53 is the mostly commonly mutated gene in many cancers and the P53 tumor suppressor protein is involved in multiple cellular processes, including transcription, DNA repair, genomic stability, senescence, cell cycle control and apoptosis. A common single nucleotide polymorphism located within the proline rich region of TP53 gene at codon 72 in exon 4 encodes either proline or arginine. TP53 Arg 72 is more active than TP53 Pro 72 in inducing apoptosis. The aim of this study was to understand the association of the 72 codon polymorphism with acute leukemia development and prognosis. A total of 288 acute leukemia cases comprising 147 acute lymphocytic leukemia (ALL) and 141 acute myeloid leukemia (AML), as well as 245 controls were recruited for analysis of the TP53 72 polymorphism using PCR-RFLP method. Significant association of homozygous arginine genotype with AML was observed (χ2- 133.53; df-2, p < 0.001. When data were analyzed with respect to clinical variables, elevation in mean WBC, blast %, LDH levels and slight reduction in DFS in ALL cases with the arginine genotype was observed. In contrast, AML patients with Pro/Pro had elevated WBC, Blast%, LDH levels with slightly reduced DFS. Our study indicates that Arg/Arg genotype might confer increased risk to development of acute myeloid leukemia.

Deletion of GSTM1 and T1 Genes as a Risk Factor for Development of Acute Leukemia

The glutathione S-transferases (GSTs) are a family of enzymes involved in the detoxification of a wide range of chemicals, including important environmental carcinogens, as well as chemotherapeutic agents. In the present study 294 acute leukemia cases, comprising 152 of acute lymphocytic leukemia (ALL) and 142 of acute myeloid leukemia, and 251 control samples were analyzed for GSTM1 and GSTT1 polymorphisms through multiplex PCR methods. Significantly increased frequencies of GSTM1 null genotype (M0), GSTT1 null genotype (T0) and GST double null genotype (T0M0) were observed in the both ALL and AML cases as compared to controls. When data were analyzed with respect to clinical variables, increased mean levels of WBC, Blast %, LDH and significant reduction in DFS were observed in both ALL and AML cases with T0 genotype. In conclusion, absence of both GST M and GST T might confer increased risk of developing ALL or AML. The absence of GST enzyme might lead to oxidative stress and subsequent DNA damage resulting in genomic instability, a hallmark of acute leukemia. The GST enzyme deficiency might also exert impact on clinical prognosis leading to poorer DFS. Hence GST genotyping can be made mandatory in management of acute leukemia so that more aggressive therapy such as allogenic stem cell transplantation may be planned in the case of patients with a null genotype.

Association of MDR1 gene polymorphism (G2677T) with chronic myeloid leukemia

Imatinib mesylate is the most opted drug used for treating ph+ve chronic myeloid leukemia (CML) patients. The up-regulation of drug transporters (ABCB1-ABCG2) is one of specific causes of Imatinib resistance. Imatinib (IM) is a substrate of the P-glycoprotein pump, which is encoded by MDR1/ABCB1 gene. Our main objective is to investigate the influence of MDR1 gene polymorphisms in CML patients. A total of 262 CML and 252 control samples were analysed for MDR1 gene (G2677T) polymorphism using PCR- RFLP technique. Genotype distribution revealed slight elevation of TT genotype frequency in CML patients (42.7%) compared to controls (38.5%). Patients in advanced phase had higher TT genotype frequency compared to patients in early phases. The frequency of heterozygous GT genotype was found to be increased in hematological poor responders (52.4%) compared to major responders (32.4%) and minor responders (30.0%). Interestingly, the frequencies of GG and GT genotypes were increased in cytogenetic poor responders with corresponding increase in G allele frequency (0.54) as compared to major responders (0.34). These results suggest that the 2677G allele with increased efflux of IM might be responsible for poor response in CML patients.

Intronic SNPs of TP53 gene in chronic myeloid leukemia: Impact on drug response

Background: TP53, located on chromosome 17p13, is one of the most mutated genes affecting many types of human cancers. Thus, we aimed at investigating the association of SNPs in TP53 gene with chronic myeloid leukemia (CML). Materials and Methods: A total of 236 CML and 157 control samples were analysed for mutations in TP53 gene using polymerase chain reaction followed by direct sequencing. Results: Sequencing analysis for mutations in exons 7–9 of the TP53 gene revealed four SNPs, three in intron 7 (C14181T, T14201G, and C14310T) and one SNP in intron 6 (A13463G) of TP53 gene. The mutation C14181T is located at position 72 base pairs downstream of the 3′-end of exon 7 of the P53 gene. This mutation is in complete linkage disequilibrium with a T14201G mutation, 20 base pairs further downstream occurring at position 14201. This mutation occurred only in the presence of C14181T mutation and these mutations showed association with advanced phase and cytogenetic poor response. Another two novel mutations, C14310T in intron 7 and A13463G in intron 6 were also found to be associated with cytogenetic poor response. Conclusion: Our study suggests that TP53 intronic SNPs might have a strong influence on disease progression and poor response in CML patients.