Can polymorphisms in genes relate to overall survival in leukemias?

Abstract

The Kaplan – Meier statistics are generally used to calculate the survival rate of post-treatment cancer patients; some authors also use multivariate analysis (p1⁄4 0.01). However to generate this data to apply such statistics, oncologists and researchers are strugling to find out what is the magic mechanism by which they can increase the disease free survival. Answers to such questions may come from unconventional centers. They could be from geneticists, molecular biologists, or epidemiological findings which relate to gene environment and gene drug interactions. In a recent article Pelloso et al. [1] have shown that the drug metabolizing enzymes CYP and GST genes which carry polymorphisms have been recognized as prognostic markers for predicting the overall survival in acute myeloid leukemia (AML). Earleir D’Alo F et al. [2] have demonstrated that these drug metabolizing genes play a critical role in over all survival (OS). These polymorphisms modify the enzyme activity, which results not only in inter individual differences, but also influence the rate of survival. Such SNP-based approaches are relatively new and must be considered by clinicians for better prognosis since they can be used along with other independent variables by applying the Cox Regression Model. In Acute Lymphocytic Leukemia patients we reported that within the GSTm subfamily the gene coding for GSTM1 exhibited a deletion polymorphism, which (GST M1 null) leads to absence of phenotypic enzyme activity [3]. Keeping in view the importance of overall survival in leukemias we present a study on the role of a tyrosine kinase receptor FLT3 that is expressed in certain cells like the bone marrow cells and the thymic progenitor cells. FLT3 is active in the very early hematopoietic cells and is believed to play an important role during early lymphopoiesis [4]. This protein (FLT3) is involved in the signal transduction pathways of the stem cells and its expression is therefore necessary for the differentiation of the stem cells and formation of mature cells. Around 90% of Acute myeloid leukemia cases show an overexpression of the FLT3 gene, suggesting its possible role in leukemogenesis. Studies involving the knockouts of FLT3 have shown poor lymphopoiesis [5]. To assess the combined role of GSTs and FLT3 in child hood acute lymphocytic leukemia (ALL) we determined the polymorphisms of these two genes to evaluate their role in relation to susceptibility in child hood leukemias. The study group consisted of 135 individuals diagnosed with ALL (Age: 1 – 10 years) and 142 matched controls and a mean age of 4.2 years. DNA was isolated from patients blood samples and control groups for the common polymorphisms of GSTM1 and GST T1. Genotyping by simple PCR with b-globulin was the internal control for the successful amplification. In the FLT3 gene PCR was performed for determining the presence of the gene and positive FLT3 PCR products were subjected to SSCP to detect the FLT3/ITD. The association between genotypes in cases and controls were computated with Epiinfo6 (CDC). The GST M1 and T1 null genotypes with FLT/ITD were determined. The GST T1 null genotypes had an increased risk of ALL unexpectedly the DNA damage was also very high in these genotypes containing cells. The FLT3/ITD was less frequent in cases and absent in controls. The FLT3/ITD was related to FAB sub types with Karyotype abnormalities. We next examined the combined effect of GST T1, GST M1 null genotypes with FLT3/ITD mutation. The detection of GST M1 had no association with these leukemias