RESUMEN
Esophageal cancer incidence is reported in high frequency in northeast India. The etiology is different from other population at India due to wide variations in dietary habits or nutritional factors, tobacco/betel quid chewing and alcohol habits. Since DNA methylation, histone modification and miRNA-mediated epigenetic processes alter the gene expression, the involvement of these processes might be useful to find out epigenetic markers of esophageal cancer risk in northeast Indian population. The present investigation was aimed to carryout differential expression profiling of chromatin modification enzymes in tumor and normal tissue collected from esophageal squamous cell carcinoma (ESCC) patients. Differential mRNA expression profiling and their validation was done by quantitative real time PCR and tissue microarray respectively. Univariate and multiple logistic regression analysis were used to analyze the epidemiological data. mRNA expression data was analyzed by Student t-test. Fisher exact test was used for tissue microarray data analysis. Higher expression of enzymes regulating methylation (DOT1L and PRMT1) and acetylation (KAT7, KAT8, KAT2A and KAT6A) of histone was found associated with ESCC risk. Tissue microarray done in independent cohort of 75 patients revealed higher nuclear protein expression of KAT8 and PRMT1 in tumor similar to mRNA expression. Expression status of PRMT1 and KAT8 was found declined as we move from low grade to high grade tumor. Betel nut chewing, alcohol drinking and dried fish intake were significantly associated with increased risk of esophageal cancer among the study subject. Study suggests the association of PRMT1 and KAT8 with esophageal cancer risk and its involvement in the transition process of low to high grade tumor formation. The study exposes the differential status of chromatin modification enzymes between tumor and normal tissue and points out that relaxed state of chromatin facilitates more transcriptionally active genome in esophageal carcinogenesis.
RESUMEN
Acute myeloid leukemia (AML) with normal karyotype represents a clinically and molecularly heterogeneous disease. Molecular markers with prognostic significance have been examined to improve risk profile characterization of this group. Activating mutations on FLT3 receptor are one of the most common genetic alterations reported. However, the prevalence and prognostic significance of FLT3 genetic alterations in AML patients with cytogenetically normal karyotype is still controversial. In this study, FLT3/ITD and FLT3/D835 mutations were analyzed in 133 patients with de novo AML with normal cytogenetics by genomic PCR assay. Of 133 patients with AML with normal cytogenetics, FLT3 internal tandem duplication (ITD) and FLT3/D835 mutations were detected in 27 (20%) and 4 (3%) samples, respectively. Although statistically insignificant, the frequency of FLT3/ITD was higher in >15 year age group when compared to <15 year group (23 vs. 13%, P = 0.2). The white blood count was found to be significantly higher in patients with FLT3/ITD mutation when compared to those without the mutation (40 × 109/L vs. 20 × 109/L, P = < 0.002) or those with FLT3/D835 mutations (30 × 109/l). Aberrant expression of CD7 was observed more frequently in patients with FLT3/ITD mutation (P < 0.002). There was no significant difference in the response rate to chemotherapy in patients with or without FLT3/ITD mutation (67 and 64%, respectively). FLT3/ITD mutation was found to be associated with the age, leukocytosis and aberrant expression of CD7, although no influence of FLT3/ITD mutation was seen on the clinical outcome of AML patients with normal cytogenetics.
