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High incidence of nasopharyngeal carcinoma (NPC) has been reported from China, Southeast Asia and Northeast (NE) region of India. Populations at geographic regions having higher incidence of NPC display human leukocyte antigen (HLA) distribution patterns different from areas having low incidence. The current study has investigated the contribution of environmental risk factors and ethnic variation of microsatellite markers in HLA region for the high incidence of NPC in NE India. Genotyping of HLA region using 33 microsatellite markers by fragment length analysis was done in 220 study subjects (120 NPC patients and 100 healthy controls). Association analysis showed two adjacent microsatellite markers HL003 (allele 121) and D6S2704 (allele 218) in the HLA class I region having association with high risk of NPC while allele 127 of HL003 and allele 255 of D6S2678 conferred a protective effect. The environmental factors mainly use of firewood (odds ratio (OR) = 3.797385, confidence interval (CI) = 1.97-7.30, P

Targeting breast cancer stem cells (BCSCs) offers a promising strategy for breast cancer treatment. We examined the plant alkaloid ellipticine for its efficacy to inhibit the expression of aldehyde dehydrogenase 1 class A1 (ALDH1A1)-positive BCSCs by in vitro and in silico methods. At 3 mM concentration, ellipticine decreased the expression of ALDH1A1-positive BCSCs by 62 % (p = 0.073) in the MCF7 cell line and by 53 % (p = 0.024) in the SUM159 cell line compared to vehicle-treated cultures. Ellipticine significantly reduced the formation of mammospheres, whereas paclitaxel enhanced mammosphere formation in both the treated cell lines. Interestingly, when treated with a combination of ellipticine and paclitaxel, the percentage of ALDH1A1-positive BCSCs dropped by several fold in vitro. A homology model of Homo sapiens ALDH1A1 was built using the crystal structure of NAD-bound sheep liver class I aldehyde dehydrogenase [PDB ID: 1BXS] as a template. Molecular simulation and docking studies revealed that the amino acids Asn-117 and Asn-121, Glu-249, Cys-302, and Gln-350, present in the active site of human ALDH1A1, played a vital role in interacting with the drug. The present study suggests that ellipticine reduces the proliferation and self-renewal ability of ALDH1A1-positive BCSCs and can be used in combination with a cytotoxic drug like paclitaxel for potential targeting of BCSCs.

Background.Mutations in NPM1 and FLT3 genes represent the most frequent genetic alterations and important diagnostic and prognostic indicators in patients with acute myeloid leukemia (AML).Objective.We investigated the prevalence and clinical characteristics of NPM1 and FLT3 mutations in 161 patients of de novo AML including adults and children.Results.NPM1 mutation was found in 21% and FLT3 mutation in 25% of the AML patients. Thirteen (8%) samples were positive for both NPM1 and FLT3/ITD mutations. Adult patients had significantly higher frequency of NPM1 mutation than children (25.8% versus 8.8%;P=0.02). Further, NPM1 mutation was found to be more frequent in patients above 45 years of age (P=0.02). NPM1 mutation was significantly associated with higher platelet count (P=0.05) and absence of hepatosplenomegaly (P=0.01), while FLT3/ITD mutation was associated with higher white blood count (P=0.01). Immunophenotypically, NPM1 mutation was associated with the lack of CD34 (P<0.001) and HLD-DR expression (P<0.001), while FLT3/ITD mutation was positively associated with the expression of CD7 (P=0.04). No correlation was found between NPM1 mutation and fusion gene. Interestingly, FLT3/ITD mutation was found to be inversely associated with AML/ETO fusion gene (P=0.04).Conclusions.The results suggest that distinct clinical and immunophenotypic characteristics of NPM1 and FLT3/ITD mutations present further insight into the molecular mechanism of leukemogenesis.

Polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia (AL). This study applied two data mining approaches to explore potential interactions among P53 and xenobiotic metabolizing genes in 230 AL patients [131 acute myeloid leukemia (AML) and 99 acute lymphoblastic leukemia (ALL)] and 199 controls. Individually, none of the genotypes showed significant associations with AML risk. However, in ALL the CYP1A12A TC genotype was associated with increased risk (OR = 2.02; 95% CI = 1.14-3.58; P = 0.01), whereas the GSTM1 null genotype imparted reduced risk (OR = 0.55; 95% CI = 0.31-0.96; P = 0.03). In classification and regression tree analysis, combinations of GSTM1 present, CYP1A12C AA or GG, EPHX1 exon3 TC, and EPHX1 exon4 AA or GG genotype strongly enhanced the risk of AML (OR = 5.89; 95% CI = 1.40-26.62; P = 0.01). In ALL, combinations of CYP1A12A TT, P53 GG or CC and GSTP1 AG genotypes conferred the highest risk (OR = 4.19; 95% CI = 1.45-12.25; P = 0.004). In multifactor dimensionality reduction analysis, a four locus model (GSTP1, P53, EPHX1 exon3, and CYP1A12A) was the best predictor model for ALL risk. The association between this model and ALL risk remained true even at low prior probabilities of 0.01% (false positive report probability = 0.05). Interaction entropy interpretations of the best model of ALL revealed that two-way interactions were mostly synergistic. These results suggest that high order gene-gene interactions play an important role in AL risk. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.

Resistance to chemotherapy is a major impediment to the successful treatment of acute leukemia (AL). Expression of genes involved in drug resistance and apoptosis may be responsible for this. This study aimed to investigate the expression of drug resistance (MDR1, MRP1, LRP, BCRP, GSTP1, DHFR) and apoptotic genes (p53, BCL-2, Survivin) in adult acute leukemias and compare them with clinical and hematological findings and response to induction chemotherapy. Eighty-five patients with AL [45 with acute myeloid leukemia (AML) and 40 with acute lymphoblastic leukemia (ALL)] were used as a study group. Real-time PCR results showed that expression level of MDR1 was significantly higher in AML whereas expression of DHFR, BCRP and Survivin was significantly higher in ALL patients. In AML, significant correlation was observed between LRP and MRP1 (r(s)=0.44, p=0.016), LRP and DHFR (r(s)=0.41, p=0.02), MDR1 and BCL-2 (r(s)=0.38, p=0.03). Expression of GSTP1 and LRP correlated with high white blood count (p=0.03 and p=0.03) and BCL-2 with high peripheral blast count (p=0.009). MDR1 expression was significantly associated with the expression of immature stem cell marker CD34 (p=0.002). In ALL, significant association was found between LRP gene and female sex (p

Widespread use of tobacco and betel quid consumption and a high incidence of tobacco-associated aerodigestive tract cancers have been reported in different ethnic groups from several regions of Northeast (NE) India. This study was done to explore the possibility of phase II metabolic enzymes being responsible for the high prevalence of cancers in this region of India.Samples from 370 cases with oral, gastric, and lung cancers and 270 controls were analyzed for polymorphism of glutathione-S-transferase (GST) genes using polymerase chain reaction-restriction fragment length polymorphism-based methods.Tobacco smoking and betel quid chewing were found to be high risk factors for oral and lung cancers but not for gastric cancer, whereas tobacco chewing was found to be a risk factor for oral cancer but not for gastric or lung cancer. The variant genotypes of GSTP1 were not associated with any of the aerodigestive tract cancers. GSTT1 and GSTM1 null genotypes appeared to play a protective role for lung cancer (odds ratio [OR] = 0.47, 95% confidence interval [95% CI]: 0.24-0.93, p = 0.03) and (OR = 0.52, 95% CI: 0.28-0.96, p = 0.04), but they were not associated with oral and gastric cancers. However, when data was analyzed in different geographic regions the GSTT1 null genotype was found to be a significant risk factor for oral (OR = 2.58, 95% CI 1.01-6.61, p = 0.05) as well as gastric cancer (OR = 3.08, 95% CI 1.32-7.19, p = 0.009) in samples obtained from the Assam region of NE India. This is the first study on the association of GST polymorphisms and aerodigestive tract cancers in the high-risk region of NE India.

Detoxifying glutathione S-transferase (GST) gene polymorphisms show variation in different ethnic populations. GST detoxifies and metabolizes carcinogens, including oxygen free radicals. GST polymorphisms have been associated with susceptibility to different diseases. In the current study, allelic polymorphisms of GSTM1 and GSTT1 were analyzed in three ethnic groups of North East (NE) India where a high prevalence of various cancers and other diseases such as hypertension, tuberculosis, and asthma have been reported.We compared the prevalence of GSTT1 and GSTM1 deletion genotypes, which were determined by multiplex polymerase chain reaction, in 422 voluntary, healthy NE Indians with those of other populations. The data was statistically analyzed.The GSTT1-null genotype was found in 51%, 34.3%, and 15.7% of individuals (from Mizoram, Sikkim, and Assam regions of NE India, respectively), whereas the GSTM1-null genotype was found in 46.9%, 46%, and 35% of individuals from the same areas.The NE Indians differ from the rest of the Indian population with reference to genotypic distribution of GST polymorphisms but the frequency was found to be similar to that which has been reported from China. This may explain the hypothesis of the common ancestral origin of both the NE Indians and the Chinese and a higher frequency of cancers such as gastric, esophageal, and oral cancers, which has been reported from these regions. This study establishes baseline frequency data for GST polymorphisms for future case control studies on the role these polymorphisms play with regard to diseases. The results presented here provide the first report on GST polymorphisms in the NE Indian population.

The IL-1β -511 C/T polymorphism is associated with increased IL-1 production and with increased risk of developing cancers. In this study, 251 patients (125 with gastric cancer [GC] and 126 with oral cancer [OC]) and 207 normal controls from northeast (NE) India were genotyped for the IL-1β -511 C/T polymorphism by PCR-restriction fragment length polymorphism (RFLP) and sequencing. Analysis of results showed betel-quid chewing to be a major risk factor (OR = 2.01, 95% CI = 1.05-3.87; P = 0.035) for OC. Inheritance of the IL-1β -511 CT or TT resulted in a 2.6- to 3.05-fold increase in the risk of developing OC relative to that of participants who possessed the reference genotype (OR = 2.57, 95% CI = 1.06-6.22; P = 0.036 and OR = 3.05, 95% CI = 1.22-7.63; P = 0.017), after adjusting for potential confounders. The dominant genetic model also confirmed the presence of the T allele as a significant risk factor for OC (OR = 2.72, 95% CI = 1.15-6.42; P = 0.02). In GC, interaction of the CT genotype with tobacco and betel-quid chewing habits conferred a significant 78% and 89% reduced risk of cancer, respectively. In conclusion, for the NE Indian population, the IL-1β -511 CC and CT genotypes were significantly associated with increased risk of OC. However, the interaction of the CT genotype with risk habits may play a preventive role for GC but not for OC.

Complex disease such as cancer results from interactions of multiple genetic and environmental factors. Studying these factors singularly cannot explain the underlying pathogenetic mechanism of the disease. Multi-analytical approach, including logistic regression (LR), classification and regression tree (CART) and multifactor dimensionality reduction (MDR), was applied in 188 lung cancer cases and 290 controls to explore high order interactions among xenobiotic metabolizing genes and environmental risk factors. Smoking was identified as the predominant risk factor by all three analytical approaches. Individually, CYP1A1*2A polymorphism was significantly associated with increased lung cancer risk (OR = 1.69;95%CI = 1.11–2.59,p = 0.01), whereas EPHX1 Tyr113His and SULT1A1 Arg213His conferred reduced risk (OR = 0.40;95%CI = 0.25–0.65,p

Polymorphisms in genes encoding detoxification enzymes have been suggested as susceptibility factors for many solid tumors. However, their association with hematological malignancies is controversial. A case-control study was done to determine the association between glutathione S-transferase M1 (GSTM1), GSTT1, GSTP1, EPHX1, and p53 codon 72 polymorphisms as risk factors in 120 adult acute myeloid leukemia (AML) cases and 202 healthy controls by polymerase chain reaction-restriction fragment length polymorphism techniques. Data were analyzed using χ(2) and conditional logistic regression model. None of the polymorphisms studied alone was associated with increased risk for AML. However, the frequency of GSTT1 null genotype was higher among controls (28.7%) than AML cases (21.6%), which showed a protective effect of the null genotype (odds ratio = 0.58, 95% confidence interval: 0.33-1.05, p = 0.07). In a combined analysis, both EPHX1 (His113His) and GSTP1 (Ile/Val) genes imparted a fourfold risk for adult AML but did not reach statistical significance (odds ratio = 4.22, 95% confidence interval: 0.992-17.99, p = 0.05). These findings suggest that the etiology of adult AML cannot be explained by polymorphism at a single locus, perhaps because of complexity involved in the metabolism of diverse xenobiotic compounds, and therefore, multiple gene-gene interactions should be investigated to predict the risk of AML.

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