Helicobacter pylori and Epstein-Barr virus infection in cell polarity alterations.

The asymmetrical distribution of the cellular organelles inside the cell is maintained by a group of cell polarity proteins. The maintenance of polarity is one of the vital host defense mechanisms against pathogens, and the loss of it contributes to infection facilitation and cancer progression. Studies have suggested that infection of viruses and bacteria alters cell polarity. Helicobacter pylori and Epstein-Barr virus are group I carcinogens involved in the progression of multiple clinical conditions besides gastric cancer (GC) and Burkitt's lymphoma, respectively. Moreover, the coinfection of both these pathogens contributes to a highly aggressive form of GC. H. pylori and EBV target the host cell polarity complexes for their pathogenesis. H. pylori-associated proteins like CagA, VacA OipA, and urease were shown to imbalance the cellular homeostasis by altering the cell polarity. Similarly, EBV-associated genes LMP1, LMP2A, LMP2B, EBNA3C, and EBNA1 also contribute to altered cell asymmetry. This review summarized all the possible mechanisms involved in cell polarity deformation in H. pylori and EBV-infected epithelial cells. We have also discussed deregulated molecular pathways like NF-κB, TGF-ß/SMAD, and ß-catenin in H. pylori, EBV, and their coinfection that further modulate PAR, SCRIB, or CRB polarity complexes in epithelial cells.

A Three-Year Study on Acute Poisoning Cases Brought for Medico-Legal Autopsy in a North-Eastern City of India.

PURPOSE: Death due to acute poisoning is one of the significant health challenges to cope-up. It is imperative to know the death victims' pattern due to acute poisoning to prepare the relevant preventive and remedial measures. Therefore, the present study aimed to assess the pattern of the dead victims of acute poisoning in a tertiary care centre. MATERIALS AND METHODS: It is a hospital record-based study and conducted in a tertiary care centre. Descriptive statistics to study the distribution of the cases among different age groups, sex, type of poison compounds was computed and analysed using SPSS software version 20. RESULTS: The present study detected poisonous substances in 244 (41.8%) cases out of 584 death cases of suspected acute poisoning with the male preponderance of 62.29%. A higher incidence of acute poisoning was noticed among the young age group 21-30 years (33.6%) with 48 (31.6%) cases among males and 34 (36.9%) cases of the female. The Organophosphates (OP) was the main compound found in 151 (61.9%) fatal cases, followed by Carbamate in 45 (18.4%) cases. We also observed a maximum, 76 (36.2%) cases of suicidal victims in the age group of 21-30 years. Children and lower age group were more vulnerable to accidental poisoning as 26.5% cases of accidental death were reported in both the age group of 0-10 and 11-20 years respectively, gradually declining and practically found nil in above 60 years group. These differences of frequencies were found statistically significant (p < 0.0001), χ 2 = 55.1. CONCLUSION: The results suggest due consideration to the young adolescents' groups without any sexual discrimination to define guidelines for appropriate handling, storage and transportation of the poisonous compounds. Organophosphate's involvement as the most preferred agent in acute poisoning is to be remembered to help manage poisoning cases.

A pilot study evaluating genetic alterations that drive tobacco- and betel quid-associated oral cancer in Northeast India.

The susceptibility of an individual to oral cancer is mediated by genetic factors and carcinogen-exposure behaviors such as betel quid chewing, tobacco use, and alcohol consumption. This pilot study was aimed to identify the genetic alteration in 100 bp upstream and downstream flanking regions in addition to the exonic regions of 169 cancer-associated genes by using Next Generation sequencing with aim to elucidate the molecular pathogenesis of tobacco- and betel quid-associated oral cancer of Northeast India. To understand the role of chemical compounds present in tobacco and betel quid associated with the progression of oral cancer, single nucleotide polymorphisms (SNPs) and insertion and deletion (Indels) found in this study were analyzed for their association with chemical compounds found in tobacco and betel quid using Comparative Toxogenomic Database. Genes (AR, BRCA1, IL8, and TP53) with novel SNP were found to be associated with arecoline which is the major component of areca nut. Genes (BARD1, BRCA2, CCND2, IGF1R, MSH6, and RASSF1) with novel deletion and genes (APC, BRMS1, CDK2AP1, CDKN2B, GAS1, IGF1R, and RB1) with novel insertion were found to be associated with aflatoxin B1 which is produced by fermented areca nut. Genes (ADH6, APC, AR, BARD1, BRMS1, CDKN1A, E2F1, FGFR4, FLNC, HRAS, IGF1R, IL12B, IL8, NBL1, STAT5B, and TP53) with novel SNP were found to be associated with aflatoxin B1. Genes (ATM, BRCA1, CDKN1A, EGFR, IL8, and TP53) with novel SNP were found to be associated with tobacco specific nitrosamines.

Association of interleukin-1ß -511 C/T polymorphism with tobacco-associated cancer in northeast India: a study on oral and gastric cancer.

The IL-1ß -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-1ß -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-1ß -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-1ß -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.

High order interactions of xenobiotic metabolizing genes and P53 codon 72 polymorphisms in acute leukemia.

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.

Association of androgen receptor, prostate-specific antigen, and CYP19 gene polymorphisms with prostate carcinoma and benign prostatic hyperplasia in a north Indian population.

The genes involved in androgen pathway and metabolism have been reported to contribute considerably to prostate carcinoma (CaP) risk. The present study investigated the association of androgen receptor (AR), prostate-specific antigen (PSA or KLK3), and cytochrome P450 (CYP19) gene polymorphisms in CaP (n=105) and benign prostatic hyperplasia (BPH) (n=120) in comparison to normal healthy controls (n=106) in an Indian population. We also evaluated the functional consequences of these gene variants on AR and PSA mRNA expression. Significant association of short AR CAG repeats (≤24) with risk of CaP (odds ratios [OR]=2.98, p<0.001) and BPH (OR=1.96, p=0.01) was observed; however, CYP19 gene polymorphism was not found to be associated with disease phenotype (p>0.05). PSA G-158A SNP was found to be significantly associated with risk of CaP (AA: OR=2.68, p=0.016 and GA: OR=2.07, p=0.018) p-trend 0.031 and BPH (AA: OR=3.46, p<0.001 and GA: OR=2.47, p=0.03) p-trend 0.009, respectively. PSA G-158A genotype independently increased the risk of developing BPH (OR=16.37, p<0.001), irrespective of AR CAG repeat length. Using quantitative real-time polymerase chain reaction, we found a significant upregulation of AR and PSA mRNA expression in CaP comparison to BPH. While short AR CAG (≤24) repeats were associated with higher AR mRNA expression in CaP (p=0.002), the PSA SNP did not correlate with its mRNA expression. Interestingly, significantly higher risk estimates for CaP were observed for the combined analysis of short AR CAG and CYP19 genotypes (A2A2) (OR=7.18, p<0.001) or A2A3 (OR=7.60, p=0.004). Our results suggest significant association of androgen signaling gene polymorphisms with risk of CaP and BPH and provide evidence for a putative functional role of AR CAG repeat in regulating its mRNA expression and warrant the need of larger studies in the Indian population to confirm our results.

Multiple analytical approaches reveal distinct gene-environment interactions in smokers and non smokers in lung cancer.

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<0.001 and OR = 0.51;95%CI = 0.33-0.78,p = 0.002 respectively). In smokers, EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms reduced the risk of lung cancer, whereas CYP1A1*2A, CYP1A1*2C and GSTP1 Ile105Val imparted increased risk in non-smokers only. While exploring non-linear interactions through CART analysis, smokers carrying the combination of EPHX1 113TC (Tyr/His), SULT1A1 213GG (Arg/Arg) or AA (His/His) and GSTM1 null genotypes showed the highest risk for lung cancer (OR = 3.73;95%CI = 1.33-10.55,p = 0.006), whereas combined effect of CYP1A1*2A 6235CC or TC, SULT1A1 213GG (Arg/Arg) and betel quid chewing showed maximum risk in non-smokers (OR = 2.93;95%CI = 1.15-7.51,p = 0.01). MDR analysis identified two distinct predictor models for the risk of lung cancer in smokers (tobacco chewing, EPHX1 Tyr113His, and SULT1A1 Arg213His) and non-smokers (CYP1A1*2A, GSTP1 Ile105Val and SULT1A1 Arg213His) with testing balance accuracy (TBA) of 0.6436 and 0.6677 respectively. Interaction entropy interpretations of MDR results showed non-additive interactions of tobacco chewing with SULT1A1 Arg213His and EPHX1 Tyr113His in smokers and SULT1A1 Arg213His with GSTP1 Ile105Val and CYP1A1*2C in nonsmokers. These results identified distinct gene-gene and gene environment interactions in smokers and non-smokers, which confirms the importance of multifactorial interaction in risk assessment of lung cancer.

Association of glutathione S-transferase, EPHX, and p53 codon 72 gene polymorphisms with adult acute myeloid leukemia.

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.

Investigation on the role of p53 codon 72 polymorphism and interactions with tobacco, betel quid, and alcohol in susceptibility to cancers in a high-risk population from North East India.

The association of TP53 codon 72 polymorphism with cancer susceptibility remains uncertain and varies with ethnicity. Northeast India represents a geographically, culturally, and ethnically isolated population. The area reports high rate of tobacco usage in a variety of ways of consumption, compared with the rest of Indian population. A total of 411 cancer patients (161 lung, 134 gastric, and 116 oral) and 282 normal controls from the ethnic population were analyzed for p53 codon 72 polymorphism by polymerase chain reaction-restriction fragment length polymorphism. No significant difference in genotypic distribution of p53 between cases and controls was observed. Results suggested betel quid chewing as a major risk factor for all the three cancers (odds ratio [OR]=3.54, confidence interval [CI]=2.01-6.25, p<0.001; OR=1.74, CI=1.04-2.92, p=0.03; and OR=1.85, CI=1.02-3.33, p=0.04 for lung, gastric, and oral cancers, respectively). Tobacco smoking was associated with risk of lung and oral cancers (OR=1.88, CI=1.11-3.19, p=0.01 and OR=1.68, CI=1.00-2.81, p=0.04). Interactions between p53 genotypes and risk factors were analyzed to look for gene-environment interactions. Interaction of smoking and p53 genotype was significant only for oral cancer. Interactions of betel quid with p53 genotypes in lung cancer showed significant increase for all the three genotypes, indicating a major role of betel quid (OR=5.90, CI=1.67-20.81, p=0.006; OR=5.44, CI=1.67-17.75, p=0.005; and OR=5.84, CI=1.70-19.97, p=0.005 for Arg/Arg, Arg/Pro, and Pro/Pro, respectively). In conclusion, high incidence of these cancers in northeast India might be an outcome of risk habits; further, tissue- and carcinogen-specific risk modification by p53 gene is probable.

Polymorphisms of glutathione-S-transferase genes and the risk of aerodigestive tract cancers in the Northeast Indian population.

BACKGROUND: 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. METHODS: 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. RESULTS AND CONCLUSIONS: 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.

Distribution of glutathione S-transferase T1 and M1 genes polymorphisms in North East Indians: a potential report.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.