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    • Mice with GSTP knock out show increased risk

    2022-01-15

    Mice with GSTP1 knock out show increased risk of skin cancer when exposed to carcinogens like polycyclic aromatic hydrocarbons [23]. Most of the genetic association studies have focused on GSTP1 c.313G > A variant which results in isoleucine to valine substitution at amino NMS-E973 residue number 105 in the polypeptide chain. Positive association has been observed between c.313A > G SNP and cancers of lung, breast and prostate [24], [25], [26]. There are several studies that have found a positive association between c.313A > G and the risk of OSCC [27], [28], [29]. However, these results have failed to reach statistical significance at the level of meta-analysis [30]. This motivated us to explore the involvement of other functional SNPs in GSTP1 gene with the risk of oral carcinogenesis. Another less explored functional SNP in the GSTP1 gene is c.341C > T which results in Alanine to Valine substitution at residue number 114 in the GST pi polypeptide chain. Experimental evidences have shown that c.341C > T SNP results in significant reduction of the enzymatic activity of GST pi [31]. Previous studies have found positive association between c.341C > T SNP and risk of cancers of oesophagus, lung, and thyroid [9], [32], [33]. In this study, we found significant association between c.341C > T SNP and risk of OSCC both at the allele and genotype level with highest association in the additive genetic model. This indicates that GST pi is probably a limiting factor in the oral mucosa for protection against carcinogenesis. Quantitative reduction in GST pi expression due to gene polymorphism may thus reflect as quantitative increase in the risk of carcinogenesis with homozygosity of the functionally reduced minor allele constituting the highest risk followed by its heterozyogisty and least risk in the case homozygosity of functionally normal major allele. All the patients recruited for the study were found to be habitual consumers of tobacco or gutkha. Tobacco consumption in smokable form is common among men while its consumption in chewable form along with betel quid is common among women particularly in the rural demography. Habit of chewing betel quid and tobacco is common among rural women in South and South East Asia NMS-E973 and its link to carcinogenesis has been indicated in previous studies [16], [17]. Human papilloma virus was absent in all the tumor samples included in the study. Thus, tobacco consumption was the major exogenous risk factor among the patients. The positive association observed in this study could be due to the homogeneity of the exogenous risk factor in the patient group. At the level of oral mucosa, GST pi expression is linked with the carcinogen detoxification capacity and protection against carcinogenesis. However, GST pi has opposite effect in the tumor tissue where it is often found to be overexpressed. Increased expression of GST pi contributes towards tumor survival by neutralising electrophilic chemotherapeutic agents like cisplatin and by minimizing the DNA damaging effect of radiation therapy [34]. We examined if c.341C > T SNP also affect GST pi expression in the tumor. We failed to find any evidence for statistically significant association between immunohistochemical grade of GST pi in tumor samples and c.341C > T SNP. This indicates that the mechanism that results in GST pi overexpression is distinct and not linked to the genotype of c.341C > T SNP. In conclusion, the results of this study indicate that c.341C > T SNP in GSTP1 gene increases of risk of OSCC in individuals habituated to consumption of tobacco products but it has no mechanistic link with the magnitude of GST pi over expression in the tumor. The genetic association observed in this study is a reflection of oxidative stress potentially caused by chewable tobacco.
    Conflict of interests
    Introduction COPD is defined as a preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases [1].