ABSTRACT
XRCC1 gene is an integral component of the base excision repair pathway regulating DNA repair, the genetic alterations in which has been documented to be associated with cancers of multiple etiologies. The present study aimed to evaluate the key polymorphisms in XRCC1 gene for its association with pathogenesis of oral cavity cancer (OCC) in Kamrup Urban District of Assam, India. Tissue biopsies (Nâ¯=â¯152) clinicopathologically characterized OCCs were collected along with whole blood samples (Nâ¯=â¯190) from healthy controls with all clinical and habitual details. A PCR-RFLP approach was used to study the XRCC1 polymorphisms, and statistical associations with pathogenesis were studied with SPSSv13.0 statistical software. The XRCC1 codon 194 polymorphism was significantly associated with the risk of OCC (odds ratio [OR] = 1.878, P = 0.048) and severity (ORâ¯=â¯2.221, P = 0.031). The presence of XRCC1 280 variant genotype increased the risk of OCC in exclusive smokers (ORâ¯=â¯3.818, P = 0.006), exclusive alcoholics (ORâ¯=â¯3.144, Pâ¯=â¯0.027), and in exclusive areca nut chewers (ORâ¯=â¯3.055, P = 0.034). Human papilloma virus cases with any other habitual risk factor carrying XRCC1 280 genotype showed 3-fold significantly increased risk compared to controls (ORâ¯=â¯3.341, P = 0.022). The presence of XRCC1 codon 399 polymorphism was also found to be associated with significantly increased risk of oral cavity carcinoma (ORâ¯=â¯1.566, P = 0.049). Distribution of altered XRCC1 gene haplotype was higher in OCC cases. Polymorphisms in XRCC1 gene is associated with OCC pathogenesis in Kamrup Urban District, Assam, India, and is of prognostic significance. It is also suggestive of the importance of base excision repair pathway alterations in OCC pathogenesis.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma/genetics , Genetic Predisposition to Disease , Mouth Neoplasms/genetics , X-ray Repair Cross Complementing Protein 1/genetics , Adult , Biopsy , Carcinoma/diagnosis , Carcinoma/epidemiology , Carcinoma/pathology , Case-Control Studies , DNA Repair , Female , Humans , India/epidemiology , Male , Middle Aged , Mouth Mucosa/pathology , Mouth Neoplasms/diagnosis , Mouth Neoplasms/epidemiology , Mouth Neoplasms/pathology , Neoplasm Staging , Polymorphism, Restriction Fragment Length , Prognosis , Risk Assessment/methods , Risk FactorsABSTRACT
We aimed to evaluate the significance of the RANTES-CCR5 axis and resulting immunomodulatory status in Dengue pathogenesis involving a Guwahati, India based population where Dengue cases have increased alarmingly. An increased CC-chemokine receptor type 5 (CCR5) messenger RNA expression and CCR5 positive cell count profile was observed in Dengue cases, the highest being in severe cases. CCR5 ligand RANTES expression was significantly decreased in Dengue cases and inversely correlated with Dengue viremia fold change in severe cases. Monocytes are involved in Dengue virus homing and replication. Its levels and activation profile were higher in Dengue cases. A hyper Th1-biased immunomodulatory profile with upregulated tumor necrosis factor-α levels, and downregulated expression of antiviral cytokine interferon-γ and key regulatory Th2 anti-inflammatory cytokine interleukin 10 was observed in severe Dengue cases compared with mild Dengue cases and controls. The results, therefore, suggest the significance of RANTES-CCR5 axis deregulation and resulting altered immunomodulation in Dengue pathogenesis, and holds prognostic and therapeutic significance.
Subject(s)
Chemokine CCL5/immunology , Dengue/immunology , Immunomodulation , Receptors, CCR5/immunology , Adult , Chemokine CCL5/genetics , Cytokines/immunology , Female , Humans , India , Interleukin-10/genetics , Interleukin-10/immunology , Lymphocyte Activation , Male , Middle Aged , Monocytes/virology , Prospective Studies , Receptors, CCR5/genetics , Severe Dengue/immunology , Th1 Cells/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Young AdultABSTRACT
Gallbladder cancer (GBC) is a fatal condition with dismal prognosis and aggressive local invasiveness; and with uncharacterised molecular pathology relating to non-specific therapeutic modalities. Given the importance of oxidative stress in chronic diseases and carcinogenesis, and the lacunae in literature regarding its role in gallbladder diseases, this study aimed to study the involvement of oxidative stress and deregulation in the base excision repair (BER) pathway in the pathogenesis of gallbladder diseases including GBC. This study involved patients from the North-East Indian population, where the numbers of reported cases are increasing rapidly and alarmingly. Oxidative stress, based on 8-OH-dG levels, was found to be significantly higher in gallbladder anomalies (cholelithiasis [CL] and cholecystitis [CS]) and GBC at the plasma and DNA level, and was associated with GBC severity. The expressions of key BER pathway genes were downregulated in gallbladder anomalies and GBC compared to controls, and in GBC compared to both non-neoplastic controls and gallbladder anomalies. Expression of XRCC1 and hOGG1 was significantly associated with both susceptibility and severity of GBC. The XRCC1 codon280 polymorphism was associated with disease susceptibility; and significantly higher oxidative stress was observed in hOGG1 genotypic variants. The genomes of GBC patients were found to be more hypermethylated compared to controls, with the promoters of XRCC1 and hOGG1 being hypermethylated and, therefore, being silenced. This study underlined the prognostic significance of the oxidative stress marker 8-OH-dG and BER pathway genes, especially hOGG1 and XRCC1, in gallbladder anomalies and GBC, as well as stated their potential for therapeutic targeting.
