BER genes expression in oral and pre-oral cancer: Combinatorial approach to propose potential biomarker.

OBJECTIVE: DNA repair genes and their variants have been found to alter the risk of oral cancer. METHOD: The level of expression of XRCC3, NBS1, and OGG1 genes among 20 cases of oral cancer, 6 pre-oral cancer, and 50 healthy control subjects was measured with RT-PCR. All the subjects were also genotyped for XRCC3 rs861539 C>T, NBS1 rs1805794 C>G, and OGG1 rs1052133 C>G polymorphisms by the PCR-RFLP method; their genotypes were correlated with their level of expression. Further, a localized fold structure analysis of the mRNA sequence surrounding the studied SNPs was performed with RNAfold. RESULTS: Results showed increased expression of XRCC3, NBS1, and OGG1 transcripts among oral cancer (4.49 fold, 3.45 fold, and 3.27 fold) as well as pre-oral cancer (3.04 fold, 5.32 fold, and 1.74 fold) as compared to control subjects. The transcript level of OGG1 was found to be significantly increased (6.68 fold, p-value 0.009) with the GG genotype compared to the CC genotype. The C>T polymorphism of XRCC3 and the C>G polymorphism of OGG1 result in an apparent change in its mRNA secondary structure. Folding energy with the C allele for XRCC3 C>T polymorphism was lower than that of the T allele (MFE C vs T: -50.20 kcal/mol vs -48.70 kcal/mol). In the case of OGG1 C>G polymorphism MFE for the C allele was higher (-23.30 kcal/mole) than with the G allele (-24.80 kcal/mol). CONCLUSION: Our results showed elevated levels of XRCC3, NBS1, and OGG1 both in oral cancer and pre-oral cancer conditions, which indicates their role as prospective biomarkers of oral cancer and pre-cancerous lesions. SNPs in these genes alter their level of expression, possibly by altering the secondary structure of their transcript. However, due to the small sample size our study can only provide a suggestive conclusion and warned future study with large sample size to verify our findings.

XRCC3 and NBS1 gene polymorphisms modulate the risk of pre-oral cancer and oral cancer in the North Indian population.

Background: Oral cancer is alarming disease in the developing countries like India. DNA repair capacity may affect by genetic polymorphisms in DNA repair genes and thus may cause to cancer. XRCC3 involves in homologous recombination repair pathway and repair DNA damage and crosslinks while, NBS1 participate in repair of double strand DNA break and starts the cell-cycle checkpoint signaling. Aims and Objectives: This study was to conducted to find the association of XRCC3, NBS1 polymorphisms with oral disease. Results: TT genotype of XRCC3 was associated with high risk of precancerous lesions and oral cancerous lesions (P value=0.0001, OR=9.68, 95% CI=2.82-33.21; and P value=0.0001, OR=13.10, 95% CI=3.38-50.73 respectively). We did not observe any interactions of XRCC3 polymorphism with demographic parameters in influencing the risk of oral diseases. Variant allele genotypes (CG, GG) of NBS1 (C>G) polymorphism showed protective association with Oral submucous fibrosis (OSMF), lichen planus as well as oral cancer (OR=0.31, OR=0.01; OR=0.39, OR=0.03; OR=0.43, OR=0.31 respectively). Particularly, tobacco chewer with CG & GG genotypes were at decrease risk of oral diseases (P value=0.02, OR=0.32, 95% CI=0.12-0.80). Compared to CC/CC combined genotype CG/CC, CG/CT, GG/CC and CG/CT genotypes decreased the risk of oral disease (OR=0.05, 0.47, 0.26 & 0.14 respectively). Conclusion: This study concludes that SNP in XRCC3, NBS1 affects susceptibility to oral disease.

The Taq 1 polymorphism of Vitamin D receptor gene is associated with oral cancer and preoral cancer in North Indian population.

Background: Oral cancer is known as one of the most common cancers, with a poor prognosis, related to delayed clinical diagnosis, either due to the lack of particular biomarkers related to the disease or costly therapeutic alternatives. Aims and Objectives: In this study association of single nucleotide polymorphism (Taq1, T>C) in Vitamin D receptor gene with oral cancer and pre oral cancer was studied. Materials and Methods: Total 230 patients of precancerous oral lesions (Leukoplakia 70, Oral Sub mucous fibrosis 90, Lichen Planus 70), 72 oral cancer patients and 300 healthy control subjects were genotyped by PCR-RFLP methods. Chi-square test was used for calculation of genotype and allele frequencies. Results: Mutant genotype CC as well as C allele were found to significantly decrease the risk of oral disease (P value=0.04, OR=0.60 and P value=0.02, OR=0.75 respectively). In particular, compared to non smokers, smokers with TC & CC genotypes were at decrease risk of oral diseases (P value=0.0001, OR=0.04). The mutant allele genotype CC as well as the mutant allele C showed protective association with leukoplakia (P value=0.01, OR=0.39 & P value=0.009, OR=0.59 respectively). However, individual with CC genotype had developed high cell differentiated grade at diagnosis (OR= 3.78, P value= 0.008). Conclusions: This study concludes that VDR (Taq1) polymorphism is associated with oral cancer and pre oral cancer susceptibility in North Indian population.

Genetic polymorphism of tumor necrosis factor alpha (TNF-α) and tumor necrosis factor beta (TNF-ß) genes and risk of oral pre-cancer and cancer in North Indian population.

OBJECTIVE: There are inconclusive data connecting single-nucleotide polymorphisms (SNPs) of TNF-α (rs361525) and TNF-ß (rs909253) to potential malignant oral disorder (PMOD) such as lichen planus and oral fibrosis. Here, we have investigated the risk of oral squamous cell carcinoma as well as oral pre-cancerous lesions in North Indian population with the polymorphism of the TNFα/ ß genes. MATERIAL AND METHODS: A total 500 patients with oral pre-cancer and OSCC and 500 healthy volunteers were genotypes for the TNF-α (-238) G/A (rs361525) and TNF-ß (252) A/G (rs909253) gene polymorphism. Genotypes were identified by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). Genotype frequencies were evaluated by Chi-square test. RESULTS: Compared to the GG genotype, the GA genotype of TNF-α (G238A) polymorphism (rs361525) has been found to significantly increase the risk of oral disease (OR = 1.99) and especially the risk of lichen planus and OSCC (OR = 2.805 and 5.790, respectively). Similarly, the risk of oral disease was also more in the heterozygote (AG) than the common allele homozygote (AA) of TNF-ß (A252G) polymorphism (rs909253) (OR = 1.483). CONCLUSION: We conclude that the SNPs rs361525 and rs909253 were significantly associated with oral pre-cancer and OSCC.

Relation of vitamin D to COVID-19.

The coronavirus pandemic has lasted for more than a year now and still remains the leading cause of concern, worldwide. The causal agent; SARS- CoV-2, leads to the development of respiratory distress in the lower respiratory tract, sometimes leading to fatalities. Keeping in mind the discovery of mutant strains across the world, as well as the delay in vaccinations across vast populations, most people speculate boosting their immune systems as a preventive and precautionary measure. One of the most commonly observed conditions that hamper immunity; Vitamin D deficiency has been linked to the onset and the alteration of course of the disease in patients and is also being explored as a potential drug supplement. These surmises make it essential to study deep into the speculations. This review aims to overview the possible correlations between Vitamin D and COVID-19.

Smoking and XPC Gene Polymorphism Interact to Modulate the Risk of Oral Cancer.

PURPOSE: Oral cancer is the most common cancer among the Indian men and the second most common cancer among the Indian women. Such high incidence of oral cancer in India is due to consumption of tobacco in different form including smoking of cigarette. Smoke of tobacco contains different carcinogens which causes DNA damage. Such DNA damage if remain unrepaired due to faulty DNA repair system can cause mutation and eventual development of cancer. METHODOLOGY: In the present study, we aimed to check the role of smoking as well as interaction of smoking and XPC polymorphism in risk modulation of oral cancer. Total of 372 subjects including 300 healthy controls and 72 patients of oral cancers been genotyped for the XPC PAT D/I, A/C and C/T polymorphisms with PCR based or PCR-RFLP based method. Genotype frequency was analyzed by chi-square test and strength of associations by odds ratio with 95% confidence intervals. RESULTS: The present study showed that compared to nonsmokers, smokers are at five times higher risk to develop oral cancer (p value= 0.001, OR= 5.03, 95% CI 2.91-8.69) and three times higher risk to develop node-positive (p value= 0.01, OR= 3.66, 95% CI 1.34-9.95) oral cancer. It has also been observed that individuals who were smokers and carrier of variant allele genotypes (AC and CC) for XPC A/C polymorphism were at threefold higher risk (p value= 0.01, OR=2.97, 95% CI 1.29-6.86) to develop oral cancer compared to individual who were smokers but do not carry the C allele (AA genotype). This observation indicates that C allele of XPC A/C polymorphism interacts with smoking and significantly increases the risk of oral cancer. CONCLUSION: This study demonstrates a possible role of smoking and gene-smoking interaction in risk enhancement of oral cancer.

Notch signaling in oral pre-cancer and oral cancer.

Notch signaling involves cell to cell contact. It is an ancient signaling mechanism that is conserved throughout the animal kingdom. The basic function of Notch signaling is to decide cell fate and execute asymmetrical division. Notch signaling is indispensable for embryo growth. Aberrant Notch signaling involves in cancer progression by altering cell proliferation rate, tumor micro-environment, stem cell activities. The role of Notch signaling in cancer progression is context-dependent. In breast cancer and T cell lymphoma Notch signaling is highly active, whereas in squamous cell carcinoma (SCC) as oral and skin cancer, the signaling is suppressed. It is believed that in SCC, Notch-mediated tumor growth is due to the cell non-autonomous function. Oral cancer is the 6th most risky cancer worldwide. In many patients, oral cancer is preceded by pre-cancer conditions. In this review, we have summarized the research knowledge related to the role of Notch signaling in oral cancer and pre-cancer conditions and the therapeutic options available targeting different components of Notch pathways.

Alteration of the risk of pre-oral cancer and cancer in North Indian population by NAT1 and NAT2 polymorphisms genotypes and haplotypes.

PURPOSE: The risk of oral cancer is strongly related to consumption of tobacco, smoking and drinking alcohol. N-acetyl transferases 1,2 are phase II metabolic enzymes, metabolize aryl and heterocyclic amines which are present in tobacco. NAT2 slows acetylator phenotype and the genotype is related to reduced ability to detoxify these xenobiotic that are carcinogenic to tissues. The aim of our study to determine the risk of oral cancer as well as oral precancerous lesions in North Indian population with polymorphisms in these two N-acetyl transferases 1,2 genes. MATERIALS AND METHODS: A total of 250 patients with pre oral cancer, oral cancer and 250 healthy volunteers were genotypes for the NAT1 and NAT2 gene polymorphisms. Genotypes were identified by PCR and RFLP. Genotype frequencies were evaluated by Chi-square test and risk of disease was estimated by Odds ratio (OR) with 95% confidence interval. RESULT: Our results showed that individuals with CT and TT genotypes of NAT1 C > T polymorphism were significantly lower risk of oral diseases (p value = 0.02, OR = 0.60 and p value = 0.04, OR = 0.58, respectively). For NAT2 C > T polymorphism, the TT genotype significantly increased the risk of OSMF (Oral Sub mucous Fibrosis) and Leukoplakia (p value = 0.001, OR = 4.16; p value = 0.002, OR = 4.38, respectively). In contrary, the CC genotype for NAT2 T > C polymorphism increased the risk of OSMF (p value = 0.01, OR = 3.00, 95% CI = 1.31-6.86). CONCLUSION: Our study concludes that the NAT1 polymorphism shows protective association with oral diseases and NAT2 polymorphism and haplotypes also influence the susceptibility to oral diseases in North Indian population subjects.

Risk Modulation of Oral Pre Cancer and Cancer with Polymorphisms in XPD and XPG Genes in North Indian Population.

Background: Environmental carcinogens cause DNA damages which if not repaired properly, may increase the risk of cancer. The Xerodermapigmentosum group D (XPD) and group G (XPG) genes are essential genes for DNA repair and alteration in DNA repair causes cancer. The present study aimed to evaluate the relationship between XPD and XPG polymorphisms and risk of oral pre cancer and cancer. Methods: Present study genotyped 302 samples of oral diseases and 300 controls for XPD (A/C) and XPG (G/C) polymorphisms with PCR-RFLP method. Results: Our result showed that compared to AA genotype frequency of AC and CC genotype for XPD(A/C) polymorphism were significantly lower among cases than in control and are associated with decreased risk of oral diseases (OR= 0.621 and 0.603 respectively). In contrast with reference to GG genotype the frequency of CC genotype of XPG (G/C) was significantly higher in case than in control population (p value=0.004) and found to increase the risk of oral diseases (OR= 2.077). Particularly C allele for XPD A/C polymorphism was found to be associated with decreased risk of Lichen planus and increased risk of ( OR = 0.470 and 1.541 respectively) oral cancer. While C allele of XPG G/C polymorphism significantly increased the risk of Oral Submucous Fibrosis and Leukoplakia (OR= 1.879 and 1.837 respectively) but not of Lichen planus and oral cancer. In combined genotype analysis from the aforesaid polymorphisms presence of C allele for XPD (A/C) polymorphisms were found to decrease the risk of oral diseases. However, the same C allele was observed to increase the chance of having high stage disease (OR= 5.71) with nodal involvement (OR= 6.78) once the cancer been initiated. Conclusion: This work shows association of XPD (A/C), XPG (G/C) polymorphisms with the development of pre oral cancer as well as oral cancer and its clinical courses.

Alteration of the Risk of Oral Pre-Cancer and Cancer in North India Population by CYP1A1 Polymorphism Genotypes and Haplotype

Background: The aim of this study was to evaluate any association between CYP1A1 (T6235C and C4887A, A4889G) gene polymorphisms and the risk of oral pre-cancer and cancer. Methods: In the present study, 250 patients with oral pre-cancer and/or cancer and 250 healthy controls were genotyped for CYP1A1 T6235C, C4887A and A4889G polymorphisms by the PCR-RFLP method. Results: None of the CYP1A1 polymorphisms were associated with the risk of either oral cancer or pre cancer. Nor were any links with clinical parameters of oral cancer found. However, among the consumers of areca nut/pan masala the TC, CA and AG genotypes respectively for the CYP1A1 T6235C,C4887Aand A4889G polymorphisms were significantly more frequent in controls compared to cases (p values for cases vs. controls of 0.0032, 0.0019 and 0.0009, respectively). Similarly, compared to the haplotype TCA, TAG constituted by CYP1A1 T6235C and C4887A and A4889G was more common in controls (6.88%) than in cases (4.07%). Conclusion: Our results suggest that genotypes regarding CYP1A1 polymorphisms may modulate the risk of oral cancer and pre-cancer among the areca nut/pan masala consumers. The haplotype may also exert an influence in our north Indian population.

Association of Interleukin-10 (A1082G) gene polymorphism with Oral squamous cell carcinoma in north Indian population.

The functional polymorphism A1082G in the gene (IL10) for interleukin-10 associated with risk of oral squamous cell carcinoma (OSCC). The present case-control study was to evaluate the possible association between IL10 A1082G gene and OSCC in north Indian population. Analysis of IL10 A1082G genotype in 232 OSCC cases and 221 healthy controls of comparable age, gender, smokers, tobacco chewing and alcohol consumption. IL10 A1082G status in cases and controls were evaluated by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The frequencies of IL10 A1082G polymorphism AA, AG, GG genotypes were 29.74, 68.10 and 2.15% in OSCC cases and 57.46, 42.08 and 0.45% in healthy controls. The average frequency of G mutant allele was 36.20% in OSCC cases compared with 21.50% among the controls and this allele was associated with increased risk for OSCC cases. Heterozygous AG genotype was found statistically significant in OSCC cases than in controls (OR = 1.6, 95% CI = 1.1-2.2, P = 0.003), whereas homozygous mutant GG genotype was not found significant (OR = 4.7, 95% CI = 0.55-41.1, P = 0.2). Moreover, we found that G allele was significant in OSCC cases of tobacco chewing. The frequency of IL10 A1082G polymorphism G allele and AG genotype is associated with OSCC cases as compared with controls; this may be due to smoking and tobacco chewing. Our findings showed that in IL10 A1082G gene polymorphism AG genotype and G allele may participate in the progression of OSCC.