Vitamin D receptor gene polymorphisms association with the risk of sepsis and mortality.

Association of vitamin D receptor (VDR) gene polymorphisms with sepsis risk and mortality was studied. VDR FokI CC genotype was associated with increased sepsis risk (OR = 13.396, p = .000009) compared to the TT genotype. Results suggest possible role of VDR FokI (rs2228570) as a molecular biomarker of increased sepsis risk.

HMGB1 genetic polymorphisms in oral squamous cell carcinoma and oral lichen planus patients.

OBJECTIVES: This study examined the single nucleotide polymorphisms (SNPs) in high-mobility group box 1 (HMGB1) gene in patients with oral squamous cell carcinoma (OSCC) and oral lichen planus (OLP). MATERIALS AND METHODS: The study was conducted on 93 patients with OSCC, 53 patients with OLP, and 100 controls, all Caucasians of the same ethnicity, matched by age. HMGB1 genotypes for 4 SNPs, 2262G/A (rs1045411), 1177G/C (rs3742305), 3814C/G (rs2249825), and rs4540927, were assessed using TaqMan SNP Genotyping Assays, Applied Biosystems. RESULTS: The HMGB1 1177GG genotype was associated with lymph-node metastasis and tumor stage in OSCCs (P = 0.016 and P = 0.030, respectively). Genotype 1177GG resulted in poorer recurrence-free survival (RFS), P = 0.000. The 1177G/C polymorphism was an independent predictor of RFS compared to GG genotype, P = 0.001. The three polymorphisms were in linkage disequilibrium (LD). The AGC and GGC haplotypes were associated with an increased oral cancer risk, determined over the haplotype odds ratios (HOR = 13.316, P = 0.015, and HOR = 5.769, P = 0.029, respectively). The AGC haplotype was related to erosive OLP progression to OSCC (HOR = 12.179, P = 0.001). CONCLUSIONS: HMGB1 polymorphism 1177G/C could be associated with tumor progression and recurrence-free survival in patients with OSCC. The haplotypes of HMGB1 gene might be associated with susceptibility to OSCC and OLP progression to OSCC.

Association of TLR2, TLR3, TLR4 and CD14 genes polymorphisms with oral cancer risk and survival.

OBJECTIVES: The aim of this study is to investigate association between polymorphisms in TLR2, TLR3, TLR4 and CD14 genes or their haplotypes with oral squamous cell carcinomas (OSCC) risk and survival. METHODS: The study was conducted on 93 OSCC patients and 104 cancer-free controls. Polymorphisms were genotyped by real-time PCR or PCR-RFLP method. RESULTS: Significant increase in oral cancer risk was observed in individuals with mutated genotype of TLR3 rs3775291 polymorphism (OR = 1.096, P = 0.036) compared to wild-type. The heterozygous and mutated genotype of TLR3 rs5743312 polymorphism had worse survival in group of patients with stage III tumours (P = 0.043). Multivariate Cox regression analysis revealed that TLR3 rs5743312 polymorphism could be considered as prognostic marker in advanced III stage OSCC (HR = 2.456, P = 0.007), but not independently of nodal status. TLR3 rs3775291 and rs5743312 polymorphisms were in strong linkage disequilibrium. Haplotype TG was associated with worse prognosis in OSCC patients in comparison with common CG haplotype (HR = 1.717, P = 0.042). Interaction among polymorphisms in TLR2, TLR3 and CD14 genes was observed (P = 0.010). CONCLUSIONS: TLR3 rs5743312 polymorphism could be considered as potential predictor of worse overall survival in advanced oral cancer, but not independently of nodal status. Haplotypes in TLR3 gene might be associated with poor prognosis in OSCC patients.

Hypermethylation of RUNX3 but not WIF1 gene and its association with stage and nodal status of tongue cancers.

OBJECTIVES: Recent studies indicate various molecular abnormalities in oral squamous cell carcinomas (OSCC), including DNA methylation of tumor-associated genes. Although promoter hypermethylation of Wnt pathway antagonists RUNX3 (Runt-related transcription factor 3) and Wnt inhibitory factor 1 (WIF1) has been identified as a common event in a number of carcinomas, methylation status and the role of RUNX3 as a possible tumor suppressor in oral and head and neck cancer are yet controversial. The aim of our study is to determine the occurrence of RUNX3 and WIF1 genes hypermethylation and correlation with tumor and host-related factors and prognosis in tongue carcinomas. MATERIAL AND METHODS: In 76 patients with tongue carcinoma, RUNX3 and WIF1 genes promoter hypermethylation analysis was assessed by nested methylation-specific PCR method. RESULTS: Hypermethylation of WIF1 and RUNX3 genes promoters was observed in 35% and 25% of carcinomas, respectively. RUNX3 gene promoter hypermethylation was significantly associated with lymph node involvement (P = 0.013) and tumor stage (P = 0.006), but not with the overall survival. Occurrence of RUNX3 and WIF1 genes comethylation was associated with nodal status (P = 0.058) and tumor stage (P = 0.055). CONCLUSIONS: Our findings indicate that RUNX3 and WIF1 are frequently aberrantly methylated and that RUNX3 promoter methylation could be considered as a potential prognostic marker in tongue carcinoma.

Towards targeted epigenetic therapy of cancer.

Increasing number of publications in the last 10 years implicated that cancer development depends, except genetic alterations, also on inheritable gene expression patterns that are not bound to DNA sequence alterations. These epigenetic mechanisms manifest mostly through changes in chromatin packing and in localized gene promoter changes that influence the transcription of the genes involved in carcinogenesis. These changes are mitoticaly inheritable and potentially reversible, providing large possibilities of epigenetic therapy of cancer. So far this therapy lacks specificity of targeting certain genes. Instead, epigenetic therapy attempts either to reactivate or to silence genes that are important for the cancer progress. Epigenetic therapy of cancer is based mostly on the usage of inhibitors of DNA methyltransferases (DNMTs), histone deacetylase (HDAC) inhibitors and anti-micro-RNA therapy. Developments that involve integration of the latest technological advances, such as whole genome microarray expression profiling, help identify mechanisms of action of epigenetic drugs, leading to development of second generation of epi-drugs which would have greater specificity and efficacy. The obtained results are promising, leaving great possibilities for improvement of cancer therapy.

Interaction between the MTHFR C677T polymorphism and alcohol--impact on oral cancer risk and multiple DNA methylation of tumor-related genes.

Several studies have reported Oral Squamous Cell Carcinoma (OSCC) association with etiological factors, such as smoking and alcohol. The aim of the present study was to establish whether the methylenetetrahydrofolate reductase (MTHFR) C677T genotype and a high alcohol intake, solely or in interaction, have an impact on the oral cancer risk, DNA methylation, or multiple methylation of tumor-related genes. MTHFR C677T genetic polymorphism was determined by the PCR/RFLP method, and DNA methylation was assessed by nested methylation-specific PCR. The risk for multiple methylation was significantly increased in heavy-drinking patients with the TT genotype, compared with CC and CT patients (OR = 10.873; 95% CI, 1.134-104.24). Multiple methylation was significantly associated with tumor stage (p = 0.018), and showed a trend of association with the presence of nodal metastases (p = 0.058). A significant association was found between TT genotype and methylation status of the RASSF1A gene in OSCC patients (p = 0.012). Heavy-drinking individuals with the TT genotype showed increased oral cancer risk compared with the CC genotype (OR = 3.601; 95% CI, 1.036-12.513), and compared with the CC and CT genotypes (OR = 4.288; 95% CI, 1.325-13.877). Our study suggested gene-environment interactions between high alcohol intake and the MTHFR 677TT genotype for elevated oral cancer risk, with a significant impact on multiple methylation of cancer-related genes.