We examined the influence of MLH1 c.293G>A, MSH2 c.211 1 9C>G, MSH3 c.3133G>A and EXO1 c.1765G>A polymorphisms, involved in DNA mismatch repair (MMR), on head and neck (HN) squamous cell carcinoma (SCC) risk and prognosis. Aiming to identify genotypes, DNA from 450 HNSCC patients and 450 controls was analyzed by PCR-RFLP or real time PCR. MSH2 GG plus MSH3 GG (31.7% vs. 18.7%, p 5 0.003) genotypes were higher in laryngeal SCC (LSCC) patients than in controls. Carriers of the respective combined genotype were under a 3.69 (95% CI: 1.54-8.81)-fold increased risk of LSCC. Interactions of tobacco and tobacco plus all the above-mentioned polymorphisms on HNSCC and LSCC risk were also evident in study (p 5 0.001). At 60 months of follow-up, relapse-free survival (RFS) was shorter in patients with EXO1 GG genotype (54.8% vs. 61.1%, p 5 0.03) and overall survival (OS) was shorter in patients with MSH3 GG genotype (42.8% vs. 52.5%, p 5 0.02) compared to those with other genotypes, respectively. After multivariate Cox analysis, patients with EXO1 GG and MSH3 GG genotypes had worst RFS (HR: 1.50, 95% CI: 1.03-2.20, p 5 0.03) and OS (HR: 1.59, 95% CI: 1.19-2.13, P 5 0.002) than those with the remaining genotypes, respectively. Our data present, for the first time, evidence that inherited MLH1 c.-93G>A, MSH2 c.211 1 9C>G, MSH3 c.3133G>A, and EXO1 c.1765G>A abnormalities of DNA MMR pathway are important determinants of HNSCC, particularly among smokers, and predictors of patient outcomes.Exposure to tobacco smoke is considered the most important etiological factor in the development of head and neck (HN) squamous cell carcinoma (SCC). 1 Carcinogens present in tobacco, such as benzo(a)pyrene, could bind to DNA from epithelial cells of the upper aerodigestive tract, forming covalent DNA adducts and inducing replication errors, which can be associated with HNSCC origin. 2,3 However, not all smokers develop HNSCC suggesting that individual genetic background may also participate in the tumor etiology. 4 DNA mismatch repair (MMR) pathway contributes to maintain genetic stability. 5 MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 3 (MSH3) and exonuclease 1 (EXO1) proteins play important roles in this process, recognizing DNA damage induced by carcinogens from tobacco, and enabling its excision. 6,7 The ability to promote DNA repair of damaged cells is variable in humans, since several DNA repair proteins, such as MLH1, MSH2, MSH3 and EXO1, are encoded by polymorphic genes. 8,9 Variant alleles of MLH1 c.293G>A, 10 MSH2 c.211 1 9C>G 11 and EXO1 c.1765G>A 12 single nucleotide polymorphisms (SNPs) reduce the expression of encoded proteins when compared with the respective wild-type alleles, and have decrease in DNA repair as consequence. The role of MSH3 c.3133G>A in protein activity is not totally clarified. 13-15 GG genotype of MLH1 c.293G>A and variant allele A of EXO1 c.1765G>A SNP were associated with increased risk of oral SCC only in India 16 and Taiwan, 17 respectively. To the best of our knowledge, the roles of the ...

Our data present, for the first time, evidence that inherited OGG1 c.977C>G; XRCC1 c.-77T>C, c.580C>T, c.839G>A and c.1196G>A abnormalities of DNA BER pathway are important determinants of OPSCC and predictors of patient outcomes.

Our data suggest that inherited abnormalities of XPC, XPF, TP53 and GSTP1 pathways of the DNA repair, apoptosis and metabolism of reactive oxygen species are important determinants of CM in individuals from south-eastern Brazil.

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We conducted a two-stage association study on patients with oropharynx (OP) squamous cell carcinoma (SCC) and healthy controls to identify single nucleotide variants (SNVs) located at the microRNA (miR)-binding sites of carcinogenesis genes associated with risk and prognosis of the disease. In stage 1, 49 patients and 49 controls were analyzed using Genome-Wide Human SNV Arrays to identify variants in the 3′-untranslated region (3′-UTR) of carcinogenesis-related genes, and one SNV was selected for data validation in stage 2 by TaqMan assays in 250 OPSCC patients and 250 controls. The ERP29 c.*293A > G (rs7114) SNV located at miR-4421 binding site was selected for data validation among 46 SNVs. The ERp29 and miR-4421 levels were evaluated by quantitative-PCR and Western blotting. Interaction between miR-4421 with 3′-UTR of ERP29 was evaluated by luciferase reporter assay. Event-free survival (EFS) was calculated by Kaplan–Meier and Cox methods. ERP29 GG variant genotype was more common in OPSCC patients than in controls (6.4% vs 3.6%, p = 0.02; odds ratio: 5.67; 95% confidence interval (CI) 1.27–25.26). Shorter EFS were seen in the base of tongue (BT) SCC patients with GG genotype (0.0% vs 36.2%, p = 0.01; hazard ratio: 2.31; 95% CI: 1.03–5.15). Individuals with ERP29 AG or GG genotypes featured lower levels of ERP29 mRNA (p = 0.005), ERp29 protein (p < 0.001) and higher levels of miR-4421 (p = 0.02). The miR-4421 showed more efficient binding with 3′-UTR of the variant G allele when compared with wild-type allele A (p = 0.001). Our data suggest that ERP29 rs7114 SNV may alter the risk and prognosis of OPSCC due to variation in the ERp29 production possibly modulated by miR-4421.

This study aimed to evaluate whether PD1.1 (c.-606G>A), PD1 (c.627 + 252C>T), PD1.5 (c.804C>T), and PD1.9 (c.644C>T) single nucleotide polymorphisms of PDCD1 gene influence the risk, clinicopathological aspects, and survival of cutaneous melanoma (CM). Individuals with phototype I or II and PD1 CC genotype were under 5.89-fold increased risk of developing CM. PD1.5 TT genotype increased PDCD1 expression (2.49 versus 1.28 arbitrary units, p = .03) and PD1.5 CT or TT genotype and allele T increased PD1 expression in TCD4 lymphocytes (16.6 versus 12.5%, p = .01; 17.0 versus 13.1%, p = .006). At 60 months of follow-up, short recurrence-free survival was seen in patients with PD1.1 AA genotype (33.3 versus 71.8%, p = .03). Patients with PD1.1 AA and PD1.5 CC genotype had 4.21 and 2.62 more chances of presenting relapse and evolving death by disease in Cox analyses, respectively. Our data provide preliminary evidence that abnormalities in regulation of T lymphocyte alter CM risk, clinical aspects, and prognosis.

Our data present, for the first time, preliminary evidence that VEGF C936T alone or combined with the COL18A1 D104N polymorphism of AG constitutes an important inherited EOC determinant.

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