Risk Of Squamous Cell Carcinoma Of The Head And Neck Research Articles

Genetic variants in CYP2B6 and HSD17B12 associated with risk of squamous cell carcinoma of the head and neck.

Polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines (TSNA) metabolism-related genes play an important role in the development of cancers. We assessed the associations of genetic variants in genes involved in the metabolism of PAHs and TSNA with riskof squamous cell carcinoma of the head and neck (SCCHN) in European populations using two published genome-wide association study datasets. In the single-locus analysis, we identified two SNPs (rs145533669 and rs35246205) in CYP2B6 to be associated with risk of SCCHN (P=1.57 × 10-4 and .004, respectively), two SNPs (EPHX1 rs117522494 and CYP2B6 rs145533669) to be associated with risk of oropharyngeal cancer (P=.001 and .004, respectively), and one SNP (rs4359199 in HSD17B12) to be associated with risk of oral cancer (P=.006). A significant interaction effect was found between rs4359199 and drinking status on risks of SCCHN and oropharyngeal cancer (P < .05). eQTL and sQTL analyzes revealed that two SNPs (CYP2B6 rs35246205 and HSD17B12 rs4359199) were correlated with alternative splicing or mRNA expression levels of the corresponding genes in liver cells (P < .05 for both). In silico functional annotation suggested that these two SNPs may regulate mRNA expression by affecting the binding of transcription factors. Results from phenome-wide association studies presented significant associations between these genes and risks of other cancers, smoking behavior and alcohol dependence (P < .05). Thus, our study provided some insight into the underlying genetic mechanism of head and neck cancer, which warrants future functional validation.

Mouthwash Use and the Risk of Oral, Pharyngeal, and Laryngeal Cancer. A Meta-Analysis.

Objective: The main aim of this study was to test whether the use of mouthwash is associated with subtypes of squamous cell carcinoma of the head and neck (SCCHN) and to test the potential risk of SCCHN depending on the mouthwash use duration, frequency, or alcoholic content. Materials and methods: We performed a meta-analysis using Web of Science and Scopus databases to detect the risk change associated with mouthwash use depending on the alcohol content, duration and frequency of use, and anatomical location. We used a random-effects model with the Sidik–Jonkman estimator for effect size model measures. Results: We included 17 studies in the meta-analysis containing 17,085 cases and 20,032 controls. The risk difference for SCCHN between mouthwash users and non-users was minimal, with a value of −0.02 [−0.05, 0.01]. Alcoholic mouthwash use was associated with a minimal decrease in risk (of −0.01 [−0.07, 0.05]). Frequent usage of mouthwash was associated with a statistically significant risk increase for SCCHN but the risk increase was marginal (0.04, [0.01, 0.06]). Conclusions: Overall, our study failed to show a statistically significant correlation between mouthwash use and the risk of SCCHN. The only statistically significant correlation that we could identify was between frequent usage and SCCHN, potentially caused by prolonged contact between some constituents of mouthwash (possibly alcohol) and the oral epithelium.

A Genome-Wide Association Study Identifies Two Novel Susceptible Regions for Squamous Cell Carcinoma of the Head and Neck.

To identify genetic variants for risk of squamous cell carcinoma of the head and neck (SCCHN), we conducted a two-phase genome-wide association study consisting of 7,858,089 SNPs in 2,171 cases and 4,493 controls of non-Hispanic white, of which, 434,839 typed and 7,423,250 imputed SNPs were used as the discovery. SNPs with P < 1 × 10-3 were further validated in the OncoArray study of oral and pharynx cancer (5,205 cases and 3,232 controls of European ancestry) from databases of Genotypes and Phenotypes. Meta-analysis of the discovery and replication studies identified one novel locus 6p22.1 (P = 2.96 × 10-9 for the leading rs259919) and two cancer susceptibility loci 6p21.32 (rs3135001, HLA-DQB1) and 6p21.33 (rs1265081, CCHCR1) associated with SCCHN risk. Further stratification by tumor site revealed four known cancer loci (5p15.33, 6p21.32, 6p21.33, and 2p23.1) associated with oral cavity cancer risk and oropharyngeal cancer risk, respectively. In addition, one novel locus 18q22.2 (P = 2.54 × 10-9 for the leading SNP rs142021700) was identified for hypopharynx and larynx cancer risk. For SNPs in those reported or novel loci, we also performed functional annotations by bioinformatics prediction and expression quantitative trait loci analysis. Collectively, our identification of four reported loci (2p23.1, 5p15.33, 6p21.32, and 6p21.33) and two novel loci (6p22.1 and 18q22.2) for SCCHN risk highlight the importance of human leukocyte antigen loci for oropharyngeal cancer risk, suggesting that immunologic mechanisms are implicated in the etiology of this subset of SCCHN. SIGNIFICANCE: Two novel risk loci for SCCHN in non-Hispanic white individuals highlight the importance of immunologic mechanism in the disease etiology.

Endothelial nitric oxide synthase gene polymorphisms modulate the risk of squamous cell carcinoma of head and neck in north Indian population

BackgroundNitric oxide (NO) is found to have both tumour promoting and inhibiting properties. Nitric oxide (NO) is synthesized by three isoforms of nitric oxide synthase (NOS) enzymes and endothelial NOS (eNOS) is one of them. Polymorphisms in eNOS 894G > T (rs1799983) and eNOS intron 4a/b geneS could modulate the risk for developing SCCHN by regulating the level of nitric oxide. ObjectiveIn this study we evaluated the association of eNOS 894G > T (rs1799983) and intron 4a/b polymorphisms with the plasma nitrite level and the risk of Squamous cell carcinoma of the head and neck (SCCHN). Materials and methodsA total of 352 subjects were genotyped for the above said polymorphisms. Genotypes were correlated with plasma nitrite level of study subjects. ResultsCompared to GG homozygote of 894G > T polymorphism a significantly increased risk of SCCHN was observed with TT homozygote (p = 0.03, OR = 2.72, 95% CI 1.14–6.50). In comparison to carrier of ‘b’ allele, ‘a’ allele carrier for intron 4a/b polymorphism were at increased risk to develop high stage diseases (p = 0.00, OR 8.67 and 95% CI 3.76–19.99). The haplotype bT constituted from 894G > T and intron 4a/b polymorphisms also showed association with increased susceptibility for SCCHN (p = 0.038 OR = 1.66, 95% CI 1.03–2.63). Plasma nitrite level was significantly higher in cases compared to control (p = 0.047). The level of plasma nitrite was also higher in individuals with TT genotype compared to those with GG genotype (p = 0.012 in SCCHN cases and 0.088 in control).Conclusions: Our results suggest that eNOS 894G > T and intron 4a/b polymorphisms influence the risk of SCCHN and, eNOS 894G > T polymorphism modulate the risk of disease by modulating plasma nitrite level.

Associations Between Poor Oral Health and Risk of Squamous Cell Carcinoma of the Head and Neck: A Meta-Analysis of Observational Studies

Many epidemiologic studies have reported an association of poor oral health, especially periodontal disease (PD) and tooth loss, with the risk of squamous cell carcinoma of the head and neck (SCCHN). However, these studies have yielded inconsistent results. Therefore, the present study investigated whether poor oral health is an independent predictor of SCCHN through a meta-analysis of observational studies. The PubMed, EMBASE, and Cochrane Library databases were systematically searched for relevant observational studies of the association between oral health and risk of SCCHN conducted up to October 2017. The meta-analysis was conducted using STATA 12.0 (StataCorp, College Station, TX). A fixed- or random-effects model was applied to evaluate pooled risk estimates, and sensitivity and subgroup analyses were performed to identify sources of heterogeneity and pooled estimation. Publication bias was assessed using the Begg test, the Egger test, and funnel plots. Twenty-seven relevant observational studies were identified, consisting of 24 case-and-control studies, 2 prospective studies, and 1 cross-sectional study, with 26,750 participants. Notably, oral health correlated meaningfully with SCCHN (odds ratio [OR]=2.24; 95% confidence interval [CI], 1.77-2.82). In subgroup analyses, participants with PD (OR=2.52; 95% CI, 1.43-4.44) had a higher risk of developing SCCHN than those with tooth loss (OR=2.13; 95% CI, 1.63-2.78). The risk estimates exhibited substantial heterogeneity. Evidence of publication bias was limited. The results of this meta-analysis suggest that patients with tooth loss or PD might face a substantial and independent risk of SCCHN, even after adjusting for smoking and alcohol consumption. However, the pooled estimates from observational studies could not establish a causative relation among PD, tooth loss, and SCCHN. Additional investigations of this correlation are warranted.

Association between a miRNA-146a polymorphism and susceptibility to head and neck squamous cell carcinoma in Chinese patients: A meta-analysis of 8 case-control studies.

A closer association has been found between the microRNA-146a rs2910164 polymorphism and the risk of head and neck carcinoma in some molecular epidemiological studies. Recently two meta-analyses were performed to explore the relationship between miRNA-146a polymorphisms and the susceptibility of squamous cell carcinoma of the head and neck (SCCHN); however, they yielded conflicting results in susceptibility regarding ethnic variations. Hence, the present study was performed to explain the relationship between the miRNA-146a rs2910164 polymorphism and the risk of SCCHN development of Chinese patients. We retrieved databases and screened eligible papers up to March 10, 2017 and then we extracted the essential data. The subgroup analyses were also performed based on the tumor site, region, and genotyping means. Crude odds ratios (OR) at 95% confidence intervals (CI) were chosen to describe the strength of the association. As a result, 6 publications were included in our study which involved 8 independent case-control studies. A significant association was found between miR-146a rs2910164 polymorphisms and the risk of SCCHN in Chinese patients according to the overall data [CC+CG vs. GG: OR = 1.13; 95%CI = 1.00–1.29; CC vs. GG: OR = 1.19; 95%CI = 1.03–1.38]. According to the subgroup analysis based on tumor site, the risk of cancer was significantly increased among laryngeal cancer (dominant model: OR = 1.76, 95%CI = 1.26~2.46, P = 0.001; homozygote model: OR = 1.83, 95%CI = 1.25~2.67, P = 0.002) and nasopharyngeal carcinoma (homozygote model: OR = 1.41, 95%CI = 1.05~1.90, P = 0.022). In summary, variant alleles of miR-146a rs2910164 alleles may have an association with the increased risk of SCCHN in Chinese patients, and these associations differed based on tumor site. Further studies including a larger sample size will be necessary to clarify these results.

Apoptotic capacity and risk of squamous cell carcinoma of the head and neck

BackgroundTobacco smoke and alcohol drinking are the major risk factors for squamous cell carcinoma of the head and neck (SCCHN). Smoking and drinking cause DNA damage leading to apoptosis, and insufficient apoptotic capacity may favour development of cancer because of the dysfunction of removing damaged cells. In the present study, we investigated the association between camptothecin (CPT)-induced apoptotic capacity and risk of SCCHN in a North American population. MethodsIn a case–control study of 708 SCCHN patients and 685 matched cancer-free controls, we measured apoptotic capacity in cultured peripheral blood lymphocytes in response to in vitro exposure to CPT by using the flow cytometry–based method. ResultsWe found that the mean level of apoptotic capacity in the cases (45.9 ± 23.3%) was significantly lower than that in the controls (49.0 ± 23.1%) (P = 0.002). When we used the median level of apoptotic capacity in the controls as the cutoff value for calculating adjusted odds ratios, subjects with a reduced apoptotic capacity had an increased risk (adjusted odds ratio = 1.42, 95% confidence interval = 1.13–1.78, P = 0.002), especially for those who were age ≥57 (1.73, 1.25–2.38, 0.0009), men (1.76, 1.36–2.27, <0.0001) and ever drinkers (1.67, 1.27–2.21, 0.0003), and these variables significantly interacted with apoptotic capacity (Pinteraction = 0.015, 0.005 and 0.009, respectively). A further fitted prediction model suggested that the inclusion of apoptotic capacity significantly improved in the prediction of SCCHN risk. ConclusionIndividuals with a reduced CPT-induced apoptotic capacity may be at an increased risk of developing SCCHN, and apoptotic capacity may be a biomarker for susceptibility to SCCHN.

Reduced DNA double-strand break repair capacity and risk of squamous cell carcinoma of the head and neck--A case-control study.

Tobacco smoke and alcohol use play important roles in the etiology of squamous cell carcinoma of the head and neck (SCCHN). Smoking causes DNA damage, including double-strand DNA breaks (DSBs), that leads to carcinogenesis. To test the hypothesis that suboptimal DSB repair capacity is associated with risk of SCCHN, we applied a flow cytometry-based method to detect the DSB repair phenotype first in four EBV-immortalized human lymphoblastoid cell lines and then in human peripheral blood T-lymphocytes (PBTLs). With this blood-based laboratory assay, we conducted a pilot case-control study of 100 patients with newly diagnosed, previously untreated SCCHN and 124 cancer-free controls of non-Hispanic whites. We found that the mean DSB repair capacity level was significantly lower in cases (42.1%) than that in controls (54.4%) (P<0.001). When we used the median DSB repair capacity level in the controls as the cutoff value for calculating the odds ratios (ORs) with adjustment for age, sex, smoking and drinking status, the cases were more likely than the controls to have a reduced DSB repair capacity (adjusted OR=1.93; 95% confidence interval, CI=1.04-3.56, P=0.037), especially for those subjects who were ever drinkers (adjusted OR=2.73; 95% CI=1.17-6.35, P=0.020) and had oropharyngeal tumors (adjusted OR=2.17; 95% CI=1.06-4.45, P=0.035). In conclusion, these findings suggest that individuals with a reduced DSB repair capacity may be at an increased risk of developing SCCHN. Larger studies are warranted to confirm these preliminary findings.

Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells

BackgroundSignal transducer and activator of transcription 3 (STAT3) is persistently activated in squamous cell carcinoma of the head and neck (SCCHN) and can cause uncontrolled cellular proliferation and division. HypothesisThus, its targeted abrogation could be an effective strategy to reduce the risk of SCCHN. Resveratrol is known for its anti-cancer efficacy in a variety of cancer models. Study designThe effect resveratrol on STAT3 activation, associated protein kinases, phosphatases, cellular proliferation and apoptosis was investigated. MethodsWe evaluated the effect of resveratrol on STAT3 signaling cascade and its regulated functional responses in SCCHN cells. ResultsWe found that HN3 and FaDu cells expressed strongly phosphorylated STAT3 on both tyrosine 705 and serine 727 residues as compared to other SCCHN cells. The phosphorylation was completely suppressed by resveratrol in FaDu cells, but not substantially in HN3 cells. STAT3 suppression was mediated through the inhibition of activation of upstream JAK2, but not of JAK1 and Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the resveratrol-induced down-regulation of STAT3, thereby indicating a critical role for a PTP. We also found that resveratrol induced the expression of the SOCS-1 protein and mRNA. Further, deletion of SOCS-1 gene by siRNA suppressed the induction of SOCS-1, and reversed the inhibition of STAT3 activation. Resveratrol down-regulated various STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced the cell accumulation in the sub-G1 phase and caused apoptosis. Beside, this phytoalexin also exhibited the enhancement of apoptosis when combined with ionizing radiation treatment. ConclusionOur results suggest that resveratrol blocks STAT3 signaling pathway through induction of SOCS-1, thus attenuating STAT3 phosphorylation and proliferation in SCCHN cells.

Telomere length, genetic variants and risk of squamous cell carcinoma of the head and neck in Southeast Chinese.

Telomere dysfunction participates in malignant transformation and tumorigenesis. Previous studies have explored the associations between telomere length (TL) and cancer susceptibility; however, the findings are inconclusive. The associations between genetic variants and TL have been verified by quite a few genome-wide association studies (GWAS). Yet, to date, there was no published study on the relationship between TL, related genetic variants and susceptibility to squamous cell carcinoma of the head and neck (SCCHN) in Chinese. Hence, we detected relative telomere length (RTL) by using quantitative PCR and genotyped seven selected single nucleotide polymorphisms by TaqMan allelic discrimination assay in 510 SCCHN cases and 913 controls in southeast Chinese. The results showed that RTL was significantly associated with SCCHN risk [(adjusted odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.08–1.32, P = 0.001]. Furthermore, among seven selected SNPs, only G allele of rs2736100 related to RTL in Caucasians was significantly associated with both the decreased RTL (P = 0.002) and the increased susceptibility to SCCHN in Chinese (additive model: adjusted OR = 1.17, 95%CI = 1.00–1.38, P = 0.049). These findings provide evidence that shortened TL is a risk factor for SCCHN, and genetic variants can contribute to both TL and the susceptibility to SCCHN in southeast Chinese population.

A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck.

DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (P trend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95% CI 1.02-1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3'-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings.

Association of p21 3' UTR gene polymorphism with cancer risk: Evidence from a meta-analysis.

Numerous studies have investigated the risk of cancer associated with the polymorphism of p21 3′ UTR (rs1059234 C > T), but results have been inconsistent. We performed this meta-analysis to drive a more precise estimation of the association between this polymorphism and risk of cancer. A comprehensive search was conducted to identify all case-control studies of the rs1059234 C > T polymorphism of p21 3′ UTR and cancer susceptibility. A total of eleven eligible studies, including 3,099 cases and 4,354 controls, relating to the rs1059234 polymorphism of p21 3′ UTR to the risk of cancer were identified. Multivariate and univariate methods revealed no association between this polymorphism and cancer risk. However, subgroup analysis by cancer type suggested that rs1059234 C > T polymorphism was associated with increased risk of squamous cell carcinoma of the head and neck (SCCHN) (dominant model CT + TT vs. CC: OR = 1.51, 95% CI = 1.17–1.94). No significant association was found in other subgroup analyses. This meta-analysis suggested that rs1059234 polymorphism of p21 3′ UTR may be associated with increased SCCHN risk. And larger scale primary studies are required to further evaluate the interaction of p21 3′ UTR rs1059234 polymorphism and cancer risk in specific populations.

RAD51 Gene 135G/C polymorphism and the risk of four types of common cancers: a meta-analysis.

ObjectivesRAD51 gene plays an important role in the pathogenesis of squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer, ovarian cancer and acute leukaemia. A number of studies assessed the association between RAD51 135G/C polymorphism and the risk of these cancers in different population. However, the results have been inconclusive. We performed a systematic meta-analysis to evaluate the association between RAD51 135G/C polymorphism and the risk of these four types of cancer.MethodsPubmed, Cochrane library and Chinese Biomedical Literature Database (CBM) were searched for case-control studies on RAD51 135G/C polymorphism and the risk of SCCHN, colorectal cancer, ovarian cancer and acute leukaemia published up to Oct 31, 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.ResultsA total of twenty-two published studies, with 6836 cases and 8507 controls were included. Overall, no significant association was found between RAD51 135G/C polymorphism and the risk of the four types of cancers (G/G vs. C/C: OR = 0.83, 95% CI: 0.43-1.59, P = 0.57). However, there was a significant association between this polymorphism and SCCHN risk in the subgroup analysis by cancer type (G/G vs. C/C: OR = 2.46, 95% CI: 1.08-5.61, P = 0.03).ConclusionThe RAD51 135G/C polymorphism was associated with the risk of SCCHN.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1383180234106945.

Functional single nucleotide polymorphisms of the RASSF3 gene and susceptibility to squamous cell carcinoma of the head and neck

BackgroundRASSF3 suppresses tumour formation through uncertain mechanisms, but it is an important gene of p53-dependent apoptosis. RASSF3 depletion impairs DNA repair after DNA damage, leading to polyploidy. The authors hypothesised that potential functional single-nucleotide polymorphisms (SNPs) of RASSF3 are associated with risk of squamous cell carcinoma of the head and neck (SCCHN). MethodsThe authors used a functional SNP approach to evaluate the associations between common (minor allele frequency⩾0.05), putative functional variants in RASSF3 and risk of SCCHN. Four selected such functional SNPs (rs6581580 T>G, rs7313765 G>A, rs12311754 G>C and rs1147098 T>C) in RASSF3 were identified and genotyped in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. ResultsThe authors found that two SNPs were significantly associated with SCCHN risk. Carriers of the variant rs6581580G and rs7313765A alleles were at a reduced SCCHN risk, compared with the corresponding common homozygotes [adjusted odds ratio (OR)=0.75 and 0.73 and 95% confidence interval (CI)=0.62–0.91 and 0.60–0.88, respectively, for dominant models; and Ptrend=0.012 and 0.041, respectively, for additive models], particularly for non-oropharyngeal tumours (adjusted OR=0.68 and 0.60 and 95% CI=0.53–0.86 and 0.47–0.77, respectively, for dominant models). In the genotype–phenotype correlation analysis of peripheral blood mononuclear cells from 102 cancer-free controls, the rs6581580 GG genotype was associated with significantly increased expression levels of RASSF3 mRNA (P=0.038), compared with the TT genotype. Additional functional experiments further showed that variant G allele of rs6581580 had a significantly stronger binding affinity to the nuclear protein extracts than the T allele. ConclusionTaken together, these findings indicate that the RASSF3 promoter rs6581580 T>G SNP is potentially functional, modulating susceptibility to SCCHN among non-Hispanic whites. Larger replication studies are needed to confirm our findings.

A functional variant at the miR‐885‐5p binding site of CASP3 confers risk of both index and second primary malignancies in patients with head and neck cancer

Caspases are important regulators and executioners in the apoptosis pathways and play crucial roles in carcinogenesis. We tested the hypothesis that functional variants of CASP genes are associated with risk of squamous cell carcinoma of the head and neck (SCCHN) and second primary malignancy (SPM). We genotyped 7 selected, potentially functional single nucleotide polymorphisms (SNPs) located in the microRNA binding sites of the 3' untranslational region (UTR; 2 in CASP3, 1 in CASP6, and 4 in CASP7) and evaluated their associations first with risk of SCCHN in 1066 patients with SCCHN and 1074 cancer-free control subjects and then with SPM in 846 patients in the same non-Hispanic white study population. We found that compared with the CASP3 TT genotype of rs1049253, the variant TC/CC genotypes were associated with significantly increased risk of SCCHN (adjusted odds ratio=1.29 and 95% confidence interval=1.07-1.56) and SPM (adjusted hazard ratio=1.79 and 95% CI=1.02-3.16) and worse SPM-free survival (log-rank P = 0.020), but no associations were found for the other 6 SNPs. We then performed additional experiments to seek functional relevance of the rs1049253 SNP. First, the luciferase activity and miR-885-5p mimic transfection tests suggested that CASP3 was the target of miR-885-5p and that rs1049253T>C resulted in altered regulation of the CASP3 expression. Second, the rs1049253 CC genotype was associated with reduced levels of CASP3 mRNA in peripheral blood mononuclear cells from 118 SCCHN patients and 103 cancer-free control subjects and lower levels of CASP3 protein expression in 11 head and neck cancer cell lines, compared with the TT genotype. Taken together, our data suggest that the miR-885-5p binding site rs1049253T>C SNP in the 3'-UTR of CASP3 modulates CASP3 expression at both mRNA and protein levels and thus contributes to SCCHN susceptibility.

Functional repeats (TGYCC)n in the p53-inducible gene 3 ( PIG3 ) promoter and susceptibility to squamous cell carcinoma of the head and neck

A polymorphic pentanucleotide microsatellite sequence (TGYCC)n within the p53-inducible gene 3 (PIG3) promoter is correlated with the extent of transcriptional activation by p53 and thought to modulate susceptibility to cancer. Using a PCR-silver staining-based single-strand conformation assay, we visualized variant genotypes of the PIG3 promoter (TGYCC)n motif in a subset of 100 subjects for each of four ethnic groups: non-Hispanic whites, African Americans, Hispanic Americans and Native Chinese. We found that PIG3 (TGYCC)15 was the most common allele but less frequent in non-Hispanic whites (0.660) than in Chinese (0.785) (P = 0.016). In an additional study of 616 patients with squamous cell carcinoma of the head and neck (SCCHN) and 623 cancer-free controls in a non-Hispanic white population, we found that compared with those who were PIG3 (TGYCC)15 homozygotes, subjects without the PIG3 (TGYCC)15 allele had a significantly increased SCCHN risk [adjusted odds ratio (OR) = 1.34; 95% CI = 1.04-1.73 for heterozygotes and OR = 1.69; 95% CI = 1.18-2.44 for variant homozygotes] in an allele-dose response manner (P = 0.002). Consistently, subsequent luciferase reporter assay revealed that the wild-type (TGYCC)15 allele had the highest p53-mediated transcriptional activity, compared with the other (TGYCC)n motifs. Our data suggest that the PIG3 variant polymorphic repeats alleles other than (TGYCC)15 may affect p53 binding and thus may be a marker for susceptibility to SCCHN, but our findings need to be validated in larger studies.

Association between Single Nucleotide Polymorphisms in ERCC4 and Risk of Squamous Cell Carcinoma of the Head and Neck

BackgroundExcision repair cross-complementation group 4 gene (ERCC4/XPF) plays an important role in nucleotide excision repair and participates in removal of DNA interstrand cross-links and DNA double-strand breaks. Single nucleotide polymorphisms (SNPs) in ERCC4 may impact repair capacity and affect cancer susceptibility.Methodology/Principal FindingsIn this case-control study, we evaluated associations of four selected potentially functional SNPs in ERCC4 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,040 non-Hispanic white patients with SCCHN and 1,046 cancer-free matched controls. We found that the variant GG genotype of rs2276466 was significantly associated with a decreased risk of SCCHN (OR = 0.69, 95% CI 0.50–0.96), and that the variant TT genotype of rs3136038 showed a borderline significant decreased risk with SCCHN (OR = 0.76, 95% CI: 0.58–1.01) in the recessive model. Such protective effects were more evident in oropharyngeal cancer (OR = 0.61, 95% CI: 0.40–0.92 for rs2276466; OR = 0.69, 95% CI: 0.48–0.98 for rs3136038). No significant associations were found for the other two SNPs (rs1800067 and rs1799798). In addition, individuals with the rs2276466 GG or with the rs3136038 TT genotypes had higher levels of ERCC4 mRNA expression than those with the corresponding wild-type genotypes in 90 Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Caucasians.ConclusionsThese results suggest that these two SNPs (rs2276466 and rs3136038) in ERCC4 may be functional and contribute to SCCHN susceptibility. However, our findings need to be replicated in further large epidemiological and functional studies.

Genetic variants of NOXA and MCL1 modify the risk of HPV16-associated squamous cell carcinoma of the head and neck

sBackgroundThe cooperation between phorbol 12-myristate 13-acetate induced protein 1 (NOXA) and myeloid cell leukemia 1 (MCL1) is critical in the intrinsic apoptotic pathway. Human papillomavirus 16 (HPV16), by inducing p53 and pRb-E2F degradation, may play an essential role in development of squamous cell carcinoma of the head and neck (SCCHN) through NOXA-MCL1 axis-mediated apoptosis. Therefore, genetic variants of NOXA and MCL1 may modify the SCCHN risk associated with HPV16 seropositivity.MethodsHPV16 serology was obtained by immunoadsorption assay. Four functional SNPs in the promoter of NOXA (rs9957673, rs4558496) and MCL1 (rs9803935, rs3738485) were genotyped for 380 cases and 335 frequency-matched cancer-free controls of non-Hispanic whites.ResultsAssociations between the four polymorphisms and SCCHN risk were not significant, while we observed a significantly joint effect on SCCHN risk between the polymorphisms and HPV16 seropositivity. Notably, this effect modification was particularly pronounced for oropharyngeal cancer in subgroups including never smokers, never drinkers and younger subjects.ConclusionsOur results suggested that polymorphisms of NOXA and MCL1 may modify the risk of HPV16-associated oropharyngeal cancer. The further identification of population subgroups at higher risk provides evidence that HPV-targeting treatment may help benefit SCCHN. However, larger studies are needed to validate our findings.

Combined effects of E2F1 and E2F2 polymorphisms on risk and early onset of squamous cell carcinoma of the head and neck

Deregulated expression of most members of the E2F family has been detected in many human cancers. We examined the association of common single nucleotide polymorphisms (SNPs) of E2F transcription factors 1 and 2 (E2F1 and E2F2) with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,096 SCCHN patients and 1,090 cancer-free controls. We genotyped 10 selected SNPs in E2F1 and E2F2, including those at the near 5'-untranslated region (UTR), microRNA (miRNA)-binding sites at the near 3'-UTR and tagSNPs according to bioinformatics analysis. Although none of the selected SNPs alone was significantly associated with risk of SCCHN, there was a statistically significantly increased risk of SCCHN associated with the combined risk genotypes (i.e., rs3213182 AA, rs3213183 GG, rs3213180 GG, rs321318121 GG, rs2742976 GT+TT, rs6667575 GA+AA, rs3218203 CC, rs3218148 AA, rs3218211 CC, and rs3218123 GT+TT). Compared with those with 0-4 risk genotypes, an increased risk was observed for those who carried 5-8 risk genotypes (adjusted OR = 1.04; 95% CI = 0.86-1.26) and 9-10 risk genotypes (adjusted OR = 1.62; 95% CI = 1.14-2.30) in a dose-response manner (P = 0.045). Furthermore, the joint effect was more pronounced among patients with oropharyngeal cancer, younger adults (≤57 yr old), men, non-smokers, non-drinkers, and individuals with family history of cancer in first-degree relatives. Additionally, we also observed that those with 5-10 risk genotypes had an earlier SCCHN onset than those with 0-4 risk genotypes, particularly for non-smokers and/or non-drinkers. We concluded that E2F1 and E2F2 genetic variants may jointly play important roles in head and neck carcinogenesis.

Polymorphisms of XPG/ERCC5 and risk of squamous cell carcinoma of the head and neck

Xeroderma pigmentosum group G (XPG) protein is essential for the nucleotide excision repair system, and genetic variations in XPG/ERCC5 that affect DNA repair capacity may contribute to the risk of tobacco-induced cancers, including squamous cell carcinoma of the head and neck (SCCHN). We investigated the association between XPG/ERCC5 polymorphisms and risk of SCCHN. We genotyped 12 tagging and potentially functional single nucleotide polymorphisms (SNPs) of XPG/ERCC5 in a case-control study of 1059 non-Hispanic white patients with SCCHN and 1066 cancer-free age- and sex-matched controls, and evaluated their associations with the risk of SCCHN. Multivariate logistic regression showed that only an intronic tagging SNP (rs4150351A/C) of XPG/ERCC5 was associated with a decreased risk of SCCHN (adjusted odds ratio=0.76, 95% confidence interval=0.62-0.92 for AC vs. AA; adjusted odds ratio=0.81, 95% confidence interval=0.67-0.98 for AC/CC vs. AA), but this association was nonsignificant after corrections by the permutation test (empirical P=0.105). In the genotype-phenotype correlation analysis using peripheral lymphocytes from 44 patients with SCCHN, we found that rs4150351 AC/CC was associated with a statistically significant increase in the XPG/ERCC5 mRNA expression. These findings suggest that genetic variation in XPG/ERCC5 may not affect the risk of SCCHN, although rs4150351 C variant genotypes were associated with an increased expression of XPG/ERCC5 mRNA and nonsignificantly decreased risk of SCCHN. Larger population-based and additional functional studies are warranted to validate our findings.