Development Of Head And Neck Cancer Research Articles

Exogenous Estrogen in the Development of Head and Neck Cancer

Sex differences in head and neck cancer (HNC) incidence suggest a potential contribution of sex hormones. To assess the role of exogenous estrogen exposure in the development of HNC in female patients. This large multicenter cohort study using clinical records from the TriNetX real-world database included 20 years of data (through May 31, 2023) from 87 health care organizations. The TriNetX database was searched for medical records for female patients with and without exogenous estrogen exposure according to their chronological age. Cohort 1 included 731 366 female patients aged 18 to 45 years old with regular oral contraceptive (OC) intake and cohort 2 included 3 886 568 patients in the same age group who did not use OC. Cohort 3 comprised 135 875 female patients at least 50 years old receiving hormone replacement therapy (HRT), whereas cohort 4 included 5 875 270 patients at least 50 years old without HRT. Propensity score matching was performed for the confounders age, alcohol dependence, and nicotine dependence. Data analyses were performed in May 2023. Diagnosis of HNC (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision: C00-C14), and after propensity score matching (1:1 nearest-neighbor greedy matching), a risk analysis to investigate risk differences and risk ratios (RRs) with a 95% CI. Among the 718 101 female patients in each of cohorts 1 and 2 (mean [SD] age at diagnosis, 25.9 [6.7] years), those with OC intake had a higher risk of an HNC diagnosis (RR, 1.47; 95% CI, 1.21-1.78) than those without OC use. Among the 131 835 female patients in each of cohorts 3 and 4 (mean [SD] age, 67.9 [12.0] years), those with postmenopausal HRT intake had a lower risk of an HNC diagnosis (RR, 0.77; 95% CI, 0.64-0.92) than those without HRT use. The findings of this cohort study illustrate a positive association between OC and a negative association between HRT and the development of HNC in female patients. Given the limitations of the TriNetX database, future research should include detailed information on the intake of OC and HRT and reproductive health information (eg, age at menarche/menopause, number of pregnancies) to more accurately define the strength and direction of the possible association between exogeneous estrogen exposure and the development of HNC in female patients.

Exploring the Link between Inflammatory Biomarkers and Head and Neck Cancer: Understanding the Impact of Smoking as a Cancer-Predisposing Factor.

Head and neck cancer (HNC) is associated with significant morbidity globally, with smoking recognized as a key risk factor. This study investigates the interplay between smoking and inflammatory biomarkers in HNC development. The study involved 50 HNC patients, divided into smoking and non-smoking groups, and a control group of 30 healthy individuals. Serum levels of 48 cytokines, chemokines, growth factors, and other inflammatory markers were meticulously assessed. Significant differences in the levels of an extensive panel of inflammatory markers were observed between the patient groups and healthy controls. Elevated macrophage colony-stimulating factor (M-CSF) in both HNC groups implicated increased activity in pathways known for immunomodulation, proliferation, and angiogenesis during HNC cancerogenesis. In contrast, non-smokers with HNC demonstrated higher levels of interleukin 10 (IL-10) and interleukin 15 (IL-15), suggesting a more robust immune response. Platelet-derived growth factor BB (PDGF-BB) levels were particularly high in smokers with HNC. Smoking seems to alter the levels of crucial biomarkers in HNC, potentially affecting disease progression and responses to treatment. The data indicate that smokers may experience a more aggressive cancer phenotype, while non-smokers maintain a profile suggestive of a more active and effective immune response against HNC.

Expression of chemokine CXCL8/9/10/11/13 and its prognostic significance in head and neck cancer.

Background:Head and neck cancer (HNC) is a very popular cancer, with many primary sites and pathological types, at the top of the list of tumors. Chemokines are a class of small molecular basic proteins, whose N-terminal cysteine residues can be divided into four subunits by location and number, which significantly enhances the expression level in all kinds of cancers. However, in HNC, especially in head and neck squamous cell carcinoma, the chemokine CXCL8/9/10/11/13 has not been clearly explored for its diagnosis and prognosis.Methods:The ONCOMINE database was used to analyze the expression of chemokine family in various cancers. After CXCL8/9/10/11/13 was screened out, the expression of CXCL 8/9/11/13 in patients with HNC/normal people were analyzed by UALCAN database. The expression and pathological stages of CXCL 8/9/10/13 in HNC tissues were analyzed by the GEPIA database, and the relationship between its mRNA expression and the overall survival (OS) time of patients with HNC was analyzed by Kaplan–Meier plotter database. In addition, 171 co-expressed genes significantly related to CXCL8/9/10/11/13 mutation were screened by online tool cBioPortal, and the protein interaction network of these genes was constructed by STRING database. Finally, the potential functions of CXCL8/9/10/11/13 and its 171 co-expressed genes were explored by the enrichment and analysis function of David database.Results:Transcriptional expression of chemokine 8/9/10/11/13 was significantly increased in patients with HNC. Clinical stage of patients with HNC was significantly correlated with overexpression of CXCL9/10/11. In addition, the chemokine CXCL8/9/10/13 was significantly correlated with over-survival of patients with HNC, so it could be distinguished between short-term and long-term survival of patients with HNC. In conclusion, CXCL8/9/10/11/13 closely connected with the expression and prognosis of HNC.Conclusion:In this study, our results suggest that chemokine CXCL8/9/10/11/13 may play a critical role in the development of HNC, and, according to relevant data, it may affect the survival and prognosis of patients with HNC.

Cell-Free RNA as a Novel Biomarker for Response to Therapy in Head & Neck Cancer.

Liquid biopsies are gaining more traction as non-invasive tools for the diagnosis and monitoring of cancer. In a new paradigm of cancer treatment, a synergistic botanical drug combination (APG-157) consisting of multiple molecules, is emerging as a new class of cancer therapeutics, targeting multiple pathways and providing a durable clinical response, wide therapeutic window and high level of safety. Monitoring the efficacy of such drugs involves assessing multiple molecules and cellular events simultaneously. We report, for the first time, a methodology that uses circulating plasma cell-free RNA (cfRNA) as a sensitive indicator of patient response upon drug treatment. Plasma was collected from six patients with head and neck cancer (HNC) and four healthy controls receiving three doses of 100 or 200 mg APG-157 or placebo through an oral mucosal route, before treatment and on multiple points post-dosing. Circulating cfRNA was extracted from plasma at 0-, 3- and 24-hours post-treatment, followed by RNA sequencing. We performed comparative analyses of the circulating transcriptome and were able to detect significant perturbation following APG-157 treatment. Transcripts associated with inflammatory response, leukocyte activation and cytokine were upregulated upon treatment with APG-157 in cancer patients, but not in healthy or placebo-treated patients. A platelet-related transcriptional signature could be detected in cancer patients but not in healthy individuals, indicating a platelet-centric pathway involved in the development of HNC. These results from a Phase 1 study are a proof of principle of the utility of cfRNAs as non-invasive circulating biomarkers for monitoring the efficacy of APG-157 in HNC.

DRP1 contributes to head and neck cancer progression and induces glycolysis through modulated FOXM1/MMP12 axis.

Abnormal DRP1 expression has been identified in a variety of human cancers. However, the prognostic potential and mechanistic role of DRP1 in head and neck cancer (HNC) are currently poorly understood. Here, we demonstrated a significant upregulation of DRP1 in HNC tissues, and that DRP1 expression correlates with poor survival of HNC patients. Diminished DRP1 expression suppressed tumor growth and metastasis in both in vitro and in vivo models. DRP1 expression was positively correlated with FOXM1 and MMP12 expression in HNC patient samples, suggesting pathological relevance in the context of HNC development. Moreover, DRP1 depletion affected aerobic glycolysis through the downregulation of glycolytic genes, and overexpression of MMP12 in DRP1‐depleted cells could help restore glucose consumption and lactate production. Using ChIP‐qPCR, we showed that DRP1 modulates FOXM1 expression, which can enhance MMP12 transcription by binding to its promoter. We also showed that miR‐575 could target 3’UTR of DRP1 mRNA and suppress DRP1 expression. Collectively, our study provides mechanistic insights into the role of DRP1 in HNC and highlights the potential of targeting the miR‐575/DRP1/FOXM1/MMP12 axis as a novel therapy for the prevention of HNC progression.

In silico assessment of DNA damage response gene variants associated with head and neck cancer

Head and neck cancer (HNC), the sixth most common cancer globally, stands first in India, especially Northeast India, where tobacco usage is predominant, which introduces various carcinogens leading to malignancies by accumulating DNA damages. Consequently, the present work aimed to predict the impact of significant germline variants in DNA repair and Tumour Suppressor genes on HNC development. WES in Ion ProtonTM platform on ‘discovery set’ (n = 15), followed by recurrence assessment of the observed variants on ‘confirmation set’ (n = 40) using Sanger Sequencing was performed on the HNC-prevalent NE Indian populations. Initially, 53 variants were identified, of which seven HNC-linked DNA damage response gene variants were frequent in the studied populations. Different tools ascertained the biological consequences of these variants, of which the non-coding variants viz. EXO1_rs4150018, RAD52_rs6413436, CHD5_rs2746066, HACE1_rs6918700 showed risk, while FLT3_rs2491227 and BMPR1A_rs7074064 conferred protection against HNC by affecting transcriptional regulation and splicing mechanism. Molecular Dynamics Simulation of the full-length p53 model predicted that the observed coding TP53_rs1042522 variant conferred HNC-risk by altering the structural dynamics of the protein, which displayed difficulty in the transition between active and inactive conformations due to high-energy barrier. Subsequent pathway and gene ontology analysis revealed that EXO1, RAD52 and TP53 variants affected the Double-Strand Break Repair pathway, whereas CHD5 and HACE1 variants inactivated DNA repair cascade, facilitating uncontrolled cell proliferation, impaired apoptosis and malignant transformation. Conversely, FLT3 and BMPR1A variants protected against HNC by controlling tumorigenesis, which requires experimental validation. These findings may serve as prognostic markers for developing preventive measures against HNC.

Association Between the Aldehyde Dehydrogenase-2 rs671 G>A Polymorphism and Head and Neck Cancer Susceptibility: A Meta-Analysis in East Asians.

Aldehyde dehydrogenase-2 (ALDH2) plays an important role in the alcohol detoxification and acetaldehyde metabolism. Published studies have demonstrated some inconsistent associations between ALDH2 rs671 G>A polymorphism and head and neck cancer (HNC) risk. A meta-analysis was performed to provide pooled data on the association between the ALDH2 rs671 G>A polymorphism and HNC risk. Electronic databases were searched to identify relevant studies. Odds ratios and 95% confidence intervals (CIs) were used to examine the pooled effect size of each genetic model. In addition, heterogeneity test, accumulative analysis, sensitivity analysis, and publication bias were conducted to test the statistical power. Thirteen publications (14 independent case-control studies) involving 10,939 subjects were selected. The stratified analysis indicated that both light/moderated drinking (e.g., GA vs. GG: OR=1.47, 95% CI=1.16 to 1.86, p<0.01, I2 =81.1%) and heavy drinking would increase HNC risk with rs671 G>A mutation (e.g., GA vs. GG: OR=2.30, 95% CI=1.11 to 4.77, p=0.03, I2 =81.9%). In summary, this meta-analysis suggested that the ALDH2 rs671 G>A polymorphism may play an important synergistic effect in the pathogenesis of HNC development in East Asians.

Association of polymorphisms in inflammatory cytokine genes with the development of head and neck cancer in Pakistani population

Head and neck cancer (HNC) is the most common type of carcinoma and represents a major health problem in developing countries. HNC is a multifactorial condition associated with a variety of risk factors comprising genetic, environmental and life style. Genetic polymorphisms of interleukin genes might contribute to the development of HNC. Present study was conducted to investigate a possible association of HNC with single nucleotide polymorphisms (SNPs) in interleukin genes (IL-8 rs4073 A/T, IL-4 rs2070874 C/T, IL-10 rs1800896 T/C, IL-10 rs180072 T/G, IL-6 rs1800796 C/G, IL-6 rs1800795 C/G, and IL-1-α rs17561 A/C) and oral hygiene in Pakistani Population. For this purpose, 231 cases and 219 controls were recruited. The SNPs were assessed through QuantStudio real time PCR system. Analysis of the data showed a significant association of IL-10 rs1800896 with HNC while other SNPs were not associated was HNC pathogenicity. Further, no significant association was observed between hygiene associated factors and HNC in the studied population. This study presents useful aspects of HNC in Pakistani cohort.

Protein Post-translational Modifications in Head and Neck Cancer.

Head and neck cancer (HNC) is one of the most common malignant tumors worldwide, and is prone to tumor recurrence and metastasis. At present, surgery combined with radiotherapy and chemotherapy is still the conventional treatment modality for patients with HNC. However, for patients with relapse or metastasis of HNC, the treatment outcome is not ideal, and the prognosis is poor. Thus, it is crucial to deepen the understand of tumor mechanisms. Post-translational modifications (PTMs) refer to covalent binding of small chemical molecular groups to amino-acid side-chain of proteins. Post-translational modification is an important regulator of protein function, and as such, a current research hotspot of epigenetics. In recent years, it has been found that tumor occurrence is often accompanied by the abnormality of PTMs. Indeed, the abnormality play an important role in tumor development, and can be used as a target for tumor diagnosis and treatment. To date, several types of protein PTMs involved in the development of HNC have been reported. This paper reviews the relationship between HNC and several major protein PTMs, including acetylation, methylation, and glycosylation, in order to provide clues for the future application about PTMs in diagnosis and treatment of HNC.

Potential oncogenic roles of mutant-p53-derived exosomes in the tumor-host interaction of head and neck cancers.

The wide-ranging collection of malignancies arising at the upper aerodigestive tract is categorized as head and neck cancer (HNC), the sixth most prevalent cancer worldwide. Infection with human papillomavirus (HPV) or exposure to carcinogens is the leading causes of HPV+ and HPV- HNCs development, respectively. HPV+ and HPV- HNCs are different in clinical and molecular aspects. Specifically, HPV- HNCs tightly associate with missense mutants of the TP53 gene (encoding for the p53 protein), suggesting a central role for mutant p53 gain-of-function (GOF) in driving tumorigenesis. In contrast, in HPV + HNC, the sequence of TP53 typically remains intact, while the protein is degraded. In tumor cells, the status of the TP53 gene affects the cargo of secreted exosomes. In this review, we describe the accumulated knowledge regarding the involvement of exosomes and p53 on cellular interactions between HPV+ and HPV- HNC cells, and the surrounding tumor microenvironment (TME). Moreover, we envision how TP53 status may determine exosomes cargo in HNC, and, consequently, modify the TME. The potential roles of exosomes described herein are based on both our studies and the studies of others on mutant p53-derived exosomes. Specifically, we showed how exosomes are shed by cancer cells harboring mutant p53 communicate with tumor-associated macrophages in the colon as well as with cancer-associated fibroblasts in the lung, creating immunosuppressive conditions and promoting invasiveness. Altogether, exosomes in HNC in the context of TP53 status are understudied and extensive research is required to shed light on the biology of HPV+ and HPV- HNC.

Long Non-Coding RNAs Emerging as Potential Epigenetic Biomarkers for Tobacco and/or Alcohol-Induced Head and Neck Cancer

Head and Neck cancer (HNC) is one of the most prevalent and lethal cancer globally. The incidence of tobacco-induced HNC is gradually increasing in low and middle income countries. Among the various causative factors associated with HNCs, tobacco and alcohol play synergistic effect and are frequently associated with the risk of HNC. Tobacco-induced HNCs show distinct genetic and epigenetic alterations leading to different clinical outcomes in comparison to HPV-infected HNCs. Tobacco-induced HNCs are often associated with tumor aggressiveness, poor prognosis and low or nil prevalence of HPV infection. Apart from carcinogenic effects of these causative factors (use of tobacco products, alcohol intake and HPV or EBV infections), recent studies show that exposure to these factors alter/disrupt the regulation of non-coding RNAs including the long non-coding RNAs (lncRNAs). Altered lncRNA regulation is brought about by signalling networks that regulate cellular differentiation, apoptosis, angiogenesis and inflammatory pathways which play key functions in the genesis of different cancers including HNCs. There are numbers of studies supporting the emerging role of lncRNAs in development of HNC; however, reports connecting lncRNAs expression and addiction habits in HNC are still preliminary and sparse. Therefore, identification and characterization of lncRNAs that are differentially expressed upon exposure to risk-factors can serve as unique therapeutic targets and potential biomarker(s) for effective treatment of HNC subtypes. In this short review, we briefly reviewed the emerging role of lncRNAs in tobacco and alcohol induced HNCs.

Screening and identification of potential target genes in head and neck cancer using bioinformatics analysis.

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Recent studies on the pathogenesis of HNC have identified some biochemical associations of this disease, but the molecular mechanisms are not clear. To explore the genetic alterations in head and neck tumors, to identify new high-specificity and high-sensitivity tumor markers, and to investigate potentially effective therapeutic targets, in silico methods were used to study HNC. The GSE58911 microarray dataset was downloaded from the Gene Expression Omnibus online database to identify potential target genes in the carcinogenesis and progression of HNC. Differentially expressed genes (DEGs) were identified and functional enrichment analysis was performed. In addition, a protein-protein interaction network was also constructed, and gene analysis was undertaken using Search Tool for the Retrieval of Interacting Genes and Cytoscape. A total of 648 differentially expressed genes were identified. Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology functional enrichment analysis of DEGs included muscle system process, extracellular matrix organization, actin binding, structural molecule activity, structural constituent of muscle, extracellular region part, ECM-receptor interaction, amoebiasis, focal adhesion, drug metabolism-cytochrome P450, and chemical carcinogenesis. There were 26 hub genes identified and biological process analysis revealed that these genes were mainly enriched in extracellular matrix organization, serine-type endopeptidase activity, extracellular matrix, and complement and coagulation cascades. Survival analysis revealed that interleukin (IL)-8 (C-X-C motif chemokine ligand 8), IL1B, and serpin family A member 1 may be involved in the carcinogenesis of HNC. In summary, the DEGs and hub genes identified in the present study may increase understanding of the molecular mechanisms of development of HNC and provide potential target genes for clinical diagnosis and targeted therapy.

THE IMPORTANCE OF EARLY RECOGNITION OF ORAL POTENTIALLY MALIGNANT DISORDERS IN HIV-AIDS INDIVIDUALS.

Objective An increase in head and neck cancer (HNC) in HIV-infected individuals has been described in several epidemiological studies, suggesting that immunosuppression, even in treated patients, may play a role in the development of HNC. A thorough oral examination is essential for the identification of potentially malignant lesions, particularly in individuals at high risk to develop cancer. Thus, we report two cases of oral potentially malignant disorders occurring in HIV individuals. Clinical Presentation Case 1. A 39-year-old male HIV+ since 2013. In 2015 presented an asymptomatic, slightly granular, red/white pediculate tumor on the left buccal mucosa, clinically compatible with multifocal epithelial hyperplasia with post-traumatic hyperkeratosis (251 cells/ml CD4+, undetectable viral load [VL]). Two weeks later, the lesion showed marked erosive/ulcerated areas, thus, a complete excision was done. The final diagnosis was in situ squamous cell carcinoma positive to HPV-16. Case 2. A 40-year-old male HIV+ since 2005, with histologically confirmed oral hairy leukoplakia, immunohistochemistry showed positive expression to EBV and negative to HPV. In 2015 presented a white well circumscribed homogeneous plaque, with a slightly rough surface and some satellite lesions, comparable with the previous hairy leukoplakia. The patient referred itching and burning sensation, so an excisional biopsy was done, showing hyper orthokeratosis with moderate dysplasia. The sample was negative for EBV and HPV. Both patients have remained asymptomatic, without signs of recurrence. Outcome The present cases evidence that some oral potentially malignant disorders may resemble other common lesions in HIV-patients that could be underdiagnosed, delaying an appropriate management and impacting prognosis. It is essential to highlight that HIV/AIDS patients should be closely monitored. Oral examination should be cautious even in the presence of lesions with a benign appearance.

The association between human papillomavirus infection and head and neck cancer: A population-based cohort study.

Human papillomavirus (HPV) has been linked with development of oropharyngeal squamous cell carcinoma, a subset of head and neck cancer (HNC). This study aimed to evaluate the association between HPV infection and subsequent development of HNC and to report epidemiological information in Taiwan.This population-based cohort study retrieved patient data from the longitudinal health insurance database (LHID) of Taiwan's National Health Insurance Research Database (NHIRD) from 2005 to 2010 and analyzed it retrospectively. The crude incidence rate and incidence rate ratios with 95% confidence intervals of HNC were estimated in patients with and without HPV infection. A time-to-event analysis was conducted and multiple regression analysis was performed to identify factors associated with HNC in HPV-infected patients, including age at baseline, sex, and comorbidities.This study included the data of 25,520 HPV-infected and 1,061,817 noninfected patients. The HPV-infected group had a significantly higher proportion of females than the noninfected group (55.80% vs 50.66%, respectively; P < .0001). The incidence rate of HNC was 11.49 (males) and 5.83 (females) per 10 person-months versus 11.38 (males) and 3.90 (females) per 10 person-months in the infected and noninfected groups, respectively. HPV was significantly associated with cancer in females (hazard ratio = 1.520, 95% confidence interval 1.166-1.981), but not in males (hazard ratio = 1.000, 95% confidence interval 0.815-1.228). No significant differences were found in age between the HPV-infected and noninfected patients (49.20 ± 14.34 years vs 49.09 ± 13.82 years, respectively); and a slightly higher percentage of HPV-infected patients had a specific comorbidity than did noninfected patients 12.54% versus 9.43%, ischemic heart disease 14.22% versus 10.51%, hypertension 22.40% versus 19.54%, liver disease 22.88% versus 16.17%, and renal disease 7.14% versus 5.39%, respectively.Results of this study may help clinicians in the diagnosis, prognosis, and treatment of head and neck cancer.

Association of IL-8 gene promoter -251 A/T and IL-18 gene promoter -137 G/C polymorphisms with head and neck cancer risk: a comprehensive meta-analysis.

PurposeNo consensus exists on the impact of polymorphisms in cytokines (such as interleukin IL-8 and IL-18) on cancer risk; moreover, there is very little evidence regarding head and neck cancer (HNC).MethodsThus, a meta-analysis including 22 studies with 4731 cases and 8736 controls was conducted to evaluate this association. The summary odds ratio (OR) and corresponding 95% confidence intervals (CIs) for C-X-C motif chemokine ligand 8 (CXCL8, which encodes IL-8) and IL-18 polymorphisms and HNC risk were estimated.ResultsThe results showed a significantly increased risk of HNC susceptibility for IL18 −137 G/C in five genetic models, but, interestingly, no significant association was found for the CXCL8 −251 A/T polymorphism. When stratified by cancer type, an increased risk of nasopharyngeal cancer was found for both −137 G/C and −251A/T. When the studies were stratified by ethnicity and genotyping method, there were significant associations between Asian populations and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) studies for −137 G/C, and African populations for −251 A/T in some genetic models. A positive association was also found between the population-based groups in some models for −137 G/C; conversely, significantly decreased risk was found among the −251 A/T hospital-based group. Meta-regression was also conducted. The publication year, control source, and cancer type contributed to CXCL8 −251 A/T heterogeneity; however, no factors were found that contributed to IL-18 −137 G/C heterogeneity. Marginal significance was found in the recessive model for IL-18 −137 G/C by Egger’s test, whereas no publication bias was detected for CXCL8 −251 A/T.ConclusionsThe results indicate that the IL-18 −137 G/C polymorphism is associated with HNC risk, especially nasopharyngeal cancer, in Asian populations and, when using PCR-RFLP, CXCL8 −251 A/T polymorphisms play a complex role in HNC development.

Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer

Head and neck cancer (HNC), the sixth most common cancer globally, stands second in India. In Northeast (NE) India, it is the sixth most common cause of death in males and seventh in females. Prolonged tobacco and alcohol consumption constitute the major etiological factors for HNC development, which induce DNA damage. Therefore, DNA repair pathway is a crucial system in maintaining genomic integrity and preventing carcinogenesis. The present work was aimed to predict the consequence of significant germline variants of the DNA repair genes in disease predisposition. Whole exome sequencing was performed in Ion Proton™ platform on 15 case-control samples from the HNC-prevalent states of Manipur, Mizoram, and Nagaland. Variant annotation was done in Ion Reporter™ as well as wANNOVAR. Subsequent statistical and bioinformatics analysis identified significant exonic and intronic variants associated with HNC. Amongst our observed variants, 78.6% occurred in ExAC, 94% reported in dbSNP and 5.8% & 9.3% variants were present in ClinVar and HGMD, respectively. The total variants were dispersed among 199 genes with DSBR and FA pathway being the most mutated pathways. The allelic association test suggested that the intronic variants in HLTF and RAD52 gene significantly associated (P < 0.05) with the risk (OR > 5), while intronic variants in PARP4, RECQL5, EXO1 and PER1 genes and exonic variant in TDP2 gene showed protection (OR < 1) for HNC. MDR analysis proposed the exonic variants in MSH6, BRCA2, PALB2 and TP53 genes and intronic variant in RECQL5 genetic region working together during certain phase of DNA repair mechanism for HNC causation. In addition, other intronic and 3′UTR variations caused modifications in the transcription factor binding sites and miRNA target sites associated with HNC. Large-scale validation in NE Indian population, in-depth structure prediction and subsequent simulation of our recognized polymorphisms is necessary to identify true causal variants related to HNC.

Quantitative assessment of the relationship between Fas/FasL genes polymorphisms and head and neck cancer risk.

Background:Molecular epidemiological studies have demonstrated a closer association between Fas/FasL polymorphisms and head and neck cancer (HNC) risk, and the results of these published studies were inconsistent. We therefore performed this meta-analysis to explore the associations between Fas/FasL polymorphisms and HNC risk.Methods:Four online databases (PubMed, Embase, CNKI, and Wanfang) were searched. Odds ratios (ORs) with 95% confidence interval (95% CIs) were calculated to assess the association between Fas -670A>G, Fas -1377G>A, and FasL -844C>T polymorphisms and HNC risk. In addition, heterogeneity, accumulative/sensitivity analysis, and publication bias were conducted to check the statistical power.Results:Overall, 9 related publications (20 independent case–control studies) involving 3179 patients and 4217 controls were identified. Significant association of protective effects was observed between FasL -844C>T polymorphism and HNC risk in codominant and dominant model models (CT vs CC: OR = 0.89, 95% CI = 0.79–1.00, P = .05, I2 = 38.3%, CT+TT vs CC: OR = 0.88, 95% CI = 0.79–0.98, P = .02, I2 = 35.8%). Furthermore, the similar protective effects were observed the subgroup analysis of in Asian population and population-based controls group.Conclusion:Our meta-analysis indicated that FasL -844C>T polymorphism plays a protective role against HNC development, but the Fas -670A>G and Fas -1377G>A polymorphisms maybe not associated with HNC risk.

SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer.

Hyperphosphorylation of signal transducer and activator of transcription 3 (STAT3) has been found in various types of human cancers, including head and neck cancer (HNC). Although smoking is critical in the development and progression of HNC, how tobacco components activate STAT3 is unclear. We demonstrated that exposure of HNC cell lines to a tobacco extract induced a rapid Y705 phosphorylation of STAT3 and a rapid increase in the SUMO protease SENP3 that depended on a simultaneous increase in reactive oxygen species. We identified that SUMOylation at the lysine 451 site facilitated STAT3 binding to the phosphatase TC45 through an SUMO-interacting motif of TC45. SENP3 could thus enhance STAT3 phosphorylation by de-conjugating the SUMO2/3 modification of STAT3. Knocking-down of SENP3 greatly impaired basal and induced STAT3 phosphorylation by tobacco extract or interleukin 6. A correlation between SENP3 protein levels and STAT3 Y705 phosphorylation levels in human laryngeal carcinoma specimens was found, which was more significant in the specimens derived from the smoker patients and with poor clinicopathological parameters. Our data identified SUMOylation as a previously undescribed post-translational modification of STAT3 and SENP3 as a critical positive modulator of tobacco- or cytokine-induced STAT3 activation. These findings provide novel insights into the hyperphosphorylation of STAT3 in development of HNC.

Increased risks between Interleukin-10 gene polymorphisms and haplotype and head and neck cancer: a meta-analysis.

Molecular epidemiological research suggests that interleukin-10 (IL-10) polymorphisms may be associated with an increased risk of head and neck cancer (HNC), but results remain controversial. To derive a more precise evaluation, we performed a meta-analysis focused on genetic polymorphisms of IL-10. PubMed, Embase, CNKI and Wanfang databases were searched for studies that examined the relationship between IL-10 polymorphisms or haplotypes and HNC risk. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the relationship strength. Publication bias, sensitivity and cumulative analyses were conducted to measure the robustness of our findings. Overall, nine related studies involving 2,258 patients and 2,887 control samples were analyzed. Significant associations between the IL-10-1082A > G polymorphism and HNC risk were observed (G vs. A: OR = 1.56, 95% CI = 1.27–1.92, P < 0.01, I2 = 69.4%; AG vs. AA: OR = 1.64, 95% CI = 1.32–2.05, P < 0.01, I2 = 55.6%; GG vs. AA: OR = 2.24, 95% CI = 1.69–2.97, P < 0.01, I2 = 38.5%; AG + GG vs. AA: OR = 1.70, 95% CI = 1.36−2.14, P = 0.02, I2 = 61.8%; GG vs. AA + AG: OR = 1.89, 95% CI = 1.23−2.90, P = 0.01, I2 = 46.3%) in the total population, as well as in subgroup analysis. Moreover, increased HNC risks were also associated with the IL-10 −819T > C polymorphism and the GCC haplotype. In conclusion, our meta-analyses suggest that IL-10 polymorphisms, specifically the −1082A > G polymorphism, may be associated with increased risk of HNC development.

Significant association between functional microRNA polymorphisms and head and neck cancer susceptibility: a comprehensive meta-analysis.

Molecular epidemiological studies have showed a closer association between microRNA polymorphisms with and head and neck cancer (HNC) risk. But the results of these studies were inconsistent. We performed this meta-analysis to clarify the associations between microRNA polymorphisms and HNC risk. Four electronic databases (PubMed, Embase, CNKI, and Wanfang) were searched. Odds ratios (ORs) with 95% confidence interval (CIs) were calculated to assess the association between microRNA-146a rs2910164 G > C, microRNA-196a2 rs11614913 C > T, microRNA-149 rs2292832 C > T, microRNA-499 rs3746444 A > G polymorphisms and HNC risk. Heterogeneity, publication bias and sensitivity analysis were conducted to guarantee the statistical power. Overall, 11 selected articles involving 16100 subjects were included in this meta-analysis. Significantly increased risk between microRNA-146a rs2910164 G > C polymorphism and HNC risk were observed in Caucasian population (GC vs. GG: OR = 1.31, 95%CI = 1.01–1.68; GC + CC vs. GG: OR = 1.26, 95%CI = 1.02–1.57). For microRNA-196a2 rs11614913 C > T, similarly increased risk were also found in Asian population (T vs. C, OR = 1.14, 95%CI = 1.04–1.25; TT vs. CC, OR = 1.33, 95%CI = 1.09–1.61; CT + TT vs. CC OR = 1.32, 95%CI = 0.99–1.76; TT vs. CC + CT, OR = 1.14, 95%CI = 0.99–1.33). In addition, no significant association was detected between microRNA-149 rs2292832 C > T and microRNA-499 rs3746444 A > G polymorphism and HNC risk. This meta-analysis demonstrates that microRNA polymorphisms are associated with HNC development based on ethnicity diversity.