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Background Head and neck squamous cell carcinoma (HNSCC) is characterised by a dismal prognosis; nonetheless, limited studies have unveiled the mechanisms underlying HNSCC relapse. Methods Next-generation sequencing was performed to identify the somatic mutations in 188 matched samples, including primary tumours, tumour-adjacent tissues (TATs), pre- and post-operative plasma, saliva and peripheral blood lymphocytes (PBLs) from 27 patients. The evolutionary relationship between TATs and tumours were analysed. The dynamic changes of tumour- and TAT-specific mutations in liquid biopsies were monitored together with survival analysis. Results Alterations were detected in 27 out of 27 and 19 out of 26 tumours and TATs, respectively. TP53 was the most prevalently mutated gene in TATs. Some TATs shared mutations with primary tumours, while some other TATs were evolutionarily unrelated to tumours. Notably, TP53 mutations in TATs are stringently associated with premalignant transformation and are indicative of worse survival (hazard ratio = 14.01). TAT-specific mutations were also detected in pre- and/or post-operative liquid biopsies and were indicative of disease relapse. Conclusions TATs might undergo the processes of premalignant transformation, tumorigenesis and eventually relapse by either inheriting tumorigenic mutations from ancestral clones where the tumour originated or gaining private mutations independent of primary tumours. Detection of tumour- and/or TAT-specific genetic alterations in post-operative biopsies shows profound potential in prognostic use.

Hypopharyngeal cancer (HPC) frequently presents at an advanced stage and displays early submucosal spread, resulting in a poor prognosis. It is among the worst of all cancers in the head and neck subsites. Therefore, detection of HPC at an earlier stage would be beneficial to patients. In this study, we used differential in-gel electrophoresis (DIGE) and two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomics analysis to identify the potential biomarkers for HPC. Among the differential proteins identified, calcium-binding protein S100A9 was overexpressed in HPC tissues compared with normal adjacent tissues, and S100A9 expression in metastatic tissues and advanced tumor tissues was higher than in nonmetastatic tissues and early tumor tissues. S100A9 expression was further confirmed in a large additional cohort. Our data showed that a higher S100A9 level was associated with a poor prognosis for HPC patients, and this may be an independent factor for predicting their prognosis. In addition, S100A9 protein expression was upregulated in human HPC cell lines compared with normal oral cavity epithelia. Knockdown of S100A9 induced significant inhibition of cell growth and their invasive ability. Mechanically, we found that downregulation of S100A9 significantly reduced the expression of NF-κB, phosphorylation of NF-κB and Bcl-2, as well as the expression of MMP7 and MMP2. Restoration of NF-κB expression sufficiently reversed the inhibitory effects on cell proliferation and invasion induced by S100A9 downregulation in vitro and in vivo. In conclusion, for the first time, we have identified S100A9 as an independent prognostic factor for HPC. Inhibiting S100A9 expression would be a potential novel diagnostic biomarker and therapeutic target for HPC treatment.

// Ping Wu 1 , Honglong Wu 2, 3, 4 , Yaoyun Tang 1 , Shi Luo 1 , Xing Fang 1 , Chubo Xie 1 , Jian He 1 , Suping Zhao 1 , Xiaofeng Wang 2, 3 , Jiajia Xu 2, 3 , Xi Chen 2, 3 , Dongfang Li 2, 3 , Huanming Yang 5, 6 and Jian Wang 5, 6 1 Department of Otorhinolaryngology Head & Neck Surgery, Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, Changsha 410008, China 2 Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China 3 Tianjin Translational Genomics Center, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China 4 Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China 5 BGI-Shenzhen, Shenzhen 518083, China 6 James D. Watson Institute of Genome Sciences, Hangzhou 310058, China Correspondence to: Yaoyun Tang, email: csuwoodpink@126.com Keywords: hypopharyngeal cancer, whole-exome sequencing, mutations, epigenetic, therapeutic target Received: April 12, 2017 Accepted: May 23, 2017 Published: July 28, 2017 ABSTRACT Hypopharyngeal cancer (HPC) frequently presents at an advanced stage, resulting in poor prognosis. Although combined surgical therapy and chemoradiotherapy have improved the survival for patients with HPC over the past 3 decades, the mortality rate in late-stage diagnosis of HPC is unsatisfactory. In this study, we performed whole-exome sequencing (WES) of 23 hypopharyngeal tumor and paired adjacent normal tissue to identify novel candidate driver genes associated with hypopharyngeal carcinoma. We identified several copy number variants (CNVs) and 15 somatic mutation genes that were associated with hypopharyngeal carcinoma. Mutations in nine new genes (PRB4, NSD1, REC8, ZNF772, ZNF69, EI24, CYFIP2, NEFH, KRTAP4-5) were also indentified. PRB4 and NSD1 expression were significantly upregulated in hypopharyngeal carcinoma, which was confirmed in an independent cohort using IHC. There was a positive relationship between PRB4 and NSD1. Downregulation of PRB4 by siRNA could inhibit cell growth, colony formation and cell invasion. Notably, we here demonstrate that NSD1 could bind to the promoter regions of PRB4 and activate promoter activity by reducing the binding of H3K27me2 and increasing the binding of H3K36me2 on PRB4 promoter. In summary, we pinpoint the predominant mutations in hypopharyngeal carcinoma by WES, highlighting the substantial genetic alterations contributing to hypopharyngeal carcinoma tumorigenesis. We also indentify a novel epigenetically regulatory between PRB4 and NSD1 that contribute to hypopharyngeal carcinoma tumorigenesis. They may become potential prognostic biomarkers and therapeutic target for hypopharyngeal carcinoma treatment.

// Jian He 1 , Ping Wu 1 , Yaoyun Tang 1 , Sulai Liu 1 , Chubo Xie 1 , Shi Luo 1 , Junfeng Zeng 1 , Jing Xu 1 and Suping Zhao 1 1 Department of Otorhinolaryngology Head & Neck Surgery, Province Key Laboratory of Otolaryngology Critical Diseases, Xiangya Hospital of Central South University, Changsha, Hunan, China Correspondence to: Ping Wu, email: // Keywords : nasopharyngeal carcinoma, chemoradiotherapy, overall survival, complete response, network meta-analysis Received : December 07, 2016 Accepted : February 20, 2017 Published : March 17, 2017 Abstract Object: A Bayesian network meta-analysis (NMA) was conducted to estimate the overall survival (OS) and complete response (CR) performance in nasopharyngeal carcinoma (NPC) patients who have been given the treatment of radiotherapy, concurrent chemoradiotherapy (C), adjuvant chemotherapy (A), neoadjuvant chemotherapy (N), concurrent chemoradiotherapy with adjuvant chemotherapy (C+A), concurrent chemoradiotherapy with neoadjuvant chemotherapy (C+N) and neoadjuvant chemotherapy with adjuvant chemotherapy (N+A). Methods: Literature search was conducted in electronic databases. Hazard ratios (HRs) accompanied their 95% confidence intervals (95%CIs) or 95% credible intervals (95%CrIs) were applied to measure the relative survival benefit between two comparators. Meanwhile odd ratios (ORs) with their 95% CIs or CrIs were given to present CR data from individual studies. Results: Totally 52 qualified studies with 10,081 patients were included in this NMA. In conventional meta-analysis (MA), patients with N+C exhibited an average increase of 9% in the 3-year OS in relation to those with C+A. As for the NMA results, five therapies were associated with a significantly reduced HR when compared with the control group when concerning 5-year OS. C, C+A and N+A also presented a decreased HR compared with A. There was continuity among 1-year, 3-year and 5-year OS status. Cluster analysis suggested that the three chemoradiotherapy appeared to be divided into the most compete group which is located in the upper right corner of the cluster plot. Conclusion: In view of survival rate and complete response, the NMA results revealed that C, C+A and C+N showed excellent efficacy. As a result, these 3 therapies were supposed to be considered as the first-line treatment according to this NMA.

Local recurrence after therapy remains a challenging problem for hypopharyngeal cancer (HPC) due to the chemotherapy resistance. Metformin is associated with reduced cancer risk through promoting global DNA methylation in cancer cells by controlling S-adenosylhomocysteine (SAHH) activity. However, the mechanisms by which metformin inhibits HPC remain elusive. In this study, we aim to investigate the role of metformin in HPC and illustrate the mechanism by which metformin regulates long non-coding RNAs (lncRNAs) expression. CCK-8 and annexin-V/PI double staining were performed to analyze the cell viability and apoptosis. LncRNA microarray analysis, QPCR, methylation specific PCR, Western blot and RNA Immunoprecipitation were performed to analyze the molecular mechanism, Here, we report that metformin inhibits FaDu cell proliferation in time- and dose-dependent manner by suppressing lncRNA SNHG7. Further investigations revealed that SNHG7 interacted with SAHH and metformin decreased SNHG7 expression by activating SAHH activity. Increased SAHH activity resulted in upregulating DNMT1 expression, leading to hypermethylation of SNHG7 promotor. In addition, upregulation of SNHG7 was associated with advanced stage. The patients with high SNHG7 have lower overall survival than that of with low SNHG7. Interestingly, SNHG7 levels were higher in taxol resistant patients than in taxol sensitive patients. Metformin sensitizes FaDu cells to taxol and irradiation through decreasing SNHG7. In conclusion, our recent study demonstrates that metformin inhibits FaDu cell proliferation by decreasing SNHG7 expression via SAHH-mediated DNA methylation. These findings indicate that combined metformin with paclitaxel or irradiation would be a novel therapeutic strategy to overcome resistance and prevent recurrence in HPC.

Due to the lack of a definite diagnosis, a frequent recurrence rate and resistance to chemotherapy or radiotherapy, the clinical outcome for patients with advanced laryngeal cancer has not improved over the last decade. Annexin A2 is associated with the invasion and metastasis of cancer cells. In the present study, it was demonstrated using differential proteomics analysis that Annexin A2 is highly expressed in laryngeal carcinoma tissues and this was confirmed using immunohistochemistry, which demonstrated that the expression of Annexin A2 in laryngeal carcinoma tissues was significantly higher than in healthy adjacent tissue. In addition, its potential predictive value in the prognosis of patients with laryngeal carcinoma was evaluated. The results demonstrated that Annexin A2 expression was significantly associated with tumor size, lymph node metastasis, distant metastasis and clinical stage. In addition, higher Annexin A2 expression was associated with a poor prognosis of patients with laryngeal cancer. Thus, the results of the present study indicate that Annexin A2 expression is an independent prognostic biomarker for evaluating the malignant progression of laryngeal cancer.

6056Background: In this study, tumor derived Cell-free DNA (cfDNA) is detected in plasma and saliva samples in head and neck squamous carcinomas (HNSCC), as well as genomic variants in para-carcino...