Prognostic Indicator In Nasopharyngeal Carcinoma Research Articles

EPHB2 as a recurrence-related gene and a prognostic indicator in nasopharyngeal carcinoma: A bioinformatics screening and immunohistochemistry verification.

Recurrence and metastasis of nasopharyngeal carcinoma (NPC) after radical treatment is a major bottleneck in clinical treatment. Therefore, we aimed to find the genes related to metastasis after radical treatment in NPC patients. Public datasets in the Gene Expression Omnibus database were consulted and the differential expression genes (DEGs) were screened out. The possible roles of the DEGs were annotated by Gene Ontology, and pathway analysis. The hub genes/proteins were then filtered out through protein-protein interaction network construction. The key genes were sifted out from the hub genes, and their expressions were verified by qPCR and immunohistochemistry assays. A total of 28 DEGs were filtered out, which may be enriched in different signaling pathways. Of these DEGs, 11 hub genes were filtered out, among which EPHB2 was shown to be over-expressed in NPC tissues. Further experimental assays confirmed that EPHB2 was overexpressed in NPC cells, which might be associated with tumor recurrence, neck lymph node metastasis, and advanced clinical stages. Moreover, high EPHB2 expression predicted poor prognosis in NPC patients. EPHB2 might be a novel recurrence-related biomarker and a prognostic factor for NPC. Moreover, it might also be used as a potential treatment target for NPC.

SDF2L1 Inhibits Cell Proliferation, Migration, and Invasion in Nasopharyngeal Carcinoma.

The purpose of this study was to explore the relationship between stromal cell-derived factor 2-like 1 (SDF2L1) and nasopharyngeal carcinoma (NPC). 12 NPC tissues and 12 chronic nasopharyngitis tissues were involved in our study. Quantitative real-time PCR (qRT-PCR) and Western Blot were utilized to detect the expression of SDF2L1. Besides, immunofluorescence analysis was utilized to determine the protein expression of 97 paraffin-embedded NPC tissues and 58 nasopharyngitis tissues. Biological functional experiment included Cell Counting Kit-8 (CCK-8) assay, cell clone formation assay, cell scratch migration assay, Transwell migration assay, and Transwell invasion assay. All data were analyzed by SPSS. Results showed that downexpression of SDF2L1 was prominently present in NPC tissues and cells. Furthermore, silencing the expression of SDF2L1 promoted NPC proliferation, migration, and invasion in vitro, while overexpression of SDF2L1 has the opposite effect. In conclusion, SDF2L1 may act as a cancer suppressor gene, play a crucial role in the occurrence and development of NPC, and be a new therapeutic target or prognostic indicator for NPC.

ZNF488 is an independent prognostic indicator in nasopharyngeal carcinoma and promotes cell adhesion and proliferation via collagen IV/FAK/AKT/Cyclin D1 pathway.

Background: ZNF488 acts as an oncogene which promotes cell invasion and endows tumor cells stem cell capacity in nasopharyngeal carcinoma (NPC), but its correlation with clinicopathologic characteristics and patients’ survival in NPC remain undefined.Methods: In this study, 158 cases of confirmed NPC were subjected to immunohistochemistry staining for evaluating endogenous expression. Kaplan–Meier method and log-rank test were used to estimate the survival rates. The relationship between ZNF488 and clinicopathological characteristics was statistically calculated by chi-squared test, univariate and multivariate analysis. In addition, adhesion assay, MTT and colony formation assays were performed for measuring adhesion and proliferation capacity. Cell cycle analysis via flow cytometry was conducted to explore cell cycle distribution. Western blot was used to detect pathway protein levels, and the pFAK (Y397) kit was used for focal adhesion kinase (FAK) activation.Results: We demonstrated that high expression of ZNF488 was significantly correlated with locoregional failure (P=0.018) and distant metastasis (P=0.001). Patients with high ZNF488 expression had poorer overall survival (P<0.001), loco-regional recurrence-free survival (P<0.001), distance metastasis-free survival (P<0.001) and progression-free survival (P<0.001) than those with low ZNF488 group. Multivariate analysis showed that ZNF488 expression was an independent prognostic indicator for predicting NPC patients’ survival (HR, 3.314; 95% CI, 1.489–7.386; P=0.003). Additionally, ZNF488-induced collagen IV/FAK/AKT to enhance adhesion ability meanwhile led to the upregulation of Cyclin D1 to facilitate cell proliferation through promoting cell cycle progression and inhibition of apoptosis through caspase-independent way.Conclusion: These results reveal that ZNF488, as an independent prognostic indicator, promotes cell adhesion and proliferation through collagen IV/FAK/AKT/Cyclin D1 pathway in NPC.

Prognostic significance of the long noncoding RNAs in nasopharyngeal carcinoma: a systematic review and meta-analysis.

Background and objectiveNasopharyngeal carcinoma (NPC) is a common head and neck malignancy. Despite recent advances in treatment, the prognosis, particularly for those at the advanced stages, remains poor. Moreover, the underlying genetic and molecular events have remained obscure so far. Recently, increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) could act as either oncogenes or tumor suppressor genes in various cancers depending on their targets. And some lncRNAs have been shown to be aberrantly expressed in NPC. In this meta-analysis, we try to elucidate the possible role of lncRNAs and their expression on prognosis in NPC.MethodsWe searched the databases of PubMed, Embase, and Web of Science for relevant articles ranging from January 2000 to December 2017. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate the prognostic value of lncRNAs in NPC. Odds ratios (ORs) were used to assess the association between lncRNAs and clinicopathological characteristics.ResultsA total of 14 eligible publications including 14 on prognosis and eight on clinicopathological characteristics were identified. Our results demonstrated that the high expression of lncRNAs was related to poor overall survival (OS; HR =1.55; 95% CI =1.01, 2.40; P=0.05) and disease-free survival (DFS; HR =1.83; 95% CI =1.07, 3.13; P=0.03) of NPC. Moreover, the expression of lncRNAs was correlated with male gender (OR =1.42; 95% CI =1.05, 1.91; P=0.02), lymph node status (OR =2.20; 95% CI =1.29, 3.73; P=0.004), and tumor node metastasis (TNM) clinical stage (OR =2.55; 95% CI =1.12, 5.78; P=0.03).ConclusionThis meta-analysis shows that the level of expression of lncRNAs may be a potential prognostic indicator in NPC.

CFTR is a potential marker for nasopharyngeal carcinoma prognosis and metastasis

While there is an increasing interest in the correlation of cystic fibrosis transmembrane conductance regulator (CFTR) and cancer incidence, the role of CFTR in nasopharyngeal carcinoma (NPC) development remains unknown. In this study, we aimed to explore the prognostic value of CFTR in NPC patients. The expression of CFTR was determined in NPC cell lines and tissues. Statistical analysis was utilized to evaluate the correlation between CFTR expression levels and clinicopathological characteristics and prognosis in 225 cases of NPC patients. The results showed that CFTR was down-regulated in NPC tissues and cell lines. Low expression of CFTR was correlated with advanced stage (p = 0.026), distant metastasis (p < 0.001) and poor prognosis (p < 0.01). Multivariate analysis identified CFTR as an independent prognostic factor (p = 0.003). Additionally, wound healing and transwell assays revealed that overexpression of CFTR inhibited NPC cell migration and invasion, whereas knockdown of CFTR promoted cell migration and invasion. Thus, the current study indicates that CFTR, as demonstrated to play an important role in tumor migration and invasion, may be used as a potential prognostic indicator in NPC.

Associations of Human Leukocyte Antigen-DRB1 Alleles with Nasopharyngeal Carcinoma and Its Clinical Significance in Xinjiang Uyghur Autonomous Region of China.

Background:Genetic susceptibility is one of the major etiological factors for nasopharyngeal carcinoma (NPC). Among the genetic predisposing factors, human leukocyte antigen (HLA) genes have been reported to be associated with NPC. This study aimed to investigate the associations of HLA-DRB1 alleles with NPC and the clinical significance of HLA-DRB1 alleles in NPC.Methods:From January 2009 to December 2013, 140 NPC patients (118 Han patients and 22 Uyghur patients) and 158 healthy controls (81 Han individuals and 77 Uyghur individuals) from Xinjiang Province were genotyped for HLA-DRB1 using the polymerase chain reaction-sequence specific primer technique. Chi-square analysis was used when comparing allele frequencies between groups. The clinical outcomes were evaluated by Kaplan-Meier method and Cox regression model.Results:Compared with healthy controls, the allele frequency of HLA-DRB1*0701 was increased in the Uyghur patients (P = 0.008) but not in the Han patients (P = 0.869). HLA-DRB1*0101 allele was presented with higher frequency in clinical Stage I + II group compared with clinical Stage III + IV group in the Han patients (P = 0.015) but not in the Uyghur patients (P = 1.000). Higher frequency of HLA-DRB1*1501 allele was observed in patients aged <45 years compared with those in patients aged ≥45 years (P = 0.002). Neither HLA-DRB1*0701 nor HLA-DRB1*0101 had a statistically significant association with 3-year survival.Conclusions:This study found HLA-DRB1*0701 in Uyghur population was associated with an increased risk of developing NPC. In Han population, we found HLA-DRB1*0101 was associated with protection from disease progression, and HLA-DRB1*1501 was associated with early age of onset. HLA-DRB1 could not be identified as a prognostic indicator for NPC in either Han or Uyghur patients.

Low expression of Aldo-keto reductase 1B10 is a novel independent prognostic indicator for nasopharyngeal carcinoma.

BackgroundNasopharyngeal carcinoma (NPC) is one of the most common human head and neck cancers with high incidence in Southern China, Southeast Asia and North Africa. Because of its nonspecific symptoms, the early diagnosis of NPC is very difficult. The 5-year survival rate is not ideal in spite of great innovations in radiation and chemotherapy treatments. Highly sensitive and specific prognostic biomarkers are eager for NPC clinical diagnosis. To find specific target molecules is very important for individualized treatment. Aldo–keto reductase B10 (AKR1B10) is closely related to tumorigenesis and tumor development, and however, its expression level in NPC tissues is not clear.ResultsAKR1B10 expression levels were validated in benign, para-cancerous nasopharyngeal and NPC tissues by immunohistochemical evaluation. AKR1B10 was positively expressed in 42 (82.4 %) of 51 benign specimens, and 235 (98.7 %) of 238 para-carcinoma specimens. This percentage was significantly higher than 44.5 % (133/299) in nasopharyngeal carcinoma tissue (p < 0.01). AKR1B10 mRNA quantitative levels detected by real-time quantitative RT-PCR in 90 NPC tissue samples (0.10 ± 0.21) were significantly lower than that in 15 benign tissue samples (1.03 ± 1.12) (p < 0.01). AKR1B10 expression levels in NPC were correlated negatively with T-classification, lymph node metastasis (p < 0.05). We established nasopharyngeal cancer monoclonal cells CNE-2/AKR1B10 with AKR1B10 stable expression and CNE-2/vector cells without AKR1B10 expression by using a modified lentivirus-mediated method, and found that AKR1B10 inhibited the proliferation of CNE-2/AKR1B10 cells by using MTT assay and flow cytometry, and cell migration by in vitro scratch test.ConclusionTaken together, our data suggest that low expression of AKR1B10 is an independent prognostic indicator in nasopharyngeal carcinoma, and that AKR1B10 may be involved in regulating the proliferation and migration of nasopharyngeal cancer cells.

Overexpression of Transient Receptor Protein Cation Channel Subfamily A Member 1, Confers an Independent Prognostic Indicator in Nasopharyngeal Carcinoma.

Background: Detection of oncogenes provides chances to understand tumor development and progression. Transient receptor protein cation channel subfamily A, member 1 (TRPA1) transcript was significantly upregulated in nasopharyngeal carcinoma (NPC) with a stepwise upregulation from low- to high-stage NPCs from a preliminary data analysis in the Gene Expression Omnibus database. The TRPA1 gene is a member of the TRP channel family, encoding integral membrane proteins that functions as cation channels. Loss of calcium homeostasis takes place in cancer cells.Methods: Immunostaining of TRPA1 was analyzed on 124 biopsies from NPC patients retrospectively. The H-score method was used to evaluate the immunoexpression of TRPA1. The correlations between H-score of TRPA1 protein level and clinicopathological factors, as well as the significances of TRPA1 protein level for disease-specific, distal-metastasis-free and local recurrence-free survivals were assessed.Results: These patients were characterized to be no initial metastasis and medicated with the traditional procedure. The TRPA1 score was found to be associated with clinicopathological parameters and patient survivals. Along with the guideline of 7th edition of the American Joint Committee on Cancer, we found that TRPA1 upregulation (50%) was associated with advanced primary tumor (P = 0.009) and overall clinical stage (P = 0.019). In univariate log-rank testing, primary tumor, nodal status, stage and TRPA1 protein level significantly contributed to worse disease-specific survival, distal metastasis-free survival and local recurrence-free survival. In multivariate analysis, high TRPA1 protein level and tumor stage emerged as independent prognostic indicators for inferior disease-specific survival (P = 0.014; P = 0.003), distal metastasis-free survival (P = 0.004; P = 0.034) and recurrence-free survival (P = 0.017; P = 0.015).Conclusions: The upregulation of TRPA1 protein level is frequently correlated to unfavorable prognosticators and gives rise to cancer progression in NPC patients.

Expression of interleukin-8, interleukin-10 and Epstein-Barr viral-load as prognostic indicator in nasopharyngeal carcinoma.

Interleukin-8 (IL-8) is angiogeneic chemokine that plays a potential role in both development and progression of many human malignancies including nasopharyngeal carcinoma (NPC). Epstein- Barr virus (EBV) is recognized to be an important etiologic agent of NPC as the viral gene products are frequently detected in NPC tissue along with the elevation of antibody titre to the viral protein (VCA-p18+ EBNA1) of IgA in the majority of patients. Elevated plasma of Viral Load is regarded as an important marker for the presence of the disease and for the monitoring of disease progression. However, other serum/plasma parameters such as the level of certain interleukins (IL-8 and IL-10) has also been implicated in NPC progression. The study aimed to investigate the correlations between plasma Viral Load and the level of interleukin (IL-8) and Interleukin (IL-10) in relating these parameters to the stages of NPC. In addition of Viral Load (VCA-p18+EBNA1) IgA, Interleukin-8 and Interleukin-10 before and after therapy will be investigated to seek the possible marker for disease progression. A total of 39 NPC patients and 29 healthy control individuals enrolled in this study. Plasma Viral Load was quantified using real-time quantitative PCR. The Level of plasma interleukins both IL-8 and IL-10 were analyzed using ELISA methods. Results indicated there was a significant decrease in viral load was detected in plasma of NPC patients following therapy. Plasma of viral load was shown to be a good prognosticator for disease progression. There were positive correlation between plasma of viral load and IL-8. These non invasive parameters expressed in blood, could be substitutes of viral load using brushing method, which is invasive. In conclusion that: Viral Load, (VCA-p18+EBNA1) IgA and IL-8 levels are promising markers for the presence of NPC and progression of the disease.

Overexpression of CIP2A is an independent prognostic indicator in nasopharyngeal carcinoma and its depletion suppresses cell proliferation and tumor growth.

BackgroundCancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that acts as a prognostic marker for several human malignancies. In this study, we investigated the clinical significance of CIP2A and its function in nasopharyngeal carcinoma (NPC).MethodsQuantitative RT-PCR, western blot, and immunohistochemistry analyses were used to quantify CIP2A expression in NPC cell lines and clinical samples. Kaplan-Meier curves were used to estimate the association between CIP2A expression and patient survival. The functional role of CIP2A in NPC cell lines was evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation and xenograft growth.ResultsCIP2A levels were upregulated in NPC cell lines and clinical samples at both the mRNA and protein levels (P < 0.01). Patients with high CIP2A expression had poorer overall survival (HR, 1.98; 95% CI, 1.16-3.34; P = 0.01) and poorer disease-free survival (HR, 1.68; 95% CI, 1.07-2.62; P = 0.02) rates than patients with low CIP2A expression. In addition, CIP2A expression status was an independent prognostic indicator for NPC patients. The depletion of CIP2A expression inhibited c-Myc protein expression in NPC cell lines, suppressed cell viability, colony formation, and anchorage-independent growth in vitro, and inhibited xenograft tumor growth in vivo.ConclusionsOur data demonstrate that high CIP2A expression in patients was associated with poor survival in NPC, and depletion of CIP2A expression inhibited NPC cell proliferation and tumor growth. Thus, these results warrant further investigation of CIP2A as a novel therapeutic target for the treatment of NPC.

Increase in IkappaB kinase alpha expression suppresses the tumor progression and improves the prognosis for nasopharyngeal carcinoma.

Recent studies have suggested that the action of IkappaB kinase alpha (IKKα) as a tumor suppressor is crucial in the development of skin carcinoma, but its role in nasopharyngeal carcinoma (NPC) remains unknown. We examined the IKKα expression in specimens from 157 NPC patients by immunohistochemistry and analyzed the effect of IKKα on prognosis. The functional significance of IKKα expression in NPC cell lines was investigated by IKKα overexpression or downregulation in in vitro studies. The in vitro assays revealed that the IKKα expression was negatively correlated with the invasiveness, migration, and angiogenesis of NPC cells. Overexpression or downregulation of IKKα could significantly repress or enhance the above characteristics, respectively, and these effects were independent of IKKα kinase or EBNA1. In 157 NPC cases, IKKα was differentially expressed in NPC tissues. High expression of IKKα was associated significantly with a high disease-free survival (DFS; P = 0.002) or overall survival (OS; P = 0.014). Multivariate analyses showed that the IKKα expression was an independent risk factor for DFS (HR, 2.302; P = 0.011) and OS (HR, 3.578; P = 0.006). Our findings indicated that IKKα plays a crucial role as a tumor suppressor that suppresses the invasion, metastasis, and angiogenesis of NPC cells in vitro and correlates with the survival in NPC patients. Therefore, IKKα is not only a novel independent prognostic indicator in NPC, but also targeting IKKα expression may provide a potential therapeutic strategy for NPC.

Quantitative expression analysis of the apoptosis‐related gene, BCL2L12, in head and neck squamous cell carcinoma

BCL2L12 is a recently identified gene belonging to the BCL2 family, members of which are implicated in head and neck squamous cell carcinoma (HNSCC). We have recently shown that BCL2L12 mRNA expression is an unfavorable prognostic indicator in nasopharyngeal carcinoma (NPC) and that BCL2L12 can be regarded as a novel, useful tissue biomarker for the prediction of NPC patients' short-term relapse. The aim of this study was to analyze the mRNA expression of the novel apoptosis-related gene BCL2L12 in patients with HNSCC. Total RNA was isolated from 53 malignant tumors originating in larynx, pharynx, tongue, buccal mucosa, parotid glands, and nasal cavity, as well as from 34 adjacent non-cancerous tissue specimens, resected from patients with HNSCC. A highly sensitive real-time PCR method for BCL2L12 mRNA quantification in head and neck tissues was developed using the SYBR(®) Green chemistry. After preparing cDNA by reverse transcription, relative quantification was performed using the comparative C(T) () method. BCL2L12 mRNA levels were lower in laryngeal tumors of advanced tumor, node, metastasis (TNM) stage or bigger size and in well-differentiated malignant tongue neoplasms, compared with early-stage laryngeal tumors or poorly differentiated tongue tumors. Interestingly, the BCL2L12 expression showed significant discriminatory value, distinguishing efficiently patients with tongue squamous cell carcinoma (SCC) from non-cancerous population. This is the first study examining the BCL2L12 mRNA expression in HNSCC. Our results suggest that BCL2L12 mRNA expression may serve as a potential prognostic biomarker in tongue and/or larynx SCC, which principally constitute the great majority of HNSCC cases worldwide.

A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma

Tumor necrosis factor alpha (TNFα) is an inflammatory cytokine that is present in the microenvironment of many tumors and is known to promote tumor progression. To examine how TNFα modulates the progression and metastasis of nasopharyngeal carcinoma, we used Affymetrix chips to identify TNFα-inducible genes that are dysregulated in this tumor. Elevated expression of TNFAIP2, which encodes TNFα-inducible protein 2 and not previously known to be associated with cancer, was found and confirmed by quantitative RT-PCR of TNFAIP2 expression in nasopharyngeal carcinoma and adjacent normal tissues. Immunohistochemical analysis showed that the TNFAIP2 protein was highly expressed in tumor cells. Analysis of 95 nasopharyngeal carcinoma biopsy specimens revealed that high TNFAIP2 expression was significantly correlated with high-level intratumoral microvessel density (P=0.005) and low distant metastasis-free survival (P=0.001). A multivariate analysis further confirmed that TNFAIP2 was an independent prognostic factor for nasopharyngeal carcinoma (P=0.002). In vitro, TNFα treatment of nasopharyngeal carcinoma HK1 cells was found to induce TNFAIP2 expression, and siRNA-based knockdown of TNFAIP2 dramatically reduced the migration and invasion of nasopharyngeal carcinoma HK1 cells. These results collectively suggest for the first time that TNFAIP2 is a cell migration-promoting protein and its expression predicts distant metastasis. Our data suggest that TNFAIP2 may serve as an independent prognostic indicator for nasopharyngeal carcinoma.

Evaluation of tumor angiogenesis measured with microvessel density (MVD) as a prognostic indicator in nasopharyngeal carcinoma: Results of RTOG 9505

The objective of this study was to evaluate tumor angiogenesis as measured by microvessel density (MVD) as an independent prognostic factor in patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy alone. Eligible patients included those with NPC treated with radiotherapy. Paraffin blocks of the primary tumor had a hematoxylin and eosin-stained section prepared at the block face. One representative section for tumor was stained for factor VIII-related antigen using a standard immunoperoxidase staining technique. MVD was determined by light microscopy in areas of invasive tumor containing the highest numbers of capillaries and microvessels per area. Individual microvessel counts were made on a 200x field within the area of most intense tumor neovascularization. Results were expressed as the highest number of microvessels identified within any single 200x field. Using a breakpoint of MVD <60 vs. > or =60, the distributions between the two MVD groups were compared by the method of Gray. Overall survival rates were estimated by the Kaplan-Meier method and compared by the log-rank test. A multivariate Cox proportional hazard model was employed to examine the relationship between MVD and disease outcomes while adjusting for other concomitant variables. One hundred sixty-six were eligible, of whom 123 had values determined for MVD. The MVD values ranged from 9 to 243 with a median of 70. In the multivariate analysis of overall survival, distant metastases, and local-regional failure, MVD did not significantly improve the model containing T stage, N stage, age, radiation dose, and World Health Organization class. We found no significant differences in overall survival, time to distant metastasis, or time to local-regional failure using a breakpoint of MVD <60 vs. MVD > or =60. The study was perhaps limited by the small size of the NPC samples.

Detection of Epstein-Barr Virus DNA in the Peripheral-Blood Cells of Patients With Nasopharyngeal Carcinoma: Relationship to Distant Metastasis and Survival

Nasopharyngeal carcinoma (NPC) has been proved to be an Epstein-Barr virus (EBV)-associated cancer. By use of nested polymerase chain reactions (PCRs), we examined whether the presence of EBV DNA in the peripheral-blood cells (PBC) can serve as a prognostic indicator for NPC. Peripheral blood from 124 patients with NPC who had no evidence of distant metastasis and 114 healthy volunteers with serologically positive findings for EBV infection was collected prospectively. Plasma and erythrocytes were separated. DNA was extracted from PBCs and analyzed by a nested PCR using primers specific to Epstein-Barr virus nuclear antigen 1 (EBNA-1). All patients were treated by radiotherapy with or without chemotherapy. Clinical parameters and status of EBNA-1 in PBCs were used for survival analysis using the Kaplan-Meier method and the Cox proportional hazards model. Positive rates of EBNA-1 DNA in PBCs of NPC patients and healthy volunteers are 71% and 14%, respectively (P =.001). No significant difference was observed with regard to the clinical characteristics of patients who were EBNA-1-positive (n = 88) and those who were EBNA-1-negative (n = 36). After a median follow-up period of 38 months (range, 24 to 56 months), 29 of 88 EBNA-1-positive patients and only one of 36 EBNA-1-negative patients developed distant metastases (P =.00015). Kaplan-Meier estimates of overall survival (P =.0010), metastasis-free survival (P =.0004), and progression-free survival (P =.0004) were significantly lower for the patients in the EBNA-1-positive group than for those in the EBNA-1-negative group. Multivariate Cox analysis confirmed the same results. The presence of EBNA-1 DNA in PBCs is a novel, important risk factor for patients with NPC that indicates a significantly higher risk of developing distant metastasis as well as a lower survival rate.