The evidence for chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) occurrence is well established. The hepatocyte epithelium carcinogenesis caused by HBV has been investigated and reviewed in depth. Nevertheless, recent findings from preclinical and observational studies suggested that chronic HBV infection is equally important in extrahepatic cancer occurrence and survival, specifically gastrointestinal system-derived cancers. Immune microenvironment changes (immune-suppressive cytokine infiltration), epigenetic modification (N6-methyladenosine), molecular signaling pathways (PI3K–Akt and Wnt), and serum biomarkers such as hepatitis B virus X (HBx) protein are potential underlying mechanisms in chronic HBV infection-induced extrahepatic cancers. This narrative review aimed to comprehensively summarize the most recent advances in evaluating the association between chronic HBV infection and extrahepatic cancer risk and explore the potential underlying molecular mechanisms in the carcinogenesis induction of extrahepatic cancers in chronic HBV conditions.

/pdf/hepatitis-b-virus-infection-an-insight-into-the-clinical-3bvwmnnb.pdf

Hepatitis B virus infection: An insight into the clinical connection and molecular interaction between hepatitis B virus and host extrahepatic cancer risk

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

Purpose:

Despite significant improvement in locoregional control following radiotherapy (RT) +/- chemotherapy (CT) in the contemporary era, nasopharyngeal carcinoma (NPC) patients still suffer from a significant risk (∼20%) of distant metastasis (DM). Identifying those patients at risk of DM would aid in personalized treatment in the future. It has become increasingly apparent that microRNAs (miRNAs) play important roles in human cancer, and a number of miRNAs have been identified whose expression is associated with prognosis in a variety of cancers; hence, we proceeded to address the primary hypothesis that there is a miRNA expression signature capable of predicting DM for NPC patients.

Materials and Methods:

The expression of 734 unique human and viral miRNAs was measured in 125 (Training Set) and 121 (Validation Set) clinically-annotated NPC diagnostic biopsy samples using the nCounter human microRNA panel from Nanostring®. A signature associated with risk of DM was generated by fitting a penalized Cox Proportion Hazard (PH) regression model to the Training data set, and this signature was subsequently tested in the Validation cohort. Pathway enrichment analysis was then performed on validated targets of the four miRNAs comprising the final signature, to determine the potential biological impact of their dysregulation.

Results:

A 4-miRNA-expression signature, consisting of miR-140-5p, miR-34c-5p, miR-154-5p, and miR-449b-5p was identified in the Training set, which was significantly associated with an increased risk of developing DM (HR 8.25; p=0.0008). This signature was then validated in an independent Validation set of 121 NPC patient samples (HR 3.2; p=0.01), and observed to be the strongest independent predictor when multivariate analysis was performed including other clinically relevant variables. Specifically, this 4-miRNA signature provided additional risk categorization value beyond nodal status. Finally, pathway enrichment analysis indicated that the targets of these miRNAs appear to be converging on cell cycle pathways.

Conclusion:

A new 4-miRNA signature set has been validated for DM in NPC, the major cause of death in the era of intensity-modulated radiation therapy. Importantly, this signature predicted for risk of DM independent of other clinical factors, including nodal stage, which is the current most important variable associated with DM in NPC. Important biological insights will be acquired with greater in-depth interrogation of these 4-miRNAs, which should facilitate the discovery and development of novel molecularly-targeted therapies that could improve outcome for future NPC patients.

Citation Format: Jeffrey Phillip Bruce. The identification of a microRNA signature associated with risk of distant metastasis in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4007. doi:10.1158/1538-7445.AM2014-4007

/pdf/abstract-4007-the-identification-of-a-microrna-signature-321elvzm5c.pdf

Abstract 4007: The identification of a microRNA signature associated with risk of distant metastasis in nasopharyngeal carcinoma

The present meta-analysis was conducted to evaluate the prognostic value of pre and post-Epstein Barr Virus (EBV) DNA load testing and to assess the clinical benefit of using this molecular approach in the prognosis for a better nasopharyngeal carcinoma (NPC) management. Relevant studies were searched in different database until May 2020. Patient´s outcomes overall survival (OS), disease free survival (DFS), progression-free survival (PFS), distant-metastasis-free survival (DMFS), and local-regional-failure-free survival (LRFS), hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted from selected studies. The association of pre and post-EBV DNA load and survival outcomes was assessed using review manager and the pooled HRs with 95% CIs were calculated. Twenty-six eligible studies were included in this meta-analysis, with a total of 9966 patients. Pooled HRs showed that EBV DNA levels before and after treatment are significantly associated with survival outcomes, with HR (95% CI) of 2.09 [1.74, 2.51] for OS, 1.77 [1.19, 2.62] for DFS, 2.53 [2.18, 2.92] for DMFS, 1.78 [1.45, 2.19] for LRFS and 2.17 [1.91, 2.47] for PFS in pre-EBV DNA, and an HR (95%) of 4.52 [2.44, 8.36], 4.08 [2.38, 6.99], 5.59 [ 3.58, 8.71] and 8.88 [5.29, 14.90] for OS, DFS and PFS and DMFS in post-EBV DNA, respectively. High pre and post-EBV DNA levels were significantly associated with poor NPC patient´s survival outcomes; which clearly confirm the high interest to introduce viral EBV DNA load as a prognostic biomarker for NPC management.

https://doi.org/10.11604/pamj.2022.41.6.28946

Prognostic value of Epstein-Barr virus DNA load in nasopharyngeal carcinoma: a meta-analysis

Purpose
In patients with Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), intertumor heterogeneity causes interpatient heterogeneity in the risk of distant metastasis. We aimed to identify novel biomarkers of metastasis risk using reverse-phase protein array (RPPA) profiling of NPC patients at risk for metastasis and considering plasma EBV DNA load.

Experimental design
A total of 98 patients with NPC with and without metastasis after treatment, matched with respect to clinical parameters, were enrolled. Total protein expression was measured by RPPA, and protein functions were analyzed by pathway bioinformatics.

Results
The RPPA analysis revealed a profile of 70 proteins that were differentially expressed in metastatic and nonmetastatic tumors. Plasma EBV DNA load after treatment correlated with protein expression level better than plasma EBV DNA load before treatment did. The biomarkers of NPC metastasis identified by proteomics regulate signaling pathways involved in cell-cycle progression, apoptosis, and EMT. We identified 26 biomarkers associated with 5-year distant failure-free survival in univariate analysis; 5 biomarkers remained significant in multivariate analysis.

Conclusions and clinical relevance
A comprehensive RPPA profiling study is warranted to identify novel metastasis-related biomarkers and further examine the activation state of signaling proteins to improve estimation of metastasis risk for patients with EBV-associated NPC.

This article is protected by copyright. All rights reserved

Novel biomarkers of nasopharyngeal carcinoma metastasis risk identified by reverse phase protein array based tumor profiling with consideration of plasma Epstein–Barr virus DNA load

This cohort study investigates the prognostic value and biological associations of hepatitis B surface antigen and plasma Epstein-Barr virus DNA levels with distant metastasis in patients with nasopharyngeal carcinoma.

https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2801196/li_2023_oi_221522_1675185292.23741.pdf

Synergistic Association of Hepatitis B Surface Antigen and Plasma Epstein-Barr Virus DNA Load on Distant Metastasis in Patients With Nasopharyngeal Carcinoma

Clinical implications of hepatitis B viral infection in Epstein–Barr virus-associated nasopharyngeal carcinoma

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Clinical implications of hepatitis B viral infection in Epstein–Barr virus-associated nasopharyngeal carcinoma

Novel biomarkers of nasopharyngeal carcinoma metastasis risk identified by reverse phase protein array based tumor profiling with consideration of plasma Epstein–Barr virus DNA load