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Epstein-Barr virus and nasopharyngeal carcinoma.

Young LS, Dawson CW - Chin J Cancer (2014)

Bottom Line: Approximately 95% of the world's population sustains an asymptomatic, life-long infection with EBV.The virus persists in the memory B-cell pool of normal healthy individuals, and any disruption of this interaction results in virus-associated B-cell tumors.The study of EBV and its role in carcinomas continues to provide insight into the carcinogenic process that is relevant to a broader understanding of tumor pathogenesis and to the development of targeted cancer therapies.

View Article: PubMed Central - PubMed

Affiliation: Warwick Medical School, The University of Warwick, Coventry, CV4 7AL, UK. L.S.Young@warwick.ac.uk.

ABSTRACT
Since its discovery 50 years ago, Epstein-Barr virus (EBV) has been linked to the development of cancers originating from both lymphoid and epithelial cells. Approximately 95% of the world's population sustains an asymptomatic, life-long infection with EBV. The virus persists in the memory B-cell pool of normal healthy individuals, and any disruption of this interaction results in virus-associated B-cell tumors. The association of EBV with epithelial cell tumors, specifically nasopharyngeal carcinoma (NPC) and EBV-positive gastric carcinoma (EBV-GC), is less clear and is currently thought to be caused by the aberrant establishment of virus latency in epithelial cells that display premalignant genetic changes. Although the precise role of EBV in the carcinogenic process is currently poorly understood, the presence of the virus in all tumor cells provides opportunities for developing novel therapeutic and diagnostic approaches. The study of EBV and its role in carcinomas continues to provide insight into the carcinogenic process that is relevant to a broader understanding of tumor pathogenesis and to the development of targeted cancer therapies.

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Schematic representation of NPC pathogenesis.This model proposes that loss of heterozygosity (LOH) occurs early in NPC pathogenesis, possibly as a result of exposure to environmental cofactors such as dietary components (e.g., salted fish). This results in low-grade, preinvasive lesions that, after additional genetic and epigenetic events, become susceptible to stable EBV infection. Once cells have become infected, EBV latent genes provide growth and survival benefits, resulting in the development of NPC. Additional genetic and epigenetic changes occur after EBV infection.
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cjc-33-12-581-g002: Schematic representation of NPC pathogenesis.This model proposes that loss of heterozygosity (LOH) occurs early in NPC pathogenesis, possibly as a result of exposure to environmental cofactors such as dietary components (e.g., salted fish). This results in low-grade, preinvasive lesions that, after additional genetic and epigenetic events, become susceptible to stable EBV infection. Once cells have become infected, EBV latent genes provide growth and survival benefits, resulting in the development of NPC. Additional genetic and epigenetic changes occur after EBV infection.

Mentions: The presence of monoclonal EBV episomes in NPC indicates that viral infection precedes the clonal expansion of malignant cells[13]. However, epithelial infection may not be the initiating event in virus-associated carcinogenesis, as tonsils from patients with infectious mononucleosis (IM) and normal nasopharyngeal biopsies from individuals at high risk of developing NPC lack evidence of epithelial EBV infection[2]. EBV infection as detected by in situ hybridization to the abundantly expressed non-polyadenylated EBER RNAs has been demonstrated in high-grade (severe dysplastic and carcinoma in situ), preinvasive lesions in the nasopharynx, but not in low-grade disease or histologically normal nasopharyngeal epithelium[35],[79]. Both high-grade and carcinoma in situ lesions carry monoclonal EBV genomes[35]. Multiple genetic changes have been found in NPC, with frequent deletion of regions on chromosomes 3p, 9p, 11q, 13q, and 14q and promoter hypermethylation of specific genes on chromosomes 3p (RASSF1A, RARĪ²2) and 9p (p16, p15, p14, DAP-kinase)[80],[81]. Both 3p and 9p deletions have been identified in the absence of EBV infection in low-grade dysplastic lesions and in normal nasopharyngeal epithelium from individuals at high risk of developing NPC, suggesting that these genetic events occur early in NPC pathogenesis and may predispose to subsequent EBV infection[79], [82]. This possibility is supported by in vitro data demonstrating that stable EBV infection of epithelial cells requires an altered, undifferentiated cellular environment[83] and that cyclin D1 overexpression (a consequence of p16 deletion on chromosome 9p and amplification of the cyclin D1 locus on chromosome 11q) facilitates persistent EBV infection of immortalized nasopharyngeal epithelial cells[84]. Thus, a scheme has been proposed whereby loss of heterozygosity occurs early in NPC pathogenesis because of exposure to environmental cofactors such as dietary components (i.e., salted fish), creating low-grade, preinvasive lesions that become susceptible to EBV infection after additional genetic and epigenetic events (Figure 2). Once infected, EBV latent genes provide growth and survival benefits, resulting in the development of NPC. Additional genetic and epigenetic changes occur after EBV infection.


Epstein-Barr virus and nasopharyngeal carcinoma.

Young LS, Dawson CW - Chin J Cancer (2014)

Schematic representation of NPC pathogenesis.This model proposes that loss of heterozygosity (LOH) occurs early in NPC pathogenesis, possibly as a result of exposure to environmental cofactors such as dietary components (e.g., salted fish). This results in low-grade, preinvasive lesions that, after additional genetic and epigenetic events, become susceptible to stable EBV infection. Once cells have become infected, EBV latent genes provide growth and survival benefits, resulting in the development of NPC. Additional genetic and epigenetic changes occur after EBV infection.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308653&req=5

cjc-33-12-581-g002: Schematic representation of NPC pathogenesis.This model proposes that loss of heterozygosity (LOH) occurs early in NPC pathogenesis, possibly as a result of exposure to environmental cofactors such as dietary components (e.g., salted fish). This results in low-grade, preinvasive lesions that, after additional genetic and epigenetic events, become susceptible to stable EBV infection. Once cells have become infected, EBV latent genes provide growth and survival benefits, resulting in the development of NPC. Additional genetic and epigenetic changes occur after EBV infection.
Mentions: The presence of monoclonal EBV episomes in NPC indicates that viral infection precedes the clonal expansion of malignant cells[13]. However, epithelial infection may not be the initiating event in virus-associated carcinogenesis, as tonsils from patients with infectious mononucleosis (IM) and normal nasopharyngeal biopsies from individuals at high risk of developing NPC lack evidence of epithelial EBV infection[2]. EBV infection as detected by in situ hybridization to the abundantly expressed non-polyadenylated EBER RNAs has been demonstrated in high-grade (severe dysplastic and carcinoma in situ), preinvasive lesions in the nasopharynx, but not in low-grade disease or histologically normal nasopharyngeal epithelium[35],[79]. Both high-grade and carcinoma in situ lesions carry monoclonal EBV genomes[35]. Multiple genetic changes have been found in NPC, with frequent deletion of regions on chromosomes 3p, 9p, 11q, 13q, and 14q and promoter hypermethylation of specific genes on chromosomes 3p (RASSF1A, RARĪ²2) and 9p (p16, p15, p14, DAP-kinase)[80],[81]. Both 3p and 9p deletions have been identified in the absence of EBV infection in low-grade dysplastic lesions and in normal nasopharyngeal epithelium from individuals at high risk of developing NPC, suggesting that these genetic events occur early in NPC pathogenesis and may predispose to subsequent EBV infection[79], [82]. This possibility is supported by in vitro data demonstrating that stable EBV infection of epithelial cells requires an altered, undifferentiated cellular environment[83] and that cyclin D1 overexpression (a consequence of p16 deletion on chromosome 9p and amplification of the cyclin D1 locus on chromosome 11q) facilitates persistent EBV infection of immortalized nasopharyngeal epithelial cells[84]. Thus, a scheme has been proposed whereby loss of heterozygosity occurs early in NPC pathogenesis because of exposure to environmental cofactors such as dietary components (i.e., salted fish), creating low-grade, preinvasive lesions that become susceptible to EBV infection after additional genetic and epigenetic events (Figure 2). Once infected, EBV latent genes provide growth and survival benefits, resulting in the development of NPC. Additional genetic and epigenetic changes occur after EBV infection.

Bottom Line: Approximately 95% of the world's population sustains an asymptomatic, life-long infection with EBV.The virus persists in the memory B-cell pool of normal healthy individuals, and any disruption of this interaction results in virus-associated B-cell tumors.The study of EBV and its role in carcinomas continues to provide insight into the carcinogenic process that is relevant to a broader understanding of tumor pathogenesis and to the development of targeted cancer therapies.

View Article: PubMed Central - PubMed

Affiliation: Warwick Medical School, The University of Warwick, Coventry, CV4 7AL, UK. L.S.Young@warwick.ac.uk.

ABSTRACT
Since its discovery 50 years ago, Epstein-Barr virus (EBV) has been linked to the development of cancers originating from both lymphoid and epithelial cells. Approximately 95% of the world's population sustains an asymptomatic, life-long infection with EBV. The virus persists in the memory B-cell pool of normal healthy individuals, and any disruption of this interaction results in virus-associated B-cell tumors. The association of EBV with epithelial cell tumors, specifically nasopharyngeal carcinoma (NPC) and EBV-positive gastric carcinoma (EBV-GC), is less clear and is currently thought to be caused by the aberrant establishment of virus latency in epithelial cells that display premalignant genetic changes. Although the precise role of EBV in the carcinogenic process is currently poorly understood, the presence of the virus in all tumor cells provides opportunities for developing novel therapeutic and diagnostic approaches. The study of EBV and its role in carcinomas continues to provide insight into the carcinogenic process that is relevant to a broader understanding of tumor pathogenesis and to the development of targeted cancer therapies.

Show MeSH
Related in: MedlinePlus