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 asympto...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 EBVpositive 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.展开更多
Among all head and neck (H&N) cancers,nasopharyngeal carcinoma (NPC) represents a distinct entity regarding epidemiology,clinical presentation,biological markers,carcinogenic risk factors,and prognostic factors.NP...Among all head and neck (H&N) cancers,nasopharyngeal carcinoma (NPC) represents a distinct entity regarding epidemiology,clinical presentation,biological markers,carcinogenic risk factors,and prognostic factors.NPC is endemic in certain regions of the world,especially in Southeast Asia,and has a poor prognosis.In Indonesia,the recorded mean prevalence is 6.2/100 000,with 13 000 yearly new NPC cases,but otherwise little is documented on NPC in Indonesia.Here,we report on a group of 1121 NPC patients diagnosed and treated at Dr.Cipto Mangunkusumo Hospital,Jakarta,Indonesia between 1996 and 2005.We studied NPC incidence among all H&N cancer cases (n=6000) observed in that period,focusing on age and gender distribution,the ethnic background of patients,and the disease etiology.We also analyzed most prevalent signs and symptoms and staging of NPC patients at first presentation.In this study population,NPC was the most frequent H&N cancer (28.4%),with a male-to-female ratio of 2.4,and was endemic in the Javanese population.Interestingly,NPC appeared to affect patients at a relatively young age (20% juvenile cases) without a bimodal age distribution.Mostly,NPC initiated in the fossa of Rosenmuller and spreaded intracranially or locally as a mass in the head.Occasionally,NPC developed at the submucosal level spreading outside the anatomic limits of the nasopharynx.At presentation,NPC associated with hearing problems,serous otitis media,tinnitus,nasal obstruction,anosmia,bleeding,difficulty in swallowing and dysphonia,and even eye symptoms with diplopia and pain.The initial diagnosis is difficult to make because early signs and symptoms of NPC are not specific to the disease.Early-age Epstein-Barr virus (EBV) infection combined with frequent exposure to environmental carcinogenic co-factors is suggested to cause NPC development.Undifferentiated NPC is the most frequent histological type and is closely associated with EBV.Expression of the EBV-encoded latent membrane protein 1(LMP1) oncogene in biopsy material was compared展开更多
AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedde...AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).T展开更多
In 1964,a new herpesvirus,Epstein-Barr virus(EBV),was discovered in cultured tumor cells derived from a Burkitt lymphoma(BL)biopsy taken from an African patient.This was a momentous event that reinvigorated research i...In 1964,a new herpesvirus,Epstein-Barr virus(EBV),was discovered in cultured tumor cells derived from a Burkitt lymphoma(BL)biopsy taken from an African patient.This was a momentous event that reinvigorated research into viruses as a possible cause of human cancers.Subsequent studies demonstrated that EBV was a potent growth-transforming agent for primary B cells,and that all cases of BL carried characteristic chromosomal translocations resulting in constitutive activation of the c-MYC oncogene.These results hinted at simple oncogenic mechanisms that would make Burkitt lymphoma paradigmatic for cancers with viral etiology.In reality,the pathogenesis of this tumor is rather complicated with regard to both the contribution of the virus and the involvement of cellular oncogenes.Here,we review the current understanding of the roles of EBV and c-MYC in the pathogenesis of BL and the implications for new therapeutic strategies to treat this lymphoma.展开更多
Epstein-Barr virus(EBV)is associated with nasopharyngeal carcinoma(NPC)tumorigenesis.However,the mechanism(s)connecting EBV infection and NPC remain unclear.Recently,a new class of EBV microRNAs(miRNAs)has been descri...Epstein-Barr virus(EBV)is associated with nasopharyngeal carcinoma(NPC)tumorigenesis.However,the mechanism(s)connecting EBV infection and NPC remain unclear.Recently,a new class of EBV microRNAs(miRNAs)has been described.To determine how EBV miRNAs control the expression of host genes,and to understand their potential role in NPC tumorigenesis,we profiled the expression of 44 mature EBV miRNAs and potential host genes in NPC and non-tumor nasopharyngeal epithelial tissues.We found that 40 EBV miRNAs from the BART transcript were highly expressed in NPC.Analysis of potential BART miRNA target genes revealed that 3140 genes and several important pathways might be involved in the carcinogenesis of NPC.A total of 105 genes with potential EBV miRNA binding sites were significantly downregulated,suggesting that EBV miRNAs may regulate these genes and contribute to NPC carcinogenesis.An EBV miRNA and host gene regulation network was generated to provide useful clues for validating of EBV miRNA functions in NPC tumorigenesis.展开更多
基金supported by Cancer Research UK and the European Commission’s FP6 Life-Sciences-Health Programme(INCA Project:LSHC-CT-2005-018704)
文摘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 EBVpositive 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.
基金supported by KWF-Kankerbestrijding(Netherlands Cancer Societygrant KWF IN2006-21)a hospital grant for the collaboration between Medical Faculty of University of Indonesia and Vrije University Medical Center,supporting the PhD programme of the author(MA)
文摘Among all head and neck (H&N) cancers,nasopharyngeal carcinoma (NPC) represents a distinct entity regarding epidemiology,clinical presentation,biological markers,carcinogenic risk factors,and prognostic factors.NPC is endemic in certain regions of the world,especially in Southeast Asia,and has a poor prognosis.In Indonesia,the recorded mean prevalence is 6.2/100 000,with 13 000 yearly new NPC cases,but otherwise little is documented on NPC in Indonesia.Here,we report on a group of 1121 NPC patients diagnosed and treated at Dr.Cipto Mangunkusumo Hospital,Jakarta,Indonesia between 1996 and 2005.We studied NPC incidence among all H&N cancer cases (n=6000) observed in that period,focusing on age and gender distribution,the ethnic background of patients,and the disease etiology.We also analyzed most prevalent signs and symptoms and staging of NPC patients at first presentation.In this study population,NPC was the most frequent H&N cancer (28.4%),with a male-to-female ratio of 2.4,and was endemic in the Javanese population.Interestingly,NPC appeared to affect patients at a relatively young age (20% juvenile cases) without a bimodal age distribution.Mostly,NPC initiated in the fossa of Rosenmuller and spreaded intracranially or locally as a mass in the head.Occasionally,NPC developed at the submucosal level spreading outside the anatomic limits of the nasopharynx.At presentation,NPC associated with hearing problems,serous otitis media,tinnitus,nasal obstruction,anosmia,bleeding,difficulty in swallowing and dysphonia,and even eye symptoms with diplopia and pain.The initial diagnosis is difficult to make because early signs and symptoms of NPC are not specific to the disease.Early-age Epstein-Barr virus (EBV) infection combined with frequent exposure to environmental carcinogenic co-factors is suggested to cause NPC development.Undifferentiated NPC is the most frequent histological type and is closely associated with EBV.Expression of the EBV-encoded latent membrane protein 1(LMP1) oncogene in biopsy material was compared
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology of Japan,to Yamamoto H and Shinomura Y
文摘AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).T
基金supported by a grant from the Cancer Research UK,London(Programme Award C5575/A15032)
文摘In 1964,a new herpesvirus,Epstein-Barr virus(EBV),was discovered in cultured tumor cells derived from a Burkitt lymphoma(BL)biopsy taken from an African patient.This was a momentous event that reinvigorated research into viruses as a possible cause of human cancers.Subsequent studies demonstrated that EBV was a potent growth-transforming agent for primary B cells,and that all cases of BL carried characteristic chromosomal translocations resulting in constitutive activation of the c-MYC oncogene.These results hinted at simple oncogenic mechanisms that would make Burkitt lymphoma paradigmatic for cancers with viral etiology.In reality,the pathogenesis of this tumor is rather complicated with regard to both the contribution of the virus and the involvement of cellular oncogenes.Here,we review the current understanding of the roles of EBV and c-MYC in the pathogenesis of BL and the implications for new therapeutic strategies to treat this lymphoma.
基金supported by the National Natural Science Foundation of China(81172189,81171930,81272298,81272254,91229122,81301757,81372907)the Natural Science Foundation of Hunan Province(14JJ1010)+1 种基金the Fundamental Research Funds for the Central Universities(2011JQ020)the Postdoctoral Science Foundation of Central South University
文摘Epstein-Barr virus(EBV)is associated with nasopharyngeal carcinoma(NPC)tumorigenesis.However,the mechanism(s)connecting EBV infection and NPC remain unclear.Recently,a new class of EBV microRNAs(miRNAs)has been described.To determine how EBV miRNAs control the expression of host genes,and to understand their potential role in NPC tumorigenesis,we profiled the expression of 44 mature EBV miRNAs and potential host genes in NPC and non-tumor nasopharyngeal epithelial tissues.We found that 40 EBV miRNAs from the BART transcript were highly expressed in NPC.Analysis of potential BART miRNA target genes revealed that 3140 genes and several important pathways might be involved in the carcinogenesis of NPC.A total of 105 genes with potential EBV miRNA binding sites were significantly downregulated,suggesting that EBV miRNAs may regulate these genes and contribute to NPC carcinogenesis.An EBV miRNA and host gene regulation network was generated to provide useful clues for validating of EBV miRNA functions in NPC tumorigenesis.
