Pub Date : 2024-11-01DOI: 10.1016/j.tvr.2024.200295
Malay K Sannigrahi, Lovely Raghav, Ahmed Diab, Devraj Basu
Human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are variable in their progression, immune landscape, treatment responses, and clinical outcomes. Their behavior is impacted not only by differences in host genomic alterations but also by diversity in levels and activity of HPV-encoded oncoproteins. Striking differences in HPV mRNA levels are found among HPV+ OPSCCs and likely derive in part from variations in the structurally diverse mix of integrated and episomal HPV genomes they often contain. Viral oncoprotein levels and function are also impacted by differential splicing of the two long polycistronic transcripts of HPV16, the HPV type within most HPV+ OPSCCs. Further variation in viral oncoprotein function arises from the distinct lineages and sub-lineages of HPV16, which encode polymorphisms in functionally important portions of oncogenes. Here we review the limited current knowledge linking HPV mRNA expression and splicing to differences in oncoprotein function that likely influence OPSCC behavior. We also summarize the evolving understanding of HPV16 physical genome state and genetic variants and their potential contributions to HPV oncoprotein levels and function. Addressing considerable remaining challenges in defining the quantitative and qualitative imprint of HPV oncoproteins on each OPSCC holds promise to guide personalization of therapy for this disease.
{"title":"The imprint of viral oncoproteins on the variable clinical behavior among human papilloma virus-related oropharyngeal squamous cell carcinomas.","authors":"Malay K Sannigrahi, Lovely Raghav, Ahmed Diab, Devraj Basu","doi":"10.1016/j.tvr.2024.200295","DOIUrl":"https://doi.org/10.1016/j.tvr.2024.200295","url":null,"abstract":"<p><p>Human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are variable in their progression, immune landscape, treatment responses, and clinical outcomes. Their behavior is impacted not only by differences in host genomic alterations but also by diversity in levels and activity of HPV-encoded oncoproteins. Striking differences in HPV mRNA levels are found among HPV+ OPSCCs and likely derive in part from variations in the structurally diverse mix of integrated and episomal HPV genomes they often contain. Viral oncoprotein levels and function are also impacted by differential splicing of the two long polycistronic transcripts of HPV16, the HPV type within most HPV+ OPSCCs. Further variation in viral oncoprotein function arises from the distinct lineages and sub-lineages of HPV16, which encode polymorphisms in functionally important portions of oncogenes. Here we review the limited current knowledge linking HPV mRNA expression and splicing to differences in oncoprotein function that likely influence OPSCC behavior. We also summarize the evolving understanding of HPV16 physical genome state and genetic variants and their potential contributions to HPV oncoprotein levels and function. Addressing considerable remaining challenges in defining the quantitative and qualitative imprint of HPV oncoproteins on each OPSCC holds promise to guide personalization of therapy for this disease.</p>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.tvr.2024.200294
Recurrent respiratory papillomatosis (RRP) is a rare, proliferative disease caused by human papillomavirus 6 (HPV6) and HPV11. RRP can occasionally spread and undergo malignant transformation.
We analysed samples across time for five RRP patients with malignant transformation and four with highly recurrent, non-malignant RRP by applying high-throughput sequencing.
Patients with malignant transformation were infected by HPV11_A1/A2, while most non-malignant cases were associated with HPV6. Transient multiple infections with HPV6 and HPV11 were found in two patients, and resolved later to single infections. Viral genome loads were homogeneous across groups (median = 78 viral genomes per human genome). Within-patient, we did not observe differences between the viral sequences in the papillomatous lesions and in the malignant tissue. Genetic analysis of the NLRP1 gene revealed no known mutations linked to idiopathic RRP, though some novel variants merit to be explored in larger cohorts.
HPV11 infections appear associated with RRP malignant transformation in young patients. Multiple infections can occur in RRP, but within-patient viral diversity is minimal for a given genotype. Our results confirm the importance of viral genotype in disease prognosis and are consistent with growing evidence of HPV11 infections to be differentially associated with RRP malignant transformation in young patients.
{"title":"Genomic diversity of HPV6 and HPV11 in recurrent respiratory papillomatosis: Association with malignant transformation in the lungs and clinical outcomes","authors":"","doi":"10.1016/j.tvr.2024.200294","DOIUrl":"10.1016/j.tvr.2024.200294","url":null,"abstract":"<div><div>Recurrent respiratory papillomatosis (RRP) is a rare, proliferative disease caused by human papillomavirus 6 (HPV6) and HPV11. RRP can occasionally spread and undergo malignant transformation.</div><div>We analysed samples across time for five RRP patients with malignant transformation and four with highly recurrent, non-malignant RRP by applying high-throughput sequencing.</div><div>Patients with malignant transformation were infected by HPV11_A1/A2, while most non-malignant cases were associated with HPV6. Transient multiple infections with HPV6 and HPV11 were found in two patients, and resolved later to single infections. Viral genome loads were homogeneous across groups (median = 78 viral genomes per human genome). Within-patient, we did not observe differences between the viral sequences in the papillomatous lesions and in the malignant tissue. Genetic analysis of the <em>NLRP1</em> gene revealed no known mutations linked to idiopathic RRP, though some novel variants merit to be explored in larger cohorts.</div><div>HPV11 infections appear associated with RRP malignant transformation in young patients. Multiple infections can occur in RRP, but within-patient viral diversity is minimal for a given genotype. Our results confirm the importance of viral genotype in disease prognosis and are consistent with growing evidence of HPV11 infections to be differentially associated with RRP malignant transformation in young patients.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.tvr.2024.200293
Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 LT. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to LT is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.
{"title":"The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity","authors":"","doi":"10.1016/j.tvr.2024.200293","DOIUrl":"10.1016/j.tvr.2024.200293","url":null,"abstract":"<div><div>Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 <em>LT</em>. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 <em>LT</em> in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to <em>LT</em> is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-25DOI: 10.1016/j.tvr.2024.200292
Cervical cancer (CaCx) is a major public health issue, with over 600,000 women diagnosed annually. CaCx kills someone every 90 s, mostly in low- and middle-income countries. There are effective yet imperfect mechanisms to prevent CaCx. Since human papillomavirus (HPV) infections cause most CaCx, they can be prevented by vaccination. Screening methodologies can identify premalignant lesions and allow interventions before a CaCx develops. However, these tools are less feasible in resource-poor environments. Additionally, current screening modalities cannot triage lesions based on their relative risk of progression, which results in overtreatment. CaCx care relies heavily on genotoxic agents that cause severe side effects. This review discusses ways that recent technological advancements could be leveraged to improve CaCx care and prevention.
{"title":"Opportunities to advance cervical cancer prevention and care","authors":"","doi":"10.1016/j.tvr.2024.200292","DOIUrl":"10.1016/j.tvr.2024.200292","url":null,"abstract":"<div><div>Cervical cancer (CaCx) is a major public health issue, with over 600,000 women diagnosed annually. CaCx kills someone every 90 s, mostly in low- and middle-income countries. There are effective yet imperfect mechanisms to prevent CaCx. Since human papillomavirus (HPV) infections cause most CaCx, they can be prevented by vaccination. Screening methodologies can identify premalignant lesions and allow interventions before a CaCx develops. However, these tools are less feasible in resource-poor environments. Additionally, current screening modalities cannot triage lesions based on their relative risk of progression, which results in overtreatment. CaCx care relies heavily on genotoxic agents that cause severe side effects. This review discusses ways that recent technological advancements could be leveraged to improve CaCx care and prevention.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1016/j.tvr.2024.200291
Human papillomaviruses (HPV) are causative agents in around 5% of all human cancers. To identify and develop new targeted HPV therapeutics we must enhance our understanding of the viral life cycle and how it interacts with the host. The HPV E2 protein dimerizes and binds to 12bp target sequences in the viral genome and segregates the viral genome during mitosis. In this function, E2 binds to the viral genome and the host chromatin simultaneously, ensuring viral genomes reside in daughter nuclei following cell division. We have demonstrated that a mitotic interaction between E2 and the DNA damage response (DDR) protein TOPBP1 is required for E2 segregation function. In non-infected cells, following DNA damage, TOPBP1 is recruited to the mitotic host genome via interaction with MDC1 and this interaction protects DNA integrity during mitosis. Recently we demonstrated that the E2-TOPBP1 interaction activates the DNA damage response (DDR) during mitosis independently from external stimuli, promoting TOPBP1 interaction with mitotic chromatin and therefore segregation of the viral genome. Therefore, the virus has hijacked an existing host mechanism in order to segregate the viral genome. This intricate E2 function will be described and discussed.
{"title":"A new role for human papillomavirus 16 E2: Mitotic activation of the DNA damage response to promote viral genome segregation","authors":"","doi":"10.1016/j.tvr.2024.200291","DOIUrl":"10.1016/j.tvr.2024.200291","url":null,"abstract":"<div><p>Human papillomaviruses (HPV) are causative agents in around 5% of all human cancers. To identify and develop new targeted HPV therapeutics we must enhance our understanding of the viral life cycle and how it interacts with the host. The HPV E2 protein dimerizes and binds to 12bp target sequences in the viral genome and segregates the viral genome during mitosis. In this function, E2 binds to the viral genome and the host chromatin simultaneously, ensuring viral genomes reside in daughter nuclei following cell division. We have demonstrated that a mitotic interaction between E2 and the DNA damage response (DDR) protein TOPBP1 is required for E2 segregation function. In non-infected cells, following DNA damage, TOPBP1 is recruited to the mitotic host genome via interaction with MDC1 and this interaction protects DNA integrity during mitosis. Recently we demonstrated that the E2-TOPBP1 interaction activates the DNA damage response (DDR) during mitosis independently from external stimuli, promoting TOPBP1 interaction with mitotic chromatin and therefore segregation of the viral genome. Therefore, the virus has hijacked an existing host mechanism in order to segregate the viral genome. This intricate E2 function will be described and discussed.</p></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666679024000156/pdfft?md5=dc35edad86e9980ce61707e0d71568ab&pid=1-s2.0-S2666679024000156-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-18DOI: 10.1016/j.tvr.2024.200290
Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma, and is closely associated with hepatitis B virus (HBV) infection status and hepatitis B X (HBx) gene integration. This project investigated the cellular biological effects and molecular mechanisms responsible for lymphomagenesis and the progression of HBx integration in DLBCL. The data showed that clinical DLBCL cells demonstrated HBx integration, and the sequencing analysis of integrated sites validated HBx integration in the constructed HBx-transfected cells. Compared with control cells, HBx-transfected cells had a significantly reduced proportion of mitochondrial membrane potential, signals of chromosomal DNA breaks, and proportion of apoptotic cells. Further studies found that this decreased apoptosis level was associated with a significant reduction of cleaved Caspase-3 and downstream poly ADP-ribose polymerase (PARP) proteins, revealing the molecular mechanisms of HBx-associated apoptosis in DLBCL. Animal experiments also demonstrated that the protein expression of cleaved Caspase-3 and PARP was prominently reduced in HBx-transfected cells from subcutaneous tumors in mice. Furthermore, the HBx-integrated cells in clinical tissues had significantly lower cleaved PARP levels than the HBx-negative samples. Therefore, HBx integration inhibits cell apoptosis through the Caspase-3-PARP pathway in DLBCL indicating a potential biomarker and therapeutic target in HBV related DLBCL.
{"title":"HBx integration in diffuse large B-cell lymphoma inhibits Caspase-3-PARP related apoptosis","authors":"","doi":"10.1016/j.tvr.2024.200290","DOIUrl":"10.1016/j.tvr.2024.200290","url":null,"abstract":"<div><p>Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma, and is closely associated with hepatitis B virus (HBV) infection status and <em>hepatitis B X</em> (<em>HBx</em>) gene integration. This project investigated the cellular biological effects and molecular mechanisms responsible for lymphomagenesis and the progression of <em>HBx</em> integration in DLBCL. The data showed that clinical DLBCL cells demonstrated <em>HBx</em> integration, and the sequencing analysis of integrated sites validated <em>HBx</em> integration in the constructed HBx-transfected cells. Compared with control cells, HBx-transfected cells had a significantly reduced proportion of mitochondrial membrane potential, signals of chromosomal DNA breaks, and proportion of apoptotic cells. Further studies found that this decreased apoptosis level was associated with a significant reduction of cleaved Caspase-3 and downstream poly ADP-ribose polymerase (PARP) proteins, revealing the molecular mechanisms of HBx-associated apoptosis in DLBCL. Animal experiments also demonstrated that the protein expression of cleaved Caspase-3 and PARP was prominently reduced in HBx-transfected cells from subcutaneous tumors in mice. Furthermore, the <em>HBx</em>-integrated cells in clinical tissues had significantly lower cleaved PARP levels than the <em>HBx</em>-negative samples. Therefore, <em>HBx</em> integration inhibits cell apoptosis through the Caspase-3-PARP pathway in DLBCL indicating a potential biomarker and therapeutic target in HBV related DLBCL.</p></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666679024000144/pdfft?md5=3ffb604d2a76191481057e06101dce0d&pid=1-s2.0-S2666679024000144-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-06DOI: 10.1016/j.tvr.2024.200289
DNA viruses are common in the human population and act as aetiological agents of cancer on a large scale globally. They include the human papillomaviruses (HPV), Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis viruses, and human polyomaviruses. Oncogenic viruses employ different mechanisms to induce cancer. Notably, cancer only develops in a minority of individuals who are infected, usually following protracted years of chronic infection. The human papillomaviruses (HPVs) are associated with the highest number of cancer cases, including cervical cancer and other epithelial malignancies. Hepatitis B virus (HBV) and the RNA virus hepatitis C (HCV) are significant contributors to hepatocellular cancer (HCC). Other oncoviruses include Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpes virus (KSHV), human T-cell leukemia virus (HTLV-I), and Merkel cell polyomavirus (MCPyV). The identification of these infectious agents as aetiological agents for cancer has led to reductions in cancer incidence through preventive interventions such as HBV and HPV vaccination, HPV-DNA based cervical cancer screening, antiviral treatments for chronic HBV and HCV infections, and screening of blood for transfusion for HBV and HCV. Successful efforts to identify additional oncogenic viruses in human cancer may provide further understanding of the aetiology and development of cancer, and novel approaches for prevention and treatment. Cervical cancer, caused by HPV, is the leading gynaecological malignancy in LMICs, with high age-standardised incidence and mortality rates, HCC due to HBV is an important cause of cancer deaths, and the burden of other cancer attributable to infections continues to rise globally. Hence, cancers attributable to DNA viruses have become a significant global health challenge. These viruses hence warrant continued attention and interrogation as efforts to understand them further and device further preventive interventions are critical.
DNA 病毒在人类中很常见,是全球范围内大规模癌症的病原体。它们包括人类乳头瘤病毒(HPV)、爱泼斯坦-巴氏病毒(EBV)、卡波西肉瘤相关疱疹病毒(KSHV)、肝炎病毒和人类多瘤病毒。致癌病毒采用不同的机制诱发癌症。值得注意的是,癌症只发生在少数感染者身上,通常是在长年慢性感染之后。人类乳头状瘤病毒(HPV)与最多的癌症病例有关,包括宫颈癌和其他上皮恶性肿瘤。乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)是导致肝细胞癌(HCC)的重要因素。其他肿瘤病毒包括爱泼斯坦-巴尔病毒(EBV)、卡波西肉瘤相关疱疹病毒(KSHV)、人类 T 细胞白血病病毒(HTLV-I)和梅克尔细胞多瘤病毒(MCPyV)。确定这些传染性病原体是癌症的病原体后,通过采取预防性干预措施,如接种 HBV 和 HPV 疫苗、进行基于 HPV DNA 的宫颈癌筛查、对慢性 HBV 和 HCV 感染进行抗病毒治疗,以及对输血进行 HBV 和 HCV 筛查,降低了癌症发病率。成功识别人类癌症中的其他致癌病毒可进一步了解癌症的病因和发展,并提供新的预防和治疗方法。由人类乳头瘤病毒(HPV)引起的宫颈癌是低收入和中等收入国家的主要妇科恶性肿瘤,其年龄标准化发病率和死亡率都很高;由乙型肝炎病毒(HBV)引起的肝转移癌是癌症死亡的重要原因之一;全球因感染引起的其他癌症的负担也在持续上升;因此,DNA 病毒引起的癌症已成为全球健康的重大挑战。因此,这些病毒值得持续关注和研究,因为进一步了解这些病毒并采取进一步的预防干预措施至关重要。
{"title":"The impact of DNA tumor viruses in low-to-middle income countries (LMICS): A literature review","authors":"","doi":"10.1016/j.tvr.2024.200289","DOIUrl":"10.1016/j.tvr.2024.200289","url":null,"abstract":"<div><p>DNA viruses are common in the human population and act as aetiological agents of cancer on a large scale globally. They include the human papillomaviruses (HPV), Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis viruses, and human polyomaviruses. Oncogenic viruses employ different mechanisms to induce cancer. Notably, cancer only develops in a minority of individuals who are infected, usually following protracted years of chronic infection. The human papillomaviruses (HPVs) are associated with the highest number of cancer cases, including cervical cancer and other epithelial malignancies. Hepatitis B virus (HBV) and the RNA virus hepatitis C (HCV) are significant contributors to hepatocellular cancer (HCC). Other oncoviruses include Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpes virus (KSHV), human T-cell leukemia virus (HTLV-I), and Merkel cell polyomavirus (MCPyV). The identification of these infectious agents as aetiological agents for cancer has led to reductions in cancer incidence through preventive interventions such as HBV and HPV vaccination, HPV-DNA based cervical cancer screening, antiviral treatments for chronic HBV and HCV infections, and screening of blood for transfusion for HBV and HCV. Successful efforts to identify additional oncogenic viruses in human cancer may provide further understanding of the aetiology and development of cancer, and novel approaches for prevention and treatment. Cervical cancer, caused by HPV, is the leading gynaecological malignancy in LMICs, with high age-standardised incidence and mortality rates, HCC due to HBV is an important cause of cancer deaths, and the burden of other cancer attributable to infections continues to rise globally. Hence, cancers attributable to DNA viruses have become a significant global health challenge. These viruses hence warrant continued attention and interrogation as efforts to understand them further and device further preventive interventions are critical.</p></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666679024000132/pdfft?md5=80e4f481a18359eac895e3e2cb06f042&pid=1-s2.0-S2666679024000132-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1016/j.tvr.2024.200288
Monica Molano , Dorothy A. Machalek , Samuel Phillips , Grace Tan , Suzanne M. Garland , David Hawkes , Prisha Balgovind , Reza Haqshenas , Steve G. Badman , John Bolnga , Josephine Gabuzzi , Zure Kombati , Gloria M. Munnull , Julia ML. Brotherton , Marion Saville , John M. Kaldor , Pamela J. Toliman , Andrew J. Vallely , Gerald L. Murray
Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea.
Methylation of EPB41L3 (1–6 CpG-sites), hTERT (1–10 CpG-sites) and FAM19A4 (1–5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for FAM19A4 directed to the first exon region not explored previously.
In clinician-collected samples, methylation at CpG-sites 4 and 5 of EPB41L3 were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of EPB41L3 sites 2/4 plus FAM19A4 site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity].
Methylation at CpG-site 5 of FAM19A4 was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of FAM19A4 for cancer (0.77). Combined, FAM19A4 site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%.
In conclusion, methylation at individual CpG-sites of EPB41L3 and FAM19A4 outperformed global analysis and improved HSIL+ detection, warranting further investigation.
{"title":"DNA methylation at individual CpG-sites of EPB41L3, HTERT and FAM19A4 are useful for detection of cervical high-grade squamous intraepithelial lesions (HSIL) or worse: Analysis of individual CpG-sites outperforms averaging","authors":"Monica Molano , Dorothy A. Machalek , Samuel Phillips , Grace Tan , Suzanne M. Garland , David Hawkes , Prisha Balgovind , Reza Haqshenas , Steve G. Badman , John Bolnga , Josephine Gabuzzi , Zure Kombati , Gloria M. Munnull , Julia ML. Brotherton , Marion Saville , John M. Kaldor , Pamela J. Toliman , Andrew J. Vallely , Gerald L. Murray","doi":"10.1016/j.tvr.2024.200288","DOIUrl":"10.1016/j.tvr.2024.200288","url":null,"abstract":"<div><p>Global methylation analysis of gene promoters is promising for detection of high-grade squamous intraepithelial lesions or worse (HSIL+) in high-risk human papillomavirus (hrHPV)-positive women. However, diagnostic performance of methylation data at individual CpG-sites is limited. We explored methylation for predicting HSIL+ in self- and clinician-collected samples from Papua New Guinea.</p><p>Methylation of <em>EPB41L3</em> (1–6 CpG-sites), <em>hTERT</em> (1–10 CpG-sites) and <em>FAM19A4</em> (1–5 CpG-sites) was assessed through pyrosequencing from 44 HPV+ samples (4 cancers, 19 HSIL, 4 low-grade squamous intraepithelial lesions (LSIL), 17 normal). New primers were designed for <em>FAM19A4</em> directed to the first exon region not explored previously.</p><p>In clinician-collected samples, methylation at CpG-sites 4 and 5 of <em>EPB41L3</em> were the best HSIL predictors (AUC >0.83) and CpG-site 4 for cancer (0.925). Combination of <em>EPB41L3</em> sites 2/4 plus <em>FAM19A4</em> site 1 were the best HSIL+ markers [100% sensitivity, 63.2% specificity].</p><p>Methylation at CpG-site 5 of <em>FAM19A4</em> was the best HSIL predictor (0.67) in self-collected samples, and CpG-sites 1 and 3 of <em>FAM19A4</em> for cancer (0.77). Combined, <em>FAM19A4</em> site 1 plus HPV 16/18 detection yielded sensitivity of 82.6% and specificity of 61.9%.</p><p>In conclusion, methylation at individual CpG-sites of <em>EPB41L3</em> and <em>FAM19A4</em> outperformed global analysis and improved HSIL+ detection, warranting further investigation.</p></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666679024000120/pdfft?md5=211b8be54b2e08277c81b68123f37b1d&pid=1-s2.0-S2666679024000120-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 10.1016/j.tvr.2024.200285
Claire D. James , Raymonde O. Otoa , Aya H. Youssef , Christian T. Fontan , Malay K. Sannigrahi , Brad Windle , Devraj Basu , Iain M. Morgan
HPV + oropharyngeal squamous cell carcinoma (OPC) incidence recently surpassed cervical cancer and is the most common HPV-related cancer in the developed world. HPV16 is in ∼90 % of HPV + OPCs, with episomal genomes in the majority of cases. Most existing HPV16+ cancer cell lines derive from outside the oropharynx and harbor integrated HPV genomes. Thus, there is need for OPC preclinical models to evaluate standard and experimental therapeutics in the presence of episomal HPV16 oncogenic drivers. Here we characterize HPV genome structures in eight HPV16+ OPC patient-derived xenografts (PDXs), and evaluate their responses to standard chemotherapy. HPV genome state was investigated by combining Southern blot, T5 exonuclease assay, whole genome sequencing, and RNAseq data. This analysis revealed complexity and variation in integrated vs. episomal HPV forms across PDXs and demonstrated that four PDXs predominantly contain episomal HPV16. Episomal status did not ensure favorable in vivo responses to cisplatin therapy, despite the more favorable prognosis previously attributed to episomal HPV + tumors; this could be due to the small number present in the dataset. Our analysis establishes PDX models as test platforms for novel therapies designed to target maintenance of the episomal forms of HPV16 that commonly appear in OPC.
{"title":"HPV16 genome structure analysis in oropharyngeal cancer PDXs identifies tumors with integrated and episomal genomes","authors":"Claire D. James , Raymonde O. Otoa , Aya H. Youssef , Christian T. Fontan , Malay K. Sannigrahi , Brad Windle , Devraj Basu , Iain M. Morgan","doi":"10.1016/j.tvr.2024.200285","DOIUrl":"10.1016/j.tvr.2024.200285","url":null,"abstract":"<div><p>HPV + oropharyngeal squamous cell carcinoma (OPC) incidence recently surpassed cervical cancer and is the most common HPV-related cancer in the developed world. HPV16 is in ∼90 % of HPV + OPCs, with episomal genomes in the majority of cases. Most existing HPV16+ cancer cell lines derive from outside the oropharynx and harbor integrated HPV genomes. Thus, there is need for OPC preclinical models to evaluate standard and experimental therapeutics in the presence of episomal HPV16 oncogenic drivers. Here we characterize HPV genome structures in eight HPV16+ OPC patient-derived xenografts (PDXs), and evaluate their responses to standard chemotherapy. HPV genome state was investigated by combining Southern blot, T5 exonuclease assay, whole genome sequencing, and RNAseq data. This analysis revealed complexity and variation in integrated vs. episomal HPV forms across PDXs and demonstrated that four PDXs predominantly contain episomal HPV16. Episomal status did not ensure favorable <em>in vivo</em> responses to cisplatin therapy, despite the more favorable prognosis previously attributed to episomal HPV + tumors; this could be due to the small number present in the dataset. Our analysis establishes PDX models as test platforms for novel therapies designed to target maintenance of the episomal forms of HPV16 that commonly appear in OPC.</p></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666679024000090/pdfft?md5=60bb17268635216a165c3c1dae1fc05d&pid=1-s2.0-S2666679024000090-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-22DOI: 10.1016/j.tvr.2024.200286
Man Teng , Jun Luo , Yaoyao Zhang , Vishwanatha R.A.P. Reddy , Priya Samuel , Yongxiu Yao , Venugopal Nair
In the past decade, research has demonstrated that viral miRNAs encoded by a number of viral genomes, particularly by most of the herpesvirus including Marek's disease virus (MDV), play important regulatory roles in viral infection, replication, and regulation of tumorigenesis. As macrovesicles in cells, exosomes can deliver viral miRNAs and exert gene regulatory functions. Whether the exosomes play a role in the replication, pathogenesis/tumorigenesis of avian herpesviruses such as oncogenic Marek's disease virus (MDV) remains unclear. Herein we extracted and identified the exosomes from MDV-transformed T cell line MSB-1 and demonstrated high abundance of MDV-1 miRNA expression. Using dual luciferase-based reporter assay, we also demonstrated that the exosomes derived from MSB-1 can deliver functional miRNA successfully into primary chicken embryo fibroblasts. These findings provide new insights into the role of exosomes and the mechanisms of how virus-encoded miRNA function in MDV latency/activation switching, viral replication, pathogenesis and/or tumorigenesis.
{"title":"Viral miRNA delivered by exosomes from Marek's disease virus-transformed lymphoma cell line exerts regulatory function in internalized primary chicken embryo fibroblast cells","authors":"Man Teng , Jun Luo , Yaoyao Zhang , Vishwanatha R.A.P. Reddy , Priya Samuel , Yongxiu Yao , Venugopal Nair","doi":"10.1016/j.tvr.2024.200286","DOIUrl":"10.1016/j.tvr.2024.200286","url":null,"abstract":"<div><p>In the past decade, research has demonstrated that viral miRNAs encoded by a number of viral genomes, particularly by most of the herpesvirus including Marek's disease virus (MDV), play important regulatory roles in viral infection, replication, and regulation of tumorigenesis. As macrovesicles in cells, exosomes can deliver viral miRNAs and exert gene regulatory functions. Whether the exosomes play a role in the replication, pathogenesis/tumorigenesis of avian herpesviruses such as oncogenic Marek's disease virus (MDV) remains unclear. Herein we extracted and identified the exosomes from MDV-transformed T cell line MSB-1 and demonstrated high abundance of MDV-1 miRNA expression. Using dual luciferase-based reporter assay, we also demonstrated that the exosomes derived from MSB-1 can deliver functional miRNA successfully into primary chicken embryo fibroblasts. These findings provide new insights into the role of exosomes and the mechanisms of how virus-encoded miRNA function in MDV latency/activation switching, viral replication, pathogenesis and/or tumorigenesis.</p></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666679024000107/pdfft?md5=366a07b88654841625509288d1263f73&pid=1-s2.0-S2666679024000107-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}