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Modulation of epithelial homeostasis by HPV using Notch and Wnt. 人乳头瘤病毒利用 Notch 和 Wnt 调节上皮细胞的稳态。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-11-13 DOI: 10.1016/j.tvr.2024.200297
June See Chong, John Doorbar

Highly conserved signalling pathways such as Notch and Wnt are essential in the regulation of differentiation and proliferation processes during adult tissue homeostasis. Human papillomaviruses (HPVs) have evolved with humans to manipulate these signalling pathways to establish a basal reservoir of infected cells by limiting HPV-infected keratinocyte differentiation whilst ensuring that differentiating cells are in a replication-competent state. Here, we focus on the canonical Notch and Wnt signalling pathways and their crosstalk to ensure cell-fate lineage determination during epithelial homeostasis. We then examine how HPVs use their E6 and E7 proteins to inhibit differentiation and maintain stem-like characteristics using Notch and Wnt in HPV-infected cells. Determining the functions of E6 and E7 in the maintenance of the infected cell reservoir, and the molecular crosstalk between Notch and Wnt is vital for our understanding of HPV persistence, and may represent an important factor in the development of therapeutic agents for HPV-associated disease.

高度保守的信号通路(如 Notch 和 Wnt)在调节成人组织稳态过程中的分化和增殖过程中至关重要。人类乳头瘤病毒(HPV)与人类共同进化,操纵这些信号通路,通过限制受 HPV 感染的角质细胞分化,同时确保分化细胞处于复制能力状态,从而建立感染细胞的基础库。在这里,我们将重点关注典型的 Notch 和 Wnt 信号通路及其相互协作,以确保上皮细胞稳态过程中的细胞命运系决定。然后,我们研究HPV如何利用其E6和E7蛋白抑制分化,并在HPV感染的细胞中利用Notch和Wnt维持干样特征。确定E6和E7在维持受感染细胞储库中的功能以及Notch和Wnt之间的分子串扰对于我们了解HPV的持久性至关重要,而且可能是开发HPV相关疾病治疗药物的一个重要因素。
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引用次数: 0
Modulation of connexin 43 in viral infections 在病毒感染中调节连接蛋白 43
IF 4.7 Q1 VIROLOGY Pub Date : 2024-11-08 DOI: 10.1016/j.tvr.2024.200296
Harry Scott , Patricia E. Martin , Sheila V. Graham
Connexins are essential for intercellular communication through gap junctions and the maintenance of cellular and tissue homeostasis. Connexin 43 (Cx43) is the most ubiquitously expressed connexin. As well as regulating homeostasis, Cx43 hemichannels and gap junctions play important roles in inflammation and the immune response. This, coupled with a range of non-channel functions performed by Cx43 makes it an attractive target for viruses. Recently, several groups have begun to explore the relationship between Cx43 and viral infection, with a diverse array of viruses being found to alter Cx43 hemichannels/gap junctions. Importantly, this includes several small DNA tumour viruses, which may target Cx43 to promote tumorigenesis. This review focuses on the ability of selected RNA/DNA viruses and retroviruses to either positively or negatively regulate Cx43 hemichannels and gap junctions in order to carry out their lifecycles. The role of Cx43 regulation by tumour viruses is also discussed in relation to tumour progression.
连接蛋白对于通过缝隙连接进行细胞间通信以及维持细胞和组织的平衡至关重要。连接蛋白 43(Cx43)是最普遍表达的连接蛋白。除了调节体内平衡外,Cx43 半通道和间隙连接还在炎症和免疫反应中发挥重要作用。这一点,再加上 Cx43 的一系列非通道功能,使其成为一个有吸引力的病毒靶标。最近,一些研究小组开始探索 Cx43 与病毒感染之间的关系,发现各种病毒都能改变 Cx43 半通道/间隙连接。重要的是,其中包括几种小型 DNA 肿瘤病毒,它们可能以 Cx43 为靶点促进肿瘤发生。本综述将重点讨论某些 RNA 和 DNA 病毒为完成其生命周期而对 Cx43 半通道和间隙连接进行正向或负向调节的能力。此外,还讨论了肿瘤病毒对 Cx43 调节的作用与肿瘤进展的关系。
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引用次数: 0
The imprint of viral oncoproteins on the variable clinical behavior among human papilloma virus-related oropharyngeal squamous cell carcinomas 病毒癌蛋白对人类乳头瘤病毒相关口咽鳞状细胞癌不同临床表现的影响。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-11-01 DOI: 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.
人乳头状瘤病毒相关(HPV+)口咽鳞状细胞癌(OPSCC)在病情进展、免疫状况、治疗反应和临床结果方面各不相同。它们的行为不仅受到宿主基因组改变差异的影响,还受到HPV编码的癌蛋白水平和活性多样性的影响。HPV+ OPSCCs的HPV mRNA水平存在显著差异,部分原因可能是它们通常包含的整合和外显子HPV基因组结构多样。HPV16是大多数HPV+ OPSCC中的HPV类型,其两个长的多聚体转录本的剪接差异也会影响病毒肿瘤蛋白的水平和功能。病毒癌蛋白功能的进一步变化来自于HPV16的不同系和亚系,它们在癌基因的重要功能部分编码了多态性。在此,我们回顾了目前将 HPV mRNA 表达和剪接与可能影响 OPSCC 行为的肿瘤蛋白功能差异联系起来的有限知识。我们还总结了对 HPV16 物理基因组状态和遗传变异及其对 HPV 肿瘤蛋白水平和功能的潜在贡献的不断发展的认识。在确定 HPV 癌症蛋白对每种 OPSCC 的定量和定性影响方面仍存在大量挑战,解决这些挑战有望为这种疾病的个性化治疗提供指导。
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引用次数: 0
Genomic diversity of HPV6 and HPV11 in recurrent respiratory papillomatosis: Association with malignant transformation in the lungs and clinical outcomes 复发性呼吸道乳头状瘤病中 HPV6 和 HPV11 的基因组多样性:与肺部恶性转化和临床结果的关系
IF 4.7 Q1 VIROLOGY Pub Date : 2024-10-29 DOI: 10.1016/j.tvr.2024.200294
Massilva Rahmoun , Audrey Aussel , Sarah Bouzidi , Vincent Pedergnana , Victor Malassigné , Julien Puech , David Veyer , Hélène Péré , Charles Lepine , Fabian Blanc , Nathalie Boulle , Valérie Costes-Martineau , Ignacio G. Bravo
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.
复发性呼吸道乳头状瘤病(RRP)是一种罕见的增殖性疾病,由人类乳头状瘤病毒 6(HPV6)和 HPV11 引起。我们应用高通量测序技术分析了 5 名恶性转化 RRP 患者和 4 名高度复发性非恶性 RRP 患者的不同时期样本。在两名患者中发现了HPV6和HPV11的一过性多重感染,后来又转变为单一感染。各组的病毒基因组载量相同(中位数 = 每个人类基因组 78 个病毒基因组)。在患者内部,我们没有观察到乳头状瘤病变和恶性组织中病毒序列的差异。对 NLRP1 基因的遗传分析表明,没有发现与特发性 RRP 相关的已知变异,但一些新型变异值得在更大的群体中进行研究。RRP可发生多重感染,但对于特定基因型而言,患者体内的病毒多样性极少。我们的研究结果证实了病毒基因型在疾病预后中的重要性,而且越来越多的证据表明,HPV11感染与年轻患者的RRP恶性转化有不同程度的关联。
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引用次数: 0
The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity SV40 病毒增强子是一种具有潜在致瘤活性的体细胞突变靶向元件
IF 4.7 Q1 VIROLOGY Pub Date : 2024-10-28 DOI: 10.1016/j.tvr.2024.200293
Filip Šenigl , Anni I. Soikkeli , Salomé Prost , David G. Schatz , Martina Slavková , Jiří Hejnar , Jukka Alinikula
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.
猿猴病毒 40(SV40)是一种猴病毒,在啮齿类动物中具有致瘤潜能,与包括淋巴瘤在内的几种人类癌症有关。一种相关的梅克尔细胞多瘤病毒通过表达截短的大肿瘤抗原(LT)导致人类患癌,截短抗原是由 APOBEC 家族的胞苷脱氨酶诱导突变引起的。AID(活化诱导胞苷脱氨酶)是 APOBEC 家族的成员之一,是抗体多样化过程(即体细胞高突变)的启动器,其异常表达和靶向是淋巴瘤发生的一个常见来源。在这项研究中,我们研究了 AID 是否会导致 SV40 LT 发生突变。我们证明,SV40增强子在几种细胞类型中具有很强的体细胞超突变靶向活性,AID诱导的突变在B细胞和肾细胞的SV40 LT中积累,并导致B细胞中LT表达截短。我们的研究结果表明,SV40增强子靶向LT的体细胞超突变能力是LT截短事件的潜在来源,而LT截短事件可能会导致各种细胞类型的肿瘤发生,从而通过一种新的突变途径将SV40感染与恶性发展联系起来。
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引用次数: 0
Opportunities to advance cervical cancer prevention and care 推进宫颈癌预防和护理的机遇
IF 4.7 Q1 VIROLOGY Pub Date : 2024-10-25 DOI: 10.1016/j.tvr.2024.200292
Grant Brooke , Sebastian Wendel , Abhineet Banerjee , Nicholas Wallace
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.
宫颈癌(CaCx)是一个重大的公共卫生问题,每年有 60 多万妇女确诊患上宫颈癌。每 90 秒就有一人死于宫颈癌,主要发生在中低收入国家。目前已有有效但不完善的机制来预防 CaCx。由于人类乳头瘤病毒(HPV)感染是大多数 CaCx 的病因,因此可以通过接种疫苗来预防。筛查方法可以发现癌前病变,并在 CaCx 发生之前进行干预。然而,在资源匮乏的环境中,这些工具的可行性较低。此外,目前的筛查方法无法根据病变发展的相对风险对病变进行分流,从而导致过度治疗。CaCx治疗严重依赖会产生严重副作用的基因毒性药物。本综述将讨论如何利用最新的技术进步来改善 CaCx 的治疗和预防。
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引用次数: 0
A new role for human papillomavirus 16 E2: Mitotic activation of the DNA damage response to promote viral genome segregation 人类乳头瘤病毒 16 E2 的新作用:有丝分裂激活 DNA 损伤反应,促进病毒基因组分离。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-09-07 DOI: 10.1016/j.tvr.2024.200291
Apurva T. Prabhakar , Iain M. Morgan

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.

人类乳头瘤病毒(HPV)是约 5%人类癌症的致病因子。为了确定和开发新的人乳头瘤病毒靶向治疗药物,我们必须加强对病毒生命周期及其如何与宿主相互作用的了解。HPV E2 蛋白会二聚化并与病毒基因组中的 12bp 目标序列结合,并在有丝分裂过程中分离病毒基因组。在这一功能中,E2 同时与病毒基因组和宿主染色质结合,确保病毒基因组在细胞分裂后驻留在子核中。我们已经证明,E2与DNA损伤应答(DDR)蛋白TOPBP1之间的有丝分裂相互作用是E2分离功能所必需的。在非感染细胞中,DNA损伤后,TOPBP1通过与MDC1的相互作用被招募到有丝分裂宿主基因组,这种相互作用在有丝分裂过程中保护了DNA的完整性。最近我们证明,E2-TOPBP1 相互作用激活了有丝分裂过程中的 DNA 损伤反应(DDR),而不受外部刺激的影响,促进了 TOPBP1 与有丝分裂染色质的相互作用,从而促进了病毒基因组的分离。因此,病毒劫持了宿主现有的机制来分离病毒基因组。本文将对这一错综复杂的 E2 功能进行描述和讨论。
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引用次数: 0
HBx integration in diffuse large B-cell lymphoma inhibits Caspase-3-PARP related apoptosis 弥漫大 B 细胞淋巴瘤中的 HBx 整合可抑制与 Caspase-3-PARP 相关的细胞凋亡。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-07-18 DOI: 10.1016/j.tvr.2024.200290
Yanchun Wang , Xiaolin Guan , Fangfang Lv , Yi Rong , Xin Meng , Ying Tong , Xiaolu Ma , Hui Zheng , Cuncun Chen , Suhong Xie , Heng Zhang , Feng Dong , Lin Guo , Renquan Lu

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.

弥漫大B细胞淋巴瘤(DLBCL)是非霍奇金淋巴瘤中最常见的病理类型,与乙型肝炎病毒(HBV)感染状态和乙型肝炎X(HBx)基因整合密切相关。该项目研究了 DLBCL 中淋巴瘤发生和 HBx 整合进展的细胞生物学效应和分子机制。数据显示,临床 DLBCL 细胞表现出 HBx 整合,整合位点的测序分析验证了 HBx 整合在构建的 HBx 转染细胞中。与对照细胞相比,HBx转染细胞的线粒体膜电位比例、染色体DNA断裂信号和凋亡细胞比例均显著降低。进一步研究发现,细胞凋亡水平的降低与裂解的Caspase-3和下游聚ADP-核糖聚合酶(PARP)蛋白的显著减少有关,揭示了HBx相关DLBCL细胞凋亡的分子机制。动物实验也表明,在小鼠皮下肿瘤的 HBx 转染细胞中,Caspase-3 和 PARP 的蛋白表达显著减少。此外,临床组织中的 HBx 整合细胞的裂解 PARP 水平明显低于 HBx 阴性样本。因此,HBx整合通过Caspase-3-PARP途径抑制DLBCL中的细胞凋亡,这表明HBV相关DLBCL是一种潜在的生物标记物和治疗靶点。
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引用次数: 0
The impact of DNA tumor viruses in low-to-middle income countries (LMICS): A literature review DNA 肿瘤病毒对中低收入国家(LMICS)的影响:文献综述。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-07-06 DOI: 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。
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引用次数: 0
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 EPB41L3、HTERT和FAM19A4的单个CpG位点的DNA甲基化有助于检测宫颈高级别鳞状上皮内病变(HSIL)或更严重的病变:对单个 CpG 位点的分析优于平均分析。
IF 4.7 Q1 VIROLOGY Pub Date : 2024-07-01 DOI: 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.

基因启动子的全局甲基化分析有望用于检测高危人类乳头瘤病毒(hrHPV)阳性妇女的高级别或更严重的鳞状上皮内病变(HSIL+)。然而,单个 CpG 位点甲基化数据的诊断性能有限。我们对巴布亚新几内亚自采样本和临床医生采集样本中预测 HSIL+ 的甲基化情况进行了研究。通过对 44 份 HPV+样本(4 例癌症、19 例 HSIL、4 例低度鳞状上皮内病变 (LSIL)、17 例正常样本)进行热测序,评估了 EPB41L3(1-6 个 CpG 位点)、hTERT(1-10 个 CpG 位点)和 FAM19A4(1-5 个 CpG 位点)的甲基化情况。针对 FAM19A4 设计了新的引物,引物指向以前未探究过的第一个外显子区域。在临床医生采集的样本中,EPB41L3的CpG位点4和5的甲基化是预测HSIL的最佳指标(AUC>0.83),CpG位点4是预测癌症的最佳指标(0.925)。EPB41L3 2/4位点和FAM19A4 1位点的组合是最佳的HSIL+标记物[敏感性100%,特异性63.2%]。在自采样本中,FAM19A4 的 CpG 位点 5 的甲基化是预测 HSIL 的最佳指标(0.67),而 FAM19A4 的 CpG 位点 1 和 3 则是预测癌症的最佳指标(0.77)。结合 FAM19A4 位点 1 和 HPV 16/18 检测,灵敏度为 82.6%,特异性为 61.9%。总之,EPB41L3 和 FAM19A4 单个 CpG 位点的甲基化优于全局分析,提高了 HSIL+ 的检测率,值得进一步研究。
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引用次数: 0
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Tumour Virus Research
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