Human oncoviruses: Mucocutaneous manifestations, pathogenesis, therapeutics, and prevention

Haley, Christopher; Mui, Uyen Ngoc; Vangipuram, Ramya; Rády, Peter L.; Tyring, Stephen K.

doi:10.1016/j.jaad.2018.09.062

Cited by 36 publications

(40 citation statements)

References 149 publications

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“…Studies of other human oncogenic viruses have revealed that viral genetic variation or de novo mutations may be important to their pathogenicity, as is the case for cancers associated with human papilloma viruses and Merkel cell polyomavirus [ 10 ]. Epstein Bar virus (EBV), another gamma-herpesvirus like KSHV, is associated with a variety of neoplasms.…”

Section: Introductionmentioning

confidence: 99%

Intra-host changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma

et al. 2021

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Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that possibly introduce more errors than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)–random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10−9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.

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Section: Introductionmentioning

confidence: 99%

Intra-host changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma

et al. 2021

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“…Studies of other human oncogenic viruses reveal that viral genetic variation or de novo mutations may be important to their pathogenicity, as is the case for cancers associated with human papilloma viruses and Merkel cell polyomavirus [10]. Epstein Bar virus (EBV), another gamma-herpesvirus like KSHV, is associated with a variety of neoplasms.…”

Section: Introductionmentioning

confidence: 99%

Tumor-specific changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma

Santiago

Goldman

Zhao

et al. 2020

Preprint

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Intra-host evolved tumor virus variants have provided insights into the risk, pathogenesis and treatment responses of associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has not been explored at the whole viral genome level. An accurate and detailed description of KSHV intra-host diversity in whole KSHV genomes from matching tumors and oral swabs from Ugandan adults with HIV-associated KS was obtained by deep, short read sequencing, using duplex unique molecular identifiers (dUMI) – random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors down to ∼10−9/base. KSHV genomes were assembled de novo, and identified rearrangements were confirmed by PCR. 131-kb KSHV genome sequences, excluding major repeat regions and averaging 2.3 × 104 reads/base, were successfully obtained from 23 specimens from 9 individuals, including 7 tumor-oral pairs. Sampling more than 100 viral genomes in at least one specimen per individual showed that KSHV genomes were virtually homogeneous within samples and within individuals at the point mutational level. Heterogeneity, if present, was due to point mutations and genomic rearrangements in tumors. In 2 individuals, the same mutations were found in distinct KS tumors. The K8.1 gene was inactivated in tumors from 3 individuals, and all KSHV genomic aberrations retained the region surrounding the first major internal repeat (IR1). These findings suggest that lytic gene alterations may contribute to KS tumorigenesis or persistence.Author summaryKaposi sarcoma (KS) is a leading cancer in sub-Saharan Africa and in those with HIV co-infection. Infection by Kaposi sarcoma-associated herpesvirus (KSHV) is necessary for KS, yet why only few KSHV infections develop into KS is largely unknown. While strain differences or mutations in other tumor viruses are known to affect the risk and progression of their associated cancers, whether KSHV genetic variation is important to the natural history of KS is unclear. Most studies of KSHV diversity have characterized only ∼4% of its 165-kb genome and may have been impacted by PCR or cloning artifacts. Here, we performed highly sensitive, single-molecule sequencing of whole KSHV genomes in paired KS tumors and oral swabs from 9 individuals with KS. We found that KSHV genomes were virtually identical within individuals, with no evidence of quasispecies formation nor multistrain infection. However, KSHV genome aberrations and inactivating mutations appeared to be a common, tumor-associated phenomenon, with some mutations shared by distinct tumors within an individual. Certain regions of the KSHV genome featured prominently among tumor-associated mutations, suggesting that they are important contributors to the pathogenesis or persistence of KS.

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“…Despite their name (poly = many and oma = cancers), MCPyV seems to be the only HPyV to induce cancer in its natural host. MCPyV is a major cause in the skin cancer called Merkel cell carcinoma [7,24]. The role of other HPyV, especially BKPyV and JCPyV, in human cancer such as prostate, colorectal, urothelial, and brain cancer is disputed (for recent reviews, see References [25,26,27,28,29]), but some of them can transform cells, including human cells, and the virus or its early proteins LT or/and sT can cause tumors in animal models [27,28,30].…”

Section: Introductionmentioning

confidence: 99%

Effect of the Large and Small T-Antigens of Human Polyomaviruses on Signaling Pathways

Moens

Macdonald

2019

IJMS

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Viruses are intracellular parasites that require a permissive host cell to express the viral genome and to produce new progeny virus particles. However, not all viral infections are productive and some viruses can induce carcinogenesis. Irrespective of the type of infection (productive or neoplastic), viruses hijack the host cell machinery to permit optimal viral replication or to transform the infected cell into a tumor cell. One mechanism viruses employ to reprogram the host cell is through interference with signaling pathways. Polyomaviruses are naked, double-stranded DNA viruses whose genome encodes the regulatory proteins large T-antigen and small t-antigen, and structural proteins that form the capsid. The large T-antigens and small t-antigens can interfere with several host signaling pathways. In this case, we review the interplay between the large T-antigens and small t-antigens with host signaling pathways and the biological consequences of these interactions.

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Human oncoviruses: Mucocutaneous manifestations, pathogenesis, therapeutics, and prevention

Cited by 36 publications

References 149 publications

Intra-host changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma

Intra-host changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma

Tumor-specific changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma

Effect of the Large and Small T-Antigens of Human Polyomaviruses on Signaling Pathways

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