Meta-Analysis of DNA Tumor-Viral Integration Site Selection Indicates a Role for Repeats, Gene Expression and Epigenetics

Doolittle-Hall, Janet; Glasspoole, Danielle L. Cunningham; Seaman, William T.; Webster‐Cyriaque, Jennifer

doi:10.3390/cancers7040887

Cited by 26 publications

(34 citation statements)

References 62 publications

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“…Data for integration sites of other known oncogenic viruses have shown that integration sites have varied from recurrent hotspots to random integration [39,40]. In the context of BK virus-associated urologic malignancies, viral integration sites have been investigated by 2 studies in renal and bladder cancers.…”

Section: Discussionmentioning

confidence: 99%

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

Sirohi

Vaske²,

Sanborn³

et al. 2018

Modern Pathology

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In recent years, there has been increased interest in carcinomas of the urologic tract, that demonstrate association with the polyoma virus BK arising in immunosuppressed individuals, though the nature of this association is uncertain. To begin to understand this phenomenon, we reviewed the clinical, morphological, and immunohistochemical features of 11 carcinomas of the urologic tract, mainly urothelial (N = 9) and collecting duct carcinomas (N = 2), occurring during immunosuppression, and expressing polyoma virus T-antigen by immunohistochemistry. These were compared to a control group of carcinomas (N = 8), also arising during immunosuppression, but without T-antigen expression. A subset of both groups were also studied by hybrid capture-based DNA sequencing, probing not only for 479 cancer-related human genes, but also for polyoma and other viral sequences. Polyoma T-antigen-expressing tumors arose in 7 males and 4 females, at a median age of 66, and were aggressive, high-grade tumors with more than 1 variant morphologic pattern identified in 81% of cases, and a majority (73%) presenting at high stage category (>pT3). Diffuse polyoma T-antigen staining was seen in 91% of cases, with co-localization of aberrant p53 staining in 89%. Sequencing detected a lower number of deleterious mutations among T-antigen-expressing cases (average 1.62; 1/8 with TP53 mutation) compared to control cases (average 3.5, 2/4 with TP53 mutation). Only BK virus was detected with clonal integration and breakpoints randomly distributed across the human and viral genomes in 5/5 of the polyoma T-antigen-expressing carcinomas, and in none of the controls (0/4). In summary, these findings identify aggressive clinicopathologic features of polyoma T-antigen-expressing carcinomas, document BK as the strain involved, and associate BK viral integration with T-antigen expression and p53 aberrancy. While the apparent randomness of viral insertion sites is functionally unclear, the differing rates of mutations between T-antigen-expressing and control cases is intriguing.

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Section: Discussionmentioning

confidence: 99%

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

Sirohi

Vaske²,

Sanborn³

et al. 2018

Modern Pathology

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“…While a recent meta-analysis of HPV, hepatitis B virus (HBV), and Merkel cell polyomavirus (MCPyV) found integrations within CFSs in cervical and other carcinomas, these integrations were not at a higher frequency in CFSs than elsewhere in the genome 100 . It is noteworthy that integration hotspots have been described in large genes that are not previously-described CFSs, such as LDL receptor related protein 1B ( LRP1B ;1.9 Mb), CUB and Sushi multiple domains 1 ( CSMD1 ; 2.1 Mb), and discs large MAGUK scaffold protein 2 ( DLG2 ; 2.2 Mb) 92, 93, 99 but are predicted to be fragile sites in cells in which they are transcribed 30 .…”

Section: Cancer and Genomic Disordersmentioning

confidence: 99%

Fragile sites in cancer: more than meets the eye

2017

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Ever since early suggestions that instability at common fragile sites (CFSs) could be responsible for chromosome rearrangements in cancers, CFSs and associated genes have been the subject of numerous studies, leading to questions and controversies about their role and importance in cancer. It is now clear that CFSs are not frequently involved in translocations or other cancer-associated recurrent gross chromosome rearrangements. However, recent studies have provided new insights into the mechanisms of CFS instability, their impact on genome instability, and their role in generating focal copy number alterations that affect the genomic landscape of many cancers.

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“…This suggests that integration may have a regulatory function, in agreement with other studies that looked at histone makers in a subset of integration events. 47,48 The overlap between prevalent mutations reported in cervical cancer and the same gene regions with integration events was 1% (9 of the 919 integration events).…”

Section: A Relationship Between Recurrent Integration Events and Affementioning

confidence: 99%

Genomic characterization of viral integration sites in HPV‐related cancers

Bodelón

Untereiner

Machiela

et al. 2016

Intl Journal of Cancer

111

114

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Persistent infection with carcinogenic human papillomaviruses (HPV) causes the majority of anogenital cancers and a subset of head and neck cancers. The HPV genome is frequently found integrated into the host genome of invasive cancers. The mechanisms of how it may promote disease progression are not well understood. Thoroughly characterizing integration events can provide insights into HPV carcinogenesis. Individual studies have reported limited number of integration sites in cell lines and human samples. We performed a systematic review of published integration sites in HPV-related cancers and conducted a pooled analysis to formally test for integration hotspots and genomic features enriched in integration events using data from the Encyclopedia of DNA Elements (ENCODE). Over 1,500 integration sites were reported in the literature, of which 90.8% (N = 1,407) were in human tissues. We found 10 cytobands enriched for integration events, three previously reported ones (3q28, 8q24.21 and 13q22.1) and seven additional ones (2q22.3, 3p14.2, 8q24.22, 14q24.1, 17p11.1, 17q23.1 and 17q23.2). Cervical infections with HPV18 were more likely to have breakpoints in 8q24.21 (p = 7.68 × 10(-4) ) than those with HPV16. Overall, integration sites were more likely to be in gene regions than expected by chance (p = 6.93 × 10(-9) ). They were also significantly closer to CpG regions, fragile sites, transcriptionally active regions and enhancers. Few integration events occurred within 50 Kb of known cervical cancer driver genes. This suggests that HPV integrates in accessible regions of the genome, preferentially genes and enhancers, which may affect the expression of target genes.

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Meta-Analysis of DNA Tumor-Viral Integration Site Selection Indicates a Role for Repeats, Gene Expression and Epigenetics

Cited by 26 publications

References 62 publications

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

Fragile sites in cancer: more than meets the eye

Genomic characterization of viral integration sites in HPV‐related cancers

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