Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription

Pang, John; Nguyen, Nam; Luebeck, Jens; Ball, Laurel; Finegersh, Andrey; Nakagawa, Takuya; Flagg, Mitchell; Sadat, Sayed; Mischel, Paul S.; Xu, Guiyin; Fisch, Kathleen; Guo, Theresa; Cahill, Gabrielle; Panuganti, Bharat; Bafna, Vineet; Califano, Joseph A.

doi:10.1158/1078-0432.ccr-21-2484

Cited by 28 publications

(43 citation statements)

References 62 publications

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“…MIDS also includes mimicry between microbial and cancer antigens. [156,157] Should genetic cargo be shared between intracellular bacteria and host cells, as biotechnology already shows is possible [24] and cancer virology affirms, [45,46] MIDS must account for DNA and RNA from multiple species.…”

Section: Implications and Hypotheses If Cancer Clonality Is Multispeciesmentioning

confidence: 99%

Cancer's second genome: Microbial cancer diagnostics and redefining clonal evolution as a multispecies process

et al. 2022

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The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome—the metagenome—are manifold, but require careful consideration of microbial experimental idiosyncrasies that are distinct from host‐centric methods. Furthermore, the discoveries of intracellular and intra‐metastatic cancer bacteria necessitate fundamental changes in describing clonal evolution and selection, reflecting bidirectional interactions with non‐human residents. Reconsidering cancer clonality as a multispecies process similarly holds key implications for understanding metastasis and prognosing therapeutic resistance while providing rational guidance for the next generation of bacterial cancer therapies. Guided by these new findings and challenges, this Review describes opportunities to exploit cancer's metagenome in oncology and proposes an evolutionary framework as a first step towards modeling multispecies cancer clonality. Also see the video abstract here: https://youtu.be/-WDtIRJYZSs

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Section: Implications and Hypotheses If Cancer Clonality Is Multispeciesmentioning

confidence: 99%

Cancer's second genome: Microbial cancer diagnostics and redefining clonal evolution as a multispecies process

et al. 2022

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“…Recently, Pang et al revealed that ecDNA was present in nearly all HPVOPCs. Additionally, a novel human-viral hybrid ecDNA was also identified in HPVOPC [86]. Moreover, hybrid ecDNA highly expresses fusion transcripts that contain promoter and oncogene sequences of HPV.…”

Section: Ecdna In Hpv-mediated Oropharyngeal Cancermentioning

confidence: 99%

“…These fusion transcripts are associated with downstream human transcripts. These downstream transcripts could drive carcinogenesis and immune evasion [86]. Viral promoters and genes account for the high expression of hybrid transcripts and human oncogenes in hybrid ecDNA structures, which is facilitated by high levels of chromatin modifications (such as H3K27 ac) in ecDNA [11,86].…”

Section: Ecdna In Hpv-mediated Oropharyngeal Cancermentioning

confidence: 99%

Pioneering insights of extrachromosomal DNA (ecDNA) generation, action and its implications for cancer therapy

Li¹,

Wang²,

Liang³

et al. 2022

Int. J. Biol. Sci.

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Extrachromosomal DNA (ecDNA) is a cancer-specific circular DNA molecule that is derived from chromosomes. In contrast with linear chromosomes, ecDNA exhibits a unique structure that can be representative of high chromosome accessibility, contributing to hyperactivated proto-oncogenes and malignant behaviours. Meanwhile, nonchromosomal inheritance and recurrent mutations of ecDNA fuel tumour heterogeneity and evolution. Recent studies have demonstrated that ecDNA drives tumorigenesis and progression and is related to poor clinical outcomes and drug resistance across widespread cancers. Although ecDNA was first observed in 1965, with technological advancements, its critical functions in tumorigenesis are currently coming forth. In this review, we summarize the current understanding of the origin, biogenesis process, discovery history, molecular mechanisms, and physiological functions of ecDNAs in cancer. Additionally, we highlight the effective research methods to study ecDNA and offer novel insights for ecDNA-directed therapies.

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“…Hybrid human–virus extra chromosomal DNA (ecDNA) was shown to induce an increase in HPV oncogenes E6 and E7 copy number. More recently, the interaction of the HPV genome with cancer‐associated ecDNA was shown to induce high expression of hybrid viral–human oncogene transcripts in OPSCC [24] .…”

Section: Introductionmentioning

confidence: 99%

Human papilloma virus integration sites and genomic signatures in head and neck squamous cell carcinoma

et al. 2022

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A prevalence of around 26% of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involving E6 and E7 viral oncoproteins. In some cases, HPV viral DNA has been detected to integrate with the host genome and possibly contributes to carcinogenesis by affecting the gene expression. We retrospectively assessed HPV integration sites and signatures in 80 HPV positive patients with HNSCC, by using a double capture‐HPV method followed by next‐generation Sequencing. We detected HPV16 in 90% of the analyzed cohort and confirmed five previously described mechanistic signatures of HPV integration [episomal (EPI), integrated in a truncated form revealing two HPV‐chromosomal junctions colinear (2J‐COL) or nonlinear (2J‐NL), multiple hybrid junctions clustering in a single chromosomal region (MJ‐CL) or scattered over different chromosomal regions (MJ‐SC) of the human genome]. Our results suggested that HPV remained episomal in 38.8% of the cases or was integrated/mixed in the remaining 61.2% of patients with HNSCC. We showed a lack of association of HPV genomic signatures to tumour and patient characteristics, as well as patient survival. Similar to other HPV associated cancers, low HPV copy number was associated with worse prognosis. We identified 267 HPV‐human junctions scattered on most chromosomes. Remarkably, we observed four recurrent integration regions: PDL1/PDL2/PLGRKT (8.2%), MYC/PVT1 (6.1%), MACROD2 (4.1%) and KLF5/KLF12 regions (4.1%). We detected the overexpression of PDL1 and MYC upon integration by gene expression analysis. In conclusion, we identified recurrent targeting of several cancer genes such as PDL1 and MYC upon HPV integration, suggesting a role of altered gene expression by HPV integration during HNSCC carcinogenesis.

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Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription

Cited by 28 publications

References 62 publications

Cancer's second genome: Microbial cancer diagnostics and redefining clonal evolution as a multispecies process

Cancer's second genome: Microbial cancer diagnostics and redefining clonal evolution as a multispecies process

Pioneering insights of extrachromosomal DNA (ecDNA) generation, action and its implications for cancer therapy

Human papilloma virus integration sites and genomic signatures in head and neck squamous cell carcinoma

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