Editing Oncovirus

{{Short description|Viruses that can cause cancer}}
{{Distinguish|Oncolytic virus}}
{{Use dmy dates|date=July 2021}}
[[File:PrevalenceHepB2014.png|300px|thumb|upright=1.6|Percentage of people infected with [[hepatitis C]] in 2015. The [[hepatitis C virus]] is the cause of hepatitis C and some cancers such as liver cancer ([[hepatocellular carcinoma]], abbreviated HCC) and [[lymphoma]]s in humans.<ref name="Ferri2015">{{cite journal | vauthors = Ferri C, Sebastiani M, Giuggioli D, Colaci M, Fallahi P, Piluso A, Antonelli A, Zignego AL | display-authors = 6 | title = Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin's lymphoma, and cancer | journal = World Journal of Hepatology | volume = 7 | issue = 3 | pages = 327–343 | date = March 2015 | pmid = 25848462 | pmc = 4381161 | doi = 10.4254/wjh.v7.i3.327 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Rusyn I, Lemon SM | title = Mechanisms of HCV-induced liver cancer: what did we learn from in vitro and animal studies? | journal = Cancer Letters | volume = 345 | issue = 2 | pages = 210–215 | date = April 2014 | pmid = 23871966 | pmc = 3844040 | doi = 10.1016/j.canlet.2013.06.028 }}</ref><ref>{{cite web |url=https://www.cancer.org/cancer/cancer-causes/infectious-agents/infections-that-can-lead-to-cancer/viruses.html |title=Viruses that can lead to cancer |author=ACS Medical and Editorial Content Team |date=30 July 2020 |website=www.cancer.org |publisher=[[American Cancer Society]] |access-date=27 February 2021}}</ref>]]

An '''oncovirus''' or '''oncogenic virus''' is a virus that can cause [[cancer]].<ref>{{cite journal | vauthors = Chang Y, Moore PS, Weiss RA | title = Human oncogenic viruses: nature and discovery | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 372 | issue = 1732 | pages = 1–9 | date = October 2017 | pmid = 28893931 | pmc = 5597731 | doi = 10.1098/rstb.2016.0264 | publisher = [[Royal Society Publishing]] | author2-link = Patrick S. Moore | jstor = 44679143 | author1-link = Yuan Chang }}</ref> This term originated from studies of acutely transforming [[retrovirus]]es in the 1950–60s,<ref name= Va>{{cite journal | vauthors = Valladares Y | title = Studies on cancerous pathogenesis. Production of leukemia and polycythemia vera by means of cancerous nucleoproteins from tissue cultures | journal = Medicina Experimentalis | volume = 2 | pages = 309–316 | date = 1960 | pmid = 13779782 | doi = 10.1159/000134890 }}</ref> when the term ''oncornaviruses'' was used to denote their [[RNA]] virus origin.<ref>
{{cite book | vauthors = Herberman RB | author-link1 = Ronald B. Herberman | chapter = 12: Immunology of Oncornaviruses | veditors = Nahmias AJ, O'Reilly RJ | title = Immunology of Human Infection: Part II: Viruses and Parasites; Immunodiagnosis and Prevention of Infectious Diseases | url = https://books.google.com/books?id=eV4FCAAAQBAJ | series = Comprehensive Immunology | volume = 9 | edition = reprint | location = New York | publisher = Plenum Publishing Corporation | date = 2012 | pages = 273, 275 | isbn = 9781468410129 | access-date = 20 October 2016 | quote = Viruses known as oncogenic RNA viruses or oncornaviruses have been described in a wide variety of vertebrate species [...] there have been very few, if any, completely convincing examples of isolation of human oncornaviruses. }}
</ref> With the letters ''RNA'' removed, it now refers to any virus with a [[DNA]] or RNA genome causing cancer and is synonymous with '''''tumor virus''''' or ''cancer virus''. The vast majority of human and animal viruses do not cause cancer, probably because of longstanding co-evolution between the virus and its host. Oncoviruses have been important not only in [[epidemiology]], but also in investigations of [[cell cycle]] control mechanisms such as the [[retinoblastoma protein]].

The [[World Health Organization]]'s [[International Agency for Research on Cancer]] estimated that in 2002, infection caused 17.8% of human cancers, with 11.9% caused by one of seven viruses.<ref name=Parkin06>{{cite journal | vauthors = Parkin DM | title = The global health burden of infection-associated cancers in the year 2002 | journal = International Journal of Cancer | volume = 118 | issue = 12 | pages = 3030–3044 | date = June 2006 | pmid = 16404738 | doi = 10.1002/ijc.21731 | s2cid = 10042384 | doi-access = free }}</ref> A 2020 study of 2,658 samples from 38 different types of cancer found that 16% were associated with a virus.<ref>{{cite journal | vauthors = Zapatka M, Borozan I, Brewer DS, Iskar M, Grundhoff A, Alawi M, Desai N, Sültmann H, Moch H, Cooper CS, Eils R, Ferretti V, Lichter P | display-authors = 6 | title = The landscape of viral associations in human cancers | journal = Nature Genetics | volume = 52 | issue = 3 | pages = 320–330 | date = March 2020 | pmid = 32025001 | pmc = 8076016 | doi = 10.1038/s41588-019-0558-9 | doi-access = free }}</ref> These cancers might be easily prevented through vaccination (e.g., [[HPV vaccine|papillomavirus vaccines]]), diagnosed with simple blood tests, and treated with less-toxic antiviral compounds.

==Causality==
Generally, tumor viruses cause little or no disease after infection in their hosts, or cause non-[[neoplastic]] diseases such as acute hepatitis for [[hepatitis B virus]] or mononucleosis for [[Epstein–Barr virus]]. A minority of persons (or animals) will go on to develop cancers after infection. This has complicated efforts to determine whether or not a given virus causes cancer. The well-known [[Koch's postulates]], 19th-century constructs developed by [[Robert Koch]] to establish the likelihood that ''[[Bacillus anthracis]]'' will cause [[anthrax]] disease, are not applicable to viral diseases. Firstly, this is because viruses cannot truly be isolated in pure culture—even stringent isolation techniques cannot exclude undetected contaminating viruses with similar density characteristics, and viruses must be grown on cells. Secondly, asymptomatic virus infection and carriage is the norm for most tumor viruses, which violates Koch's third principle. Relman and Fredericks have described the difficulties in applying Koch's postulates to virus-induced cancers.<ref name="pmid8665474">{{cite journal | vauthors = Fredricks DN, Relman DA | title = Sequence-based identification of microbial pathogens: a reconsideration of Koch's postulates | journal = Clinical Microbiology Reviews | volume = 9 | issue = 1 | pages = 18–33 | date = January 1996 | pmid = 8665474 | pmc = 172879 | doi = 10.1128/CMR.9.1.18 }}</ref> Finally, the host restriction for human viruses makes it unethical to experimentally transmit a suspected cancer virus. Other measures, such as [[Bradford Hill criteria|A. B. Hill's criteria]],<ref name="pmid14283879">{{cite journal | vauthors = Hill AB | title = The Environment and Disease: Association or Causation? | journal = Proceedings of the Royal Society of Medicine | volume = 58 | issue = 5 | pages = 295–300 | date = May 1965 | pmid = 14283879 | pmc = 1898525 | doi = 10.1177/003591576505800503 }}</ref> are more relevant to cancer virology but also have some limitations in determining causality.

[[File:Viral Tegument.svg|thumb|right|300px|Simplified diagram of the structure of the [[Epstein–Barr virus]] (EBV).]]
Tumor viruses come in a variety of forms: Viruses with a [[DNA]] [[genome]], such as [[adenovirus]], and viruses with an RNA genome, like the [[hepatitis C virus]] (HCV), can cause cancers, as can retroviruses having both DNA and RNA genomes ([[Human T-lymphotropic virus]] and [[hepatitis B virus]], which normally replicates as a mixed double and single-stranded DNA virus but also has a retroviral replication component). In many cases, tumor viruses do not cause cancer in their native hosts but only in dead-end species. For example, adenoviruses do not cause cancer in humans but are instead responsible for colds, conjunctivitis and other acute illnesses. They only become tumorigenic when infected into certain rodent species, such as Syrian hamsters. Some viruses are tumorigenic when they infect a cell and persist as circular [[episome]]s or plasmids, replicating separately from host cell DNA ([[Epstein–Barr virus]] and [[Kaposi's sarcoma-associated herpesvirus]]). Other viruses are only carcinogenic when they integrate into the host cell genome as part of a biological accident, such as polyomaviruses and papillomaviruses.{{citation needed|date=December 2020}}

==Oncogenic viral mechanism==
[[File:Oncogenes illustration.jpg|thumb|300px|Illustration of how a normal cell is converted to a cancer cell, when an [[oncogene]] becomes activated.]]
A direct oncogenic viral mechanism<ref>{{Cite book|author=Parsonnet, Julie |author-link=Julie Parsonnet |title=Microbes and malignancy: infection as a cause of human cancers |publisher=Oxford University Press |location=Oxford |year=1999 |isbn=978-0-19-510401-1}}{{Page needed|date=September 2010}}</ref> involves either insertion of additional viral oncogenic genes into the host cell or to enhance already existing oncogenic genes ([[proto-oncogenes]]) in the genome. For example, it has been shown that vFLIP and vCyclin interfere with the TGF-β signaling pathway indirectly by inducing oncogenic host mir17-92 cluster.<ref>{{cite journal | vauthors = Choi HS, Jain V, Krueger B, Marshall V, Kim CH, Shisler JL, Whitby D, Renne R | display-authors = 6 | title = Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Induces the Oncogenic miR-17-92 Cluster and Down-Regulates TGF-β Signaling | journal = PLOS Pathogens | volume = 11 | issue = 11 | pages = e1005255 | date = 2015 | pmid = 26545119 | pmc = 4636184 | doi = 10.1371/journal.ppat.1005255 | doi-access = free }}</ref>

Indirect viral oncogenicity involves chronic nonspecific inflammation occurring over decades of infection, as is the case for HCV-induced liver cancer. These two mechanisms differ in their biology and epidemiology: direct tumor viruses must have at least one virus copy in every tumor cell expressing at least one protein or RNA that is causing the cell to become cancerous. Because foreign virus [[antigen]]s are expressed in these tumors, persons who are immunosuppressed such as AIDS or transplant patients are at higher risk for these types of cancers.{{citation needed|date=December 2020}}

Chronic indirect tumor viruses, on the other hand, can be lost (at least theoretically) from a mature tumor that has accumulated sufficient mutations and growth conditions (hyperplasia) from the chronic inflammation of viral infection. In this latter case, it is controversial but at least theoretically possible that an indirect tumor virus could undergo "hit-and-run" and so the virus would be lost from the clinically diagnosed tumor. In practical terms, this is an uncommon occurrence if it does occur.{{citation needed|date=December 2020}}

==DNA oncoviruses==
[[File:Anaplastic astrocytoma - p53 - very high mag.jpg|thumb|A [[micrograph]] showing cells with abnormal p53 expression (brown) in a brain tumor.]]
DNA oncoviruses typically impair two families of tumor suppressor proteins: tumor proteins [[p53]] and the [[retinoblastoma protein]]s (Rb). It is evolutionarily advantageous for viruses to inactivate p53 because p53 can trigger cell cycle arrest or apoptosis in infected cells when the virus attempts to replicate its DNA.<ref name= Ma>{{cite journal | vauthors = Mantovani F, Banks L | title = The human papillomavirus E6 protein and its contribution to malignant progression | journal = Oncogene | volume = 20 | issue = 54 | pages = 7874–7887 | date = November 2001 | pmid = 11753670 | doi = 10.1038/sj.onc.1204869 | doi-access = free }}</ref> Similarly, Rb proteins regulate many essential cell functions, including but not limited to a crucial cell cycle checkpoint, making them a target for viruses attempting to interrupt regular cell function.<ref name= Fm>{{cite journal | vauthors = Felsani A, Mileo AM, Paggi MG | title = Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins | journal = Oncogene | volume = 25 | issue = 38 | pages = 5277–5285 | date = August 2006 | pmid = 16936748 | doi = 10.1038/sj.onc.1209621 | doi-access = free }}</ref>

While several DNA oncoviruses have been discovered, three have been studied extensively. [[Adenoviruses]] can lead to tumors in rodent models but do not cause cancer in humans; however, they have been exploited as delivery vehicles in gene therapy for diseases such as cystic fibrosis and cancer.<ref name= GastonK>{{cite book | veditors = Gaston, K| year=2012 | title=Small DNA Tumor Viruses | publisher=[[Caister Academic Press]] | isbn= 978-1-904455-99-8}}</ref> [[Simian virus 40]] (SV40), a [[polyomavirus]], can cause tumors in rodent models but is not oncogenic in humans.<ref name= Po>{{cite journal | vauthors = Poulin DL, DeCaprio JA | title = Is there a role for SV40 in human cancer? | journal = Journal of Clinical Oncology | volume = 24 | issue = 26 | pages = 4356–4365 | date = September 2006 | pmid = 16963733 | doi = 10.1200/JCO.2005.03.7101 }}</ref> This phenomenon has been one of the major controversies of oncogenesis in the 20th century because an estimated 100 million people were inadvertently exposed to SV40 through polio vaccines.<ref name= Po/> The [[human papillomavirus]]-16 (HPV-16) has been shown to lead to cervical cancer and other cancers, including head and neck cancer.<ref name= Wi>{{cite journal | vauthors = Wiest T, Schwarz E, Enders C, Flechtenmacher C, Bosch FX | title = Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control | journal = Oncogene | volume = 21 | issue = 10 | pages = 1510–1517 | date = February 2002 | pmid = 11896579 | doi = 10.1038/sj.onc.1205214 | doi-access = free }}</ref> These three viruses have parallel mechanisms of action, forming an archetype for DNA oncoviruses. All three of these DNA oncoviruses are able to integrate their DNA into the host cell, and use this to transcribe it and transform cells by bypassing the G1/S checkpoint of the cell cycle.{{citation needed|date=May 2021}}

===Integration of viral DNA===

DNA oncoviruses transform infected cells by integrating their DNA into the host cell's genome.<ref name= Sa>{{cite journal | vauthors = Sambrook J, Greene R, Stringer J, Mitchison T, Hu SL, Botchan M | title = Analysis of the sites of integration of viral DNA sequences in rat cells transformed by adenovirus 2 or SV40 | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 44 | issue = 1 | pages = 569–584 | date = 1980 | pmid = 6253158 | doi = 10.1101/sqb.1980.044.01.059 }}</ref> The DNA is believed to be inserted during transcription or replication, when the two annealed strands are separated.<ref name= Sa/> This event is relatively rare and generally unpredictable; there seems to be no deterministic predictor of the site of integration.<ref name= Sa/> After integration, the host's cell cycle loses regulation from Rb and p53, and the cell begins cloning to form a tumor.<ref>{{Cite journal |last=Levine |first=Arnold J. |date=1997-02-07 |title=p53, the Cellular Gatekeeper for Growth and Division |journal=Cell |language=English |volume=88 |issue=3 |pages=323–331 |doi=10.1016/S0092-8674(00)81871-1 |issn=0092-8674 |pmid=9039259|doi-access=free }}</ref>

===G1/S Checkpoint===

Rb and p53 regulate the transition between [[G1 phase|G1]] and [[S phase]], arresting the cell cycle before DNA replication until the appropriate checkpoint inputs, such as DNA damage repair, are completed.<ref name= Mo>{{cite book | author= Morgan, D. O. | year=2007 | title=The cell cycle: principles of control | publisher=New Science Press | isbn= 978-1-904455-99-8}}</ref> p53 regulates the p21 gene, which produces a protein which binds to the Cyclin D-Cdk4/6 complex.<ref name= Le>{{cite journal | vauthors = Levine AJ | title = The common mechanisms of transformation by the small DNA tumor viruses: The inactivation of tumor suppressor gene products: p53 | journal = Virology | volume = 384 | issue = 2 | pages = 285–293 | date = February 2009 | pmid = 19081592 | doi = 10.1016/j.virol.2008.09.034 | doi-access = free }}</ref> This prevents Rb phosphorylation and prevents the cell from entering S phase.<ref name= Le/> In mammals, when Rb is active (unphosphorylated), it inhibits the [[E2F]] family of transcription factors, which regulate the [[Cyclin E]]-[[Cdk2]] complex, which inhibits Rb, forming a positive feedback loop, keeping the cell in G1 until the input crosses a threshold.<ref name= Mo/> To drive the cell into S phase prematurely, the viruses must inactivate p53, which plays a central role in the G1/S checkpoint, as well as Rb, which, though downstream of it, is typically kept active by a positive feedback loop.{{citation needed|date=May 2021}}

===Inactivation of p53===

Viruses employ various methods of inactivating p53. The [[adenovirus E1B protein]] (55K) prevents p53 from regulating genes by binding to the site on p53 which binds to the genome.<ref name= Ma/> In SV40, the [[large T antigen]] (LT) is an analogue; LT also binds to several other cellular proteins, such as [[Retinoblastoma-like protein 1|p107]] and [[Retinoblastoma-like protein 2|p130]], on the same residues.<ref name= Dc>{{cite journal | vauthors = DeCaprio JA | title = How the Rb tumor suppressor structure and function was revealed by the study of Adenovirus and SV40 | journal = Virology | volume = 384 | issue = 2 | pages = 274–284 | date = February 2009 | pmid = 19150725 | doi = 10.1016/j.virol.2008.12.010 | doi-access = free }}</ref> LT binds to p53's binding domain on the DNA (rather than on the protein), again preventing p53 from appropriately regulating genes.<ref name= Ma/> HPV instead degrades p53: the HPV protein E6 binds to a cellular protein called the E6-associated protein (E6-AP, also known as [[UBE3A]]), forming a complex which causes the rapid and specific [[ubiquitination]] of p53.<ref name= Sc>{{cite journal | vauthors = Scheffner M, Huibregtse JM, Vierstra RD, Howley PM | title = The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53 | journal = Cell | volume = 75 | issue = 3 | pages = 495–505 | date = November 1993 | pmid = 8221889 | doi = 10.1016/0092-8674(93)90384-3 | s2cid = 27437768 }}</ref>

===Inactivation of Rb===

Rb is inactivated (thereby allowing the G1/S transition to progress unimpeded) by different but analogous viral oncoproteins. The [[adenovirus early region 1A]] (E1A) is an oncoprotein which binds to Rb and can stimulate transcription and transform cells.<ref name= Ma/> SV40 uses the same protein for inactivating Rb, LT, to inactivate p53.<ref name= Le/> HPV contains a protein, E7, which can bind to Rb in much the same way.<ref name= Dy>{{cite journal | vauthors = Dyson N, Howley PM, Münger K, Harlow E | title = The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product | journal = Science | volume = 243 | issue = 4893 | pages = 934–937 | date = February 1989 | pmid = 2537532 | doi = 10.1126/science.2537532 | bibcode = 1989Sci...243..934D }}</ref> Rb can be inactivated by phosphorylation, or by being bound to a viral oncoprotein, or by mutations—mutations which prevent oncoprotein binding are also associated with cancer.<ref name= Dc/>

===Variations===

DNA oncoviruses typically cause cancer by inactivating p53 and Rb, thereby allowing unregulated cell division and creating tumors. There may be many different mechanisms which have evolved separately; in addition to those described above, for example, the [[Human Papillomavirus]] inactivates p53 by sequestering it in the cytoplasm.<ref name= Ma/>

SV40 has been well studied and does not cause cancer in humans, but a recently discovered analogue called [[Merkel cell polyomavirus]] has been associated with [[Merkel cell carcinoma]], a form of skin cancer.<ref name= Fe>{{cite journal | vauthors = Feng H, Shuda M, Chang Y, Moore PS | title = Clonal integration of a polyomavirus in human Merkel cell carcinoma | journal = Science | volume = 319 | issue = 5866 | pages = 1096–1100 | date = February 2008 | pmid = 18202256 | pmc = 2740911 | doi = 10.1126/science.1152586 | bibcode = 2008Sci...319.1096F }}</ref> The Rb binding feature is believed to be the same between the two viruses.<ref name= Fe/>

==RNA oncoviruses==
{{unreferenced section|date=July 2020}}
In the 1960s, the replication process of RNA virus was believed to be similar to other single-stranded RNA. Single-stranded RNA replication involves RNA-dependent RNA synthesis which meant that virus-coding enzymes would make partial double-stranded RNA. This belief was shown to be incorrect because there were no double-stranded RNA found in the retrovirus cell. In 1964, Howard Temin proposed a provirus hypothesis, but shortly after reverse transcription in the retrovirus genome was discovered.<ref>{{cite journal |last1=Fisher |first1=Susie |title=Not Beyond Reasonable Doubt: Howard Temin's Provirus Hypothesis Revisited |journal=[[Journal of the History of Biology]] |date=December 2010 |volume=43 |issue=4 |pages=661–696 |doi=10.1007/s10739-009-9202-3 |pmid=20665081 |url=https://pubmed.ncbi.nlm.nih.gov/20665081/ |access-date=10 December 2024}}</ref>

===Description of virus===
All retroviruses have three major coding domains; ''[[Group-specific antigen|gag]]'', ''pol'' and ''[[Env (gene)|env]]''. In the ''gag'' region of the virus, the synthesis of the internal virion proteins are maintained which make up the matrix, capsid and nucleocapsid proteins. In ''pol'', the information for the reverse transcription and integration enzymes are stored. In ''env'', it is derived from the surface and transmembrane for the viral envelope protein. There is a fourth coding domain which is smaller, but exists in all retroviruses. ''Pol'' is the domain that encodes the virion protease.

===Retrovirus enters host cell===
The retrovirus begins the journey into a host cell by attaching a surface glycoprotein to the cell's plasma membrane receptor. Once inside the cell, the retrovirus goes through reverse transcription in the cytoplasm and generates a double-stranded DNA copy of the RNA genome. Reverse transcription also produces identical structures known as long terminal repeats (LTRs). Long terminal repeats are at the ends of the DNA strands and regulates viral gene expression. The viral DNA is then translocated into the nucleus where one strand of the retroviral genome is put into the chromosomal DNA by the help of the virion integrase. At this point the retrovirus is referred to as provirus. Once in the chromosomal DNA, the provirus is transcribed by the cellular RNA polymerase II. The transcription leads to the splicing and full-length mRNAs and full-length progeny virion RNA. The virion protein and progeny RNA assemble in the cytoplasm and leave the cell, whereas the other copies send translated viral messages in the cytoplasm.

==Classification==
[[File:Kaposis sarcoma 01.jpg|thumb|[[Kaposi's sarcoma]] is a cancer that can form masses in the skin and is caused by the [[Kaposi's sarcoma-associated herpesvirus]] (KSHV), also called HHV-8.]]

===DNA viruses===
* [[Human papillomavirus]] (HPV), a DNA virus, causes [[Malignant transformation|transformation]] in cells through interfering with tumor suppressor proteins such as [[p53]]. Interfering with the action of p53 allows a cell infected with the virus to move into a different stage of the cell cycle, enabling the virus genome to be replicated. Forcing the cell into the S phase of the [[cell cycle]] could cause the cell to become transformed.<ref>{{cite journal | vauthors = Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM | title = The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53 | journal = Cell | volume = 63 | issue = 6 | pages = 1129–1136 | date = December 1990 | pmid = 2175676 | doi = 10.1016/0092-8674(90)90409-8 | s2cid = 7268482 }}</ref> Human papillomavirus infection is a major cause of [[cervical cancer]], [[vulvar cancer]], [[vaginal cancer]], [[penis cancer]], [[anal cancer]], and [[HPV-positive oropharyngeal cancer|HPV-positive]] [[oropharyngeal cancer]]s.<ref name=Parkin06/><ref name="NEJM2003">{{cite journal | vauthors = Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ | display-authors = 6 | title = Epidemiologic classification of human papillomavirus types associated with cervical cancer | journal = The New England Journal of Medicine | volume = 348 | issue = 6 | pages = 518–527 | date = February 2003 | pmid = 12571259 | doi = 10.1056/NEJMoa021641 | hdl-access = free | df = dmy-all | s2cid = 1451343 | collaboration = International Agency for Research on Cancer Multicenter Cervical Cancer Study Group | hdl = 2445/122831 }}</ref><ref name=schiffman2007>{{cite journal | vauthors = Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S | title = Human papillomavirus and cervical cancer | journal = Lancet | volume = 370 | issue = 9590 | pages = 890–907 | date = September 2007 | pmid = 17826171 | doi = 10.1016/S0140-6736(07)61416-0 | s2cid = 20196938 }}</ref><ref name="Kreimer 2014">{{cite journal | vauthors = Kreimer AR | title = Prospects for prevention of HPV-driven oropharynx cancer | journal = Oral Oncology | volume = 50 | issue = 6 | pages = 555–559 | date = June 2014 | pmid = 23876626 | pmc = 4058827 | doi = 10.1016/j.oraloncology.2013.06.007 | s2cid = 13768854 }}</ref><ref name=Lj2014>{{cite journal | vauthors = Ljubojevic S, Skerlev M | title = HPV-associated diseases | journal = Clinics in Dermatology | volume = 32 | issue = 2 | pages = 227–234 | year = 2014 | pmid = 24559558 | doi = 10.1016/j.clindermatol.2013.08.007 | s2cid = 24219797 }}</ref><ref name=WHO2016>{{cite web|title=Human papillomavirus (HPV) and cervical cancer|url=https://www.who.int/mediacentre/factsheets/fs380/en/|website=WHO |date=June 2016|url-status=live|archive-url=https://web.archive.org/web/20160805111143/http://www.who.int/mediacentre/factsheets/fs380/en/|archive-date=5 August 2016}}</ref><ref name="StatPearls 2020">{{cite book | vauthors = Anjum T, Zohaib J |title=Definitions |chapter=Oropharyngeal Squamous Cell Carcinoma |date=4 December 2020 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK563268/ |place=Treasure Island (FL) |publisher=StatPearls Publishing |edition=Updated |id=Bookshelf ID: NBK563268 |doi=10.32388/G6TG1L |pmid=33085415 |s2cid=229252540 |via=[[NCBI]] |access-date=7 February 2021}}</ref> There are nearly 200 distinct human papillomaviruses (HPVs),<ref name=Lj2014/> and many HPV types are carcinogenic.<ref name=Parkin06/><ref name="NEJM2003"/>
*[[Hepatitis B virus]] (HBV) is associated with [[Hepatocarcinoma]]<ref name=":0" />
* [[Epstein–Barr virus]] (EBV or HHV-4) is associated with four types of cancers
* [[Human cytomegalovirus]] (CMV or HHV-5) is associated with [[mucoepidermoid carcinoma]] and possibly other malignancies.<ref name="pmid22101257">{{cite journal | vauthors = Melnick M, Sedghizadeh PP, Allen CM, Jaskoll T | title = Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship | journal = Experimental and Molecular Pathology | volume = 92 | issue = 1 | pages = 118–125 | date = February 2012 | pmid = 22101257 | doi = 10.1016/j.yexmp.2011.10.011 | s2cid = 41446671 }}</ref>
*[[Kaposi's sarcoma-associated herpesvirus]] (KSHV or HHV-8) is associated with [[Kaposi's sarcoma]], a type of skin cancer.<ref>{{cite journal | vauthors = Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS | title = Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma | journal = Science | volume = 266 | issue = 5192 | pages = 1865–1869 | date = December 1994 | pmid = 7997879 | doi = 10.1126/science.7997879 | bibcode = 1994Sci...266.1865C | s2cid = 29977325 | url = https://zenodo.org/record/842914 }}</ref>
*[[Merkel cell polyomavirus]]{{spaced ndash}}a [[polyoma virus]]{{spaced ndash}}is associated with the development of [[Merkel cell carcinoma]]<ref name="Fe" />

===RNA viruses===
Not all oncoviruses are [[DNA virus]]es. Some [[RNA virus]]es have also been associated such as the [[hepatitis C virus]] as well as certain retroviruses, e.g., [[human T-lymphotropic virus]] (HTLV-1) and [[Rous sarcoma virus]] (RSV).

===Overview table===
{|class=wikitable
|-
! Virus
! Percent of cancers<ref name=Parkin06 />
! Associated cancer types
|-
|[[Hepatitis B virus]] (HBV) ||   ||[[Hepatocarcinoma]]<ref name=":0">{{cite journal | vauthors = Tang CM, Yau TO, Yu J | title = Management of chronic hepatitis B infection: current treatment guidelines, challenges, and new developments | journal = World Journal of Gastroenterology | volume = 20 | issue = 20 | pages = 6262–6278 | date = May 2014 | pmid = 24876747 | pmc = 4033464 | doi = 10.3748/wjg.v20.i20.6262 | doi-access = free }}</ref>
|-
|[[Hepatitis C virus]] (HCV) ||    || HCV is a known carcinogen, causing [[hepatocarcinoma]]<ref name="NTP-ReportonCarcinogens-2016">{{cite book|last1=NTP (National Toxicology Program)|url=http://ntp.niehs.nih.gov/go/roc14|title=Report on Carcinogens|date=2016|publisher=U.S. Department of Health and Human Services, Public Health Service.|edition=Fourteenth|location=Research Triangle Park, NC|access-date=8 January 2017}}</ref>
|-
| [[Human T-lymphotropic virus]] (HTLV)  || 0.03 || [[Adult T-cell leukemia]]<ref>{{cite journal | vauthors = Bellon M, Nicot C | title = Telomerase: a crucial player in HTLV-I-induced human T-cell leukemia | journal = Cancer Genomics & Proteomics | volume = 4 | issue = 1 | pages = 21–25 | year = 2007 | pmid = 17726237 | url = http://cgp.iiarjournals.org/cgi/pmidlookup?view=long&pmid=17726237 }}</ref>
|-
| [[Human papillomaviruses]] (HPV) || 5.2 || HPV types 16 and 18 are associated with cancers of [[Cervical cancer|cervix]],<ref name=Parkin06/><ref name="NEJM2003"/><ref name=schiffman2007/><ref name=Lj2014/><ref name=WHO2016/> [[Anal cancer|anus]],<ref name=Parkin06/><ref name="Kreimer 2014"/><ref name=Lj2014/> [[Penile cancer|penis]],<ref name=Parkin06/><ref name="Kreimer 2014"/><ref name=Lj2014/> [[Vulvar cancer|vulva]],<ref name=Parkin06/><ref name="Kreimer 2014"/><ref name=Lj2014/> [[Vaginal cancer|vagina]],<ref name=Parkin06/><ref name="Kreimer 2014"/><ref name=Lj2014/> and [[HPV-positive oropharyngeal cancer|HPV-positive]] [[oropharyngeal cancer]]s.<ref name=Parkin06/><ref name="Kreimer 2014"/><ref name="StatPearls 2020"/> According to statistics in the United States, females are more impacted by HPV-associated cancers (83%) than males (74%).<ref>[https://www.cdc.gov/cancer/hpv/statistics/cases.htm How Many Cancers Are Linked with HPV Each Year?] CDC.gov</ref>
|-
| [[Kaposi's sarcoma-associated herpesvirus]] (HHV-8)  || 0.9 || [[Kaposi's sarcoma]], multicentric [[Castleman's disease]] and [[primary effusion lymphoma]]
|-
| [[Merkel cell polyomavirus]] (MCV) || NA || [[Merkel cell carcinoma]]
|-
|[[Epstein–Barr virus]] (EBV) || NA || [[Burkitt's lymphoma]], [[Hodgkin's lymphoma]], [[post-transplant lymphoproliferative disease]], [[nasopharyngeal carcinoma]]<ref>{{cite journal | vauthors = Klein E, Kis LL, Klein G | title = Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions | journal = Oncogene | volume = 26 | issue = 9 | pages = 1297–1305 | date = February 2007 | pmid = 17322915 | doi = 10.1038/sj.onc.1210240 | doi-access = free }}</ref> and a subtype of [[stomach cancer]].<ref>{{cite journal | vauthors = Yau TO, Tang CM, Yu J | title = Epigenetic dysregulation in Epstein-Barr virus-associated gastric carcinoma: disease and treatments | journal = World Journal of Gastroenterology | volume = 20 | issue = 21 | pages = 6448–6456 | date = June 2014 | pmid = 24914366 | pmc = 4047330 | doi = 10.3748/wjg.v20.i21.6448 | doi-access = free }}</ref>
|}

Estimated percent of new cancers attributable to the virus worldwide in 2002.<ref name=Parkin06 /> NA indicates not available. The association of other viruses with human cancer is continually under research.

== Main viruses associated with human cancer ==
[[File:2r5k.jpg|thumb|Major capsid protein L1 pentamer, Human papillomavirus 11]]
[[File:HBV.png|thumb|The structure of the [[hepatitis B]] virus]]
The main viruses associated with human cancers are the [[human papillomavirus]], the [[hepatitis B]] and [[hepatitis C]] viruses, the [[Epstein–Barr virus]], the [[human T-lymphotropic virus]], the [[Kaposi's sarcoma-associated herpesvirus]] (KSHV) and the [[Merkel cell polyomavirus]]. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage.<ref name="zur Hausen-viruses">{{cite journal | vauthors = zur Hausen H | title = Viruses in human cancers | journal = Science | volume = 254 | issue = 5035 | pages = 1167–1173 | date = November 1991 | pmid = 1659743 | doi = 10.1126/science.1659743 | bibcode = 1991Sci...254.1167Z }}</ref> The mode of virally induced tumors can be divided into two, ''acutely transforming'' or ''slowly transforming''. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of [[retrovirus]]es, near a proto-oncogene in the host genome. The viral [[promoter (biology)|promoter]] or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly transforming viruses have very long tumor latency compared to acutely transforming viruses, which already carry the viral oncogene.{{citation needed|date=December 2020}}

Hepatitis viruses, including [[hepatitis B]] and [[hepatitis C]], can induce a chronic viral infection that leads to [[Hepatocellular carcinoma|liver cancer]] in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of [[viral hepatitis]] transmission and disease.{{citation needed|date=December 2020}}

Through advances in cancer research, vaccines designed to prevent cancer have been created. The hepatitis B vaccine is the first vaccine that has been established to prevent cancer ([[hepatocellular carcinoma]]) by preventing infection with the causative virus. In 2006, the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] approved a [[human papilloma virus]] vaccine, called [[Gardasil]]. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US [[Centers for Disease Control and Prevention]] (CDC) [[Advisory Committee on Immunization Practices]] (ACIP) officially recommended that females aged 11–12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.{{citation needed|date=December 2020}}

==History==
The history of cancer virus discovery is intertwined with the [[history of cancer]] research and the [[history of virology]]. The oldest surviving record of a human cancer is the [[Babylonia]]n [[Code of Hammurabi]] (dated ca. 1754 BC) but scientific [[oncology]] could only emerge in the 19th century, when [[tumor]]s were studied at microscopic level with the help of the [[compound microscope]] and [[achromatic lense]]s. 19th century [[microbiology]] accumulated evidence that implicated bacteria, [[yeast]]s, fungi, and [[protozoa]] in the development of cancer. In 1926 the Nobel Prize was awarded for documenting that a [[nematode worm]] could provoke [[stomach cancer]] in rats. But it was not recognized that cancer could have infectious origins until much later as virus had first been discovered by [[Dmitri Ivanovsky]] and [[Martinus Beijerinck]] at the close of the 19th century.<ref name="The History of Tumor Virology">{{cite journal | vauthors = Javier RT, Butel JS | title = The history of tumor virology | journal = Cancer Research | volume = 68 | issue = 19 | pages = 7693–7706 | date = October 2008 | pmid = 18829521 | pmc = 3501656 | doi = 10.1158/0008-5472.CAN-08-3301 }}</ref>

===History of non-human oncoviruses===
[[File:Rabbit shopes papilloma virus 3.jpg|thumb|Rabbit with [[Shope papilloma virus]] infection.]]
The theory that cancer could be caused by a virus began with the experiments of [[Oluf Bang]] and [[Vilhelm Ellerman]] in 1908 at the [[University of Copenhagen]]. Bang and Ellerman demonstrated that [[avian sarcoma leukosis virus]] could be transmitted between chickens after cell-free filtration and subsequently cause leukemia.<ref>{{cite journal |author1=Ellermann V. |author2=Bang O. |title=Experimentelle Leukämie bei Hühnern |journal=Zentralbl. Bakteriol. Parasitenkd. Infectionskr. Hyg. Abt. Orig. |year=1908 |volume=46 |pages=595–609 }}</ref><ref>{{Cite journal|vauthors=Ellerman C, Bang O |title=Experimentelle Leukämie bei Hühnern |journal=Zentralbl. Bakteriol. Parasitenkd. Infectionskr. Hyg. Abt. Orig. |volume=46 |pages=595–609 |date=1908}}</ref> This was subsequently confirmed for solid tumors in chickens in 1910–1911 by [[Peyton Rous]].<ref>{{cite journal | vauthors = Rous P | title = A Transmissible Avian Neoplasm. (Sarcoma of the Common Fowl.) | journal = The Journal of Experimental Medicine | volume = 12 | issue = 5 | pages = 696–705 | date = September 1910 | pmid = 19867354 | pmc = 2124810 | doi = 10.1084/jem.12.5.696 }}</ref><ref name="pmid19867421"/> Rous at the [[Rockefeller University]] extended Bang and Ellerman's experiments to show cell-free transmission of a solid tumor sarcoma to chickens (now known as ''Rous sarcoma''). The reasons why chickens are so receptive to such transmission may involve unusual characteristics of stability or instability as they relate to [[endogenous retroviruses]].<ref name="pmid19867421">{{cite journal | vauthors = Rous P | title = A sarcoma of the fowl transmissible by an agent separable from the tumor cells | journal = The Journal of Experimental Medicine | volume = 13 | issue = 4 | pages = 397–411 | date = April 1911 | pmid = 19867421 | pmc = 2124874 | doi = 10.1084/jem.13.4.397 }}</ref><ref name="pmid15756727">{{cite journal | title = Peyton Rous: father of the tumor virus | journal = The Journal of Experimental Medicine | volume = 201 | issue = 3 | pages = 320 | date = February 2005 | pmid = 15756727 | pmc = 2213042 | doi = 10.1084/jem.2013fta | last1 = Van Epps | first1 = H. L. }}</ref> [[Charlotte Friend]] confirmed Bang and Ellerman findings for [[liquid tumor]] in mice by .<ref name="pmid13416470" /> In 1933 [[Richard Shope]] and [[Edward Weston Hurst]] showed that [[wart]]s from wild [[cottontail rabbit]]s contained the [[Shope papilloma virus]].<ref name="The History of Tumor Virology"/> In 1936 [[John Joseph Bittner]] identified the [[mouse mammary tumor virus]], an "extrachromosomal factor" (i.e. virus) that could be transmitted between laboratory strains of mice by breast feeding.<ref>{{cite journal | vauthors = Bittner JJ | title = The Milk-Influence of Breast Tumors in Mice | journal = Science | volume = 95 | issue = 2470 | pages = 462–463 | date = May 1942 | pmid = 17736889 | doi = 10.1126/science.95.2470.462 | s2cid = 10527142 | bibcode = 1942Sci....95..462B }}</ref>

By the early 1950s, it was known that viruses could remove and incorporate genes and genetic material in cells. It was suggested that such types of viruses could cause cancer by introducing new genes into the genome. Genetic analysis of mice infected with [[Friend virus]] confirmed that [[retrovirus|retroviral]] integration could disrupt tumor suppressor genes, causing cancer.<ref name="pmid2842714">{{cite journal | vauthors = Ben David Y, Prideaux VR, Chow V, Benchimol S, Bernstein A | title = Inactivation of the p53 oncogene by internal deletion or retroviral integration in erythroleukemic cell lines induced by Friend leukemia virus | journal = Oncogene | volume = 3 | issue = 2 | pages = 179–185 | date = August 1988 | pmid = 2842714 }}</ref> Viral [[oncogenes]] were subsequently discovered and identified to cause cancer.{{citation needed|date=December 2020}} [[Ludwik Gross]] identified the first mouse leukemia virus ([[murine leukemia virus]]) in 1951<ref name="The History of Tumor Virology"/> and in 1953 reported on a component of mouse [[leukemia]] extract capable of causing solid [[tumor]]s in mice.<ref>{{cite journal | vauthors = Gross L | title = A filterable agent, recovered from Ak leukemic extracts, causing salivary gland carcinomas in C3H mice | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 83 | issue = 2 | pages = 414–421 | date = June 1953 | pmid = 13064287 | doi = 10.3181/00379727-83-20376 | s2cid = 34223353 }}</ref> This compound was subsequently identified as a virus by [[Sarah Stewart (cancer researcher)|Sarah Stewart]] and [[Bernice Eddy]] at the [[National Cancer Institute]], after whom it was once called "SE polyoma".<ref>{{cite journal | vauthors = Stewart SE, Eddy BE, Borgese N | title = Neoplasms in mice inoculated with a tumor agent carried in tissue culture | journal = Journal of the National Cancer Institute | volume = 20 | issue = 6 | pages = 1223–1243 | date = June 1958 | pmid = 13549981 | doi = 10.1093/jnci/20.6.1223 }}</ref><ref>{{cite journal | vauthors = Eddy BE, Stewart SE | title = Characteristics of the SE polyoma virus | journal = American Journal of Public Health and the Nation's Health | volume = 49 | issue = 11 | pages = 1486–1492 | date = November 1959 | pmid = 13819251 | pmc = 1373056 | doi = 10.2105/AJPH.49.11.1486 }}</ref><ref name=pathology>{{cite book| vauthors = Percy DH, Barthold SW |title=Pathology of Laboratory Rodents and Rabbits|date=2013|publisher=John Wiley & Sons|isbn=978-1118704639|edition=3rd|chapter=Polyoma Virus Infection}}</ref> In 1957 [[Charlotte Friend]] discovered the [[Friend virus]], a strain of murine leukemia virus capable of causing cancers in immunocompetent mice.<ref name="pmid13416470">{{cite journal | vauthors = Friend C | title = Cell-free transmission in adult Swiss mice of a disease having the character of a leukemia | journal = The Journal of Experimental Medicine | volume = 105 | issue = 4 | pages = 307–318 | date = April 1957 | pmid = 13416470 | pmc = 2136697 | doi = 10.1084/jem.105.4.307 }}</ref> Though her findings received significant backlash, they were eventually accepted by the field and cemented the validity of viral oncogenesis.<ref name="MSCC Charlotte Friend">{{cite news | vauthors = Tontonoz M |date=13 March 2019 |title=From Controversy to Consensus: How Charlotte Friend Changed Cancer Biology  |url=https://www.mskcc.org/blog/from-controversy-consensus-charlotte-friend-changed-cancer-biology |publisher=Memorial Sloan Kettering Cancer Center |access-date=18 April 2019}}</ref>

In 1961 Eddy discovered the simian vacuolating virus 40 ([[SV40]]). [[Merck & Co.|Merck Laboratory]] also confirmed the existence of a rhesus macaque virus contaminating cells used to make [[Polio vaccine|Salk and Sabin polio vaccines]]. Several years later, it was shown to cause cancer in [[Syrian hamster]]s, raising concern about possible human health implications. Scientific consensus now strongly agrees that this is not likely to cause human cancer.<ref name="pmid11720463">{{cite journal | vauthors = Carroll-Pankhurst C, Engels EA, Strickler HD, Goedert JJ, Wagner J, Mortimer EA | title = Thirty-five year mortality following receipt of SV40- contaminated polio vaccine during the neonatal period | journal = British Journal of Cancer | volume = 85 | issue = 9 | pages = 1295–1297 | date = November 2001 | pmid = 11720463 | pmc = 2375249 | doi = 10.1054/bjoc.2001.2065 }}</ref><ref name="pmid17131333">{{cite journal | vauthors = Shah KV | title = SV40 and human cancer: a review of recent data | journal = International Journal of Cancer | volume = 120 | issue = 2 | pages = 215–223 | date = January 2007 | pmid = 17131333 | doi = 10.1002/ijc.22425 | s2cid = 20679358 | doi-access = free }}</ref>

===History of human oncoviruses===
In 1964 [[Anthony Epstein]], [[Bert Achong]] and [[Yvonne Barr]] identified the first human oncovirus from [[Burkitt's lymphoma]] cells. A herpesvirus, this virus is formally known as human herpesvirus 4 but more commonly called [[Epstein–Barr virus]] or EBV.<ref>{{cite journal | vauthors = Epstein MA, Achong BG, Barr YM | title = Virus Particles in Cultured Lymphoblasts from Burkitt's Lymphoma | journal = Lancet | volume = 1 | issue = 7335 | pages = 702–703 | date = March 1964 | pmid = 14107961 | doi = 10.1016/S0140-6736(64)91524-7 }}</ref> In the mid-1960s [[Baruch Blumberg]] first physically isolated and characterized [[Hepatitis B]] while working at the [[National Institute of Health]] (NIH) and later the [[Fox Chase Cancer Center]].<ref>{{Cite web|url=http://nobelprize.org/nobel_prizes/medicine/laureates/1976/blumberg-autobio.html |title=Baruch S. Blumberg – Autobiography |publisher=Nobelprize.org |access-date=17 March 2010}}</ref> Although this agent was the clear cause of hepatitis and might contribute to liver cancer [[hepatocellular carcinoma]], this link was not firmly established until epidemiologic studies were performed in the 1980s by [[R. Palmer Beasley]] and others.<ref>{{cite journal | vauthors = Beasley RP, Hwang LY, Lin CC, Chien CS | title = Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan | journal = Lancet | volume = 2 | issue = 8256 | pages = 1129–1133 | date = November 1981 | pmid = 6118576 | doi = 10.1016/S0140-6736(81)90585-7 | s2cid = 32264986 }}</ref>

In 1980 the first human retrovirus, [[Human T-lymphotropic virus 1]] (HTLV-I), was discovered by [[Bernard Poiesz]] and [[Robert Gallo]] at NIH,<ref>{{Cite journal | vauthors = Yoshida M, Jeang KT |doi=10.1038/sj.onc.1208967 |title=Preface to 25 years of HTLV-1 and ATL research |year=2005 |journal=Oncogene |volume=24 |page=5925 |issue=39|doi-access=free }}</ref><ref>{{cite journal | vauthors = Gallo RC | title = History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2 | journal = Oncogene | volume = 24 | issue = 39 | pages = 5926–5930 | date = September 2005 | pmid = 16155599 | doi = 10.1038/sj.onc.1208980 | doi-access = free }}</ref> and independently by [[Mitsuaki Yoshida]] and coworkers in Japan.<ref>{{cite journal | vauthors = Seiki M, Hattori S, Yoshida M | title = Human adult T-cell leukemia virus: molecular cloning of the provirus DNA and the unique terminal structure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 22 | pages = 6899–6902 | date = November 1982 | pmid = 6294664 | pmc = 347241 | doi = 10.1073/pnas.79.22.6899 | doi-access = free | bibcode = 1982PNAS...79.6899S }}</ref> But it was not certain whether HTLV-I promoted leukemia. In 1981 [[Yorio Hinuma]] and his colleagues at [[Kyoto University]] reported visualization of retroviral particles produced by a leukemia cell line derived from patients with [[Adult T-cell leukemia/lymphoma]]. This virus turned out to be HTLV-1 and the research established the causal role of the HTLV-1 virus to ATL.<ref name="The History of Tumor Virology"/>

[[File:15 Hegasy Nobel Prize 2020 HepC.jpg|thumb|upright=1.5|Nobel Prize in Physiology or Medicine 2020: Seminal experiments by [[Harvey J. Alter]], [[Michael Houghton (virologist)|Michael Houghton]] and [[Charles M. Rice]] leading to the discovery of HCV as the causative agent of non-A, non-B hepatitis.]]
Between 1984 and 1986 [[Harald zur Hausen]] and [[Lutz Gissmann]] discovered HPV16 and HPV18, together these [[Papillomaviridae]] viruses (HPV) are responsible for approximately 70% of [[human papillomavirus infection]]s that cause [[cervical cancer]]s. For the discovery that HPV cause human cancer the 2008 Nobel Prize was awarded.<ref>{{Cite web|url=http://nobelprize.org/nobel_prizes/medicine/laureates/2008/hausen-autobio.html |title=Harald zur Hausen – Autobiography |publisher=Nobelprize.org |access-date=17 March 2010}}</ref> In 1987 the [[Hepatitis C virus]] (HCV) was discovered by panning a cDNA library made from diseased tissues for foreign antigens recognized by patient sera. This work was performed by [[Michael Houghton (virologist)|Michael Houghton]] at [[Chiron Corporation|Chiron]], a biotechnology company, and [[Daniel W. Bradley]] at the [[Centers for Disease Control and Prevention]] (CDC).<ref>{{cite journal | vauthors = Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M | title = Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome | journal = Science | volume = 244 | issue = 4902 | pages = 359–362 | date = April 1989 | pmid = 2523562 | doi = 10.1126/science.2523562 | bibcode = 1989Sci...244..359C }}</ref> HCV was subsequently shown to be a major contributor to [[Hepatocellular carcinoma]] (liver cancer) worldwide.<ref name="The History of Tumor Virology"/>

In 1994 [[Patrick S. Moore]] and [[Yuan Chang]] at [[Columbia University]]), working together with [[Ethel Cesarman]],<ref name="pmid18398088">{{cite journal | vauthors = Schmidt C | title = Yuan Chang and Patrick Moore: teaming up to hunt down cancer-causing viruses | journal = Journal of the National Cancer Institute | volume = 100 | issue = 8 | pages = 524–5, 529 | date = April 2008 | pmid = 18398088 | doi = 10.1093/jnci/djn122 | doi-access = free }}</ref><ref>{{Cite web|url=http://www.med.cornell.edu/research/ecesarman/ |title=Ethel Cesarman, M.D., Ph.D. {{pipe}} Weill Cornell Medical College |publisher=Med.cornell.edu |access-date=17 March 2010}}</ref> isolated [[Kaposi's sarcoma-associated herpesvirus]] (KSHV or HHV8) using [[representational difference analysis]]. This search was prompted by work from [[Valerie Beral]] and colleagues who inferred from the epidemic of [[Kaposi's sarcoma]] among patients with AIDS that this cancer must be caused by another infectious agent besides HIV, and that this was likely to be a second virus.<ref>{{cite journal | vauthors = Beral V, Peterman TA, Berkelman RL, Jaffe HW | title = Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? | journal = Lancet | volume = 335 | issue = 8682 | pages = 123–128 | date = January 1990 | pmid = 1967430 | doi = 10.1016/0140-6736(90)90001-L | s2cid = 35639169 | url = https://zenodo.org/record/1258307 }}</ref> Subsequent studies revealed that KSHV is the "KS agent" and is responsible for the epidemiologic patterns of KS and related cancers.<ref>{{cite journal | vauthors = Antman K, Chang Y | title = Kaposi's sarcoma | journal = The New England Journal of Medicine | volume = 342 | issue = 14 | pages = 1027–1038 | date = April 2000 | pmid = 10749966 | doi = 10.1056/NEJM200004063421407 }}</ref>

In 2008 [[Yuan Chang]] and [[Patrick S. Moore]] developed a new method to identify cancer viruses based on computer subtraction of human sequences from a tumor [[transcriptome]], called digital transcriptome subtraction (DTS).<ref>{{cite journal | vauthors = Feng H, Taylor JL, Benos PV, Newton R, Waddell K, Lucas SB, Chang Y, Moore PS | display-authors = 6 | title = Human transcriptome subtraction by using short sequence tags to search for tumor viruses in conjunctival carcinoma | journal = Journal of Virology | volume = 81 | issue = 20 | pages = 11332–11340 | date = October 2007 | pmid = 17686852 | pmc = 2045575 | doi = 10.1128/JVI.00875-07 }}</ref> DTS was used to isolate DNA fragments of [[Merkel cell polyomavirus]] from a Merkel cell carcinoma and it is now believed that this virus causes 70–80% of these cancers.<ref name="Fe" />

== See also ==
* [[Infectious causes of cancer]]
* [[Carcinogen]]
* [[Oncogenic]]
* [[Oncogene]]
* [[Adult T-cell leukemia/lymphoma]]
* [[Cancer bacteria]]
* [[Oncolytic virus]], a virus that infects and kills cancer cells
* [[Gag-onc fusion protein]]
* [[List of infectious diseases]]

== References ==
{{Reflist|2}}

== External links ==
* {{MeshName|Oncoviruses}}

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[[Category:Viruses]]
[[Category:Infectious causes of cancer]]