Virus‐Induced Human Oncogenesis


Infectious agents are estimated to contribute to oncogenesis in c. 25% of human cancers worldwide. Approximately half of them are attributed to infection by oncogenic viruses. Viruses are obligatory intracellular pathogens, which disrupt host cell homeostasis during their life cycle. The induction of malignancy is not part of their life cycle, but rather a multistep outcome, that may occur several years after the infection. Oncogenesis is initiated by the disruption of cellular mechanisms (detecting and repairing DNA damage, activating checkpoints and inducing apoptosis or survival) through the activity of viral proteins. Host and environmental factors further contribute to the multistep aetiology of cancer development and progression. This article describes the common molecular mechanisms by which human oncogenic viruses disrupt cell homeostasis and the prophylactic and therapeutic treatment options for virus‐induced malignancies and discusses the identification of emerging oncogenic infectious agents.

Key Concepts

  • Oncogenic viruses are estimated to contribute to approximately 15% of all human malignancies.
  • Human oncogenic viruses include both DNA viruses (EBV, HPV, MCV, HBV and KSHV) and RNA viruses (HCV and HTLV‐1).
  • Induction of malignancy is not part of the viral life cycle and confers no benefit to the virus per se.
  • Oncogenic viruses disrupt host cellular pathways (DNA repair mechanisms, cellular checkpoints and apoptosis) for efficient viral replication, consequently initiating cancer development.
  • Viral oncogenesis is a multi‐step process, initiated by the action of viral proteins but requiring additional factors for disease development and progression.
  • Transmission of oncogenic viruses takes place mainly via human contact including, but not limited to, sexual transmission.
  • Prophylactic (vaccine) treatment options are limited. Therapeutic treatments include anti‐virals in combination with chemotherapy and surgical removal of the tumours.
  • Emerging oncogenic viruses comprise a growing group of newly identified viruses with putative oncogenic potential, which have been detected in association with human cancers.

Keywords: oncogenic viruses; cancer; DNA virus; RNA virus; EBV ; HPV ; HBV ; HCV ; HTLV‐I ; KSHV ; MCV

Figure 1. Overview of molecular mechanisms that facilitate viral replication and promote cancer initiation. Latent or chronic infections by oncogenic viruses are associated with viral modulation of cellular pathways, which facilitate efficient viral replication, albeit with oncogenic consequences for the infected host. The viruses modulating each pathway are indicated. The modulation of these cellular pathways, via the activity of the indicated viral proteins, confers specific cancer hallmarks (Hanahan and Weinberg, ) to the infected cells. The colour code indicates the respective viral proteins of each virus: EBV – orange, HBV – blue, HCV – red, HPV – green, HTLV‐1 – brown, KSHV – purple, MCV – turquoise.
Figure 2. Schematic overview of the signalling pathways modulated upon infection by oncogenic viruses, in order to sustain proliferative signalling of the infected cell. The viral proteins and their cellular targets are indicated. Colour code, indicating each virus and its proteins, as in Figure. Host proteins are indicated in black.


Bartosch B , Thimme R , Blum HE , et al. (2009) Hepatitis C virus induced hepatocarcinogenesis. Journal of Hepatology 51 (4): 810–820.

Bouvard V , Baan R , Straif K , et al. (2009) A review of human carcinogens – Part B: biological agents. The Lancet Oncology 10 (4): 321–322.

Cai Q , Verma SC , Lu J , et al. (2010) Molecular biology of Kaposi's Sarcoma Herpesvirus and related oncogenesis. Advances in Virus Research 78: 87–142.

Chang Y , Cesarman E , Pessin MS , et al. (1994) Identification of herpesvirus‐like DNA sequences in AIDS‐associated Kaposi's sarcoma. Science 266 (5192): 1865–1869.

da Silva‐Diz V , Sole‐Sanchez S , Valdes‐Gutierrez A , et al. (2013) Progeny of Lgr5‐expressing hair follicle stem cell contributes to papillomavirus‐induced tumor development in epidermis. Oncogene 32 (32): 3732–3743.

De Mattei M , Martini F , Corallini A , et al. (1995) High incidence of BK virus large‐T‐antigen‐coding sequences in normal human tissues and tumors of different histotypes. International Journal of Cancer 61 (6): 756–760.

De Paoli P and Carbone A (2013) Carcinogenic viruses and solid cancers without sufficient evidence of causal association. International Journal of Cancer 133 (7): 1517–1529.

Feng H , Shuda M , Chang Y , et al. (2008) Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319 (5866): 1096–1100.

Fu Q , He C and Mao Z (2013) Epstein‐Barr virus interactions with the Bcl‐2 protein family and apoptosis in human tumor cells. Journal of Zhejiang University‐Science B (Biomedicine & Biotechnology) 14 (1): 8–24.

Galluzzi L , Brenner C , Morselli E , et al. (2009) Viral control of mitochondrial apoptosis. PLoS Pathogen 4 (5): e1000018.

Gardner SD , Field AM , Coleman DV , et al. (1971) New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 1 (7712): 1253–1257.

Green PL and Chen ISY (2002) Human T‐cell leukemia virus types 1 and 2. In: Knipe DM and Howley PM (eds) Fields' Virology, 4th edn, pp. 1941–1969. Philadelphia, PA: Lippincott Williams & Wilkins.

Hanahan D and Weinberg RA (2000) The Hallmarks of Cancer. Cell 100: 57–70.

Hill AB (1965) The environment and disease: association or causation? Proceedings of the Royal Society of Medicine 58 (5): 295–300.

Hohn O , Hanke K and Bannert N (2013) HERV‐K(HML‐2), the best preserved family of HERVs: endogenization, expression, and implications in health and disease. Frontiers in Oncology 3 (246): 1–12.

Hollinger FB and Liang TJ (2002) Hepatitis B virus. In: Knipe DM and Howley PM (eds) Fields' Virology, 4th edn, pp. 2971–3036. Philadelphia, PA: Lippincott Williams & Wilkins.

Jones MS , Kapoor A , Lukashov VV , et al. (2005) New DNA viruses identified in patients with acute viral infection syndrome. Journal of Virology 79 (13): 8230–8236.

Lowy DR and Howley PM (2002) Papillomaviruses. In: Knipe DM and Howley PM (eds) Fields' Virology, 4th edn, pp. 2231–2264. Philadelphia, PA: Lippincott Williams & Wilkins.

Maginnis MS and Atwood WJ (2009) JC virus: an oncogenic virus in animals and humans? Seminars in Cancer Biology 19 (4): 261–269.

Major ME , Rehermann B and Feinstone SM (2002) Hepatitis C viruses. In: Knipe DM and Howley PM (eds) Fields' Virology, 4th edn, pp. 1127–1161. Philadelphia, PA: Lippincott Williams & Wilkins.

Matsuoka M and Jeang KT (2007) Human T‐cell leukaemia virus type 1 (HTLV‐1) infectivity and cellular transformation. Nature Reviews Cancer 7 (4): 270–280.

McAloose D and Newton AL (2009) Wildlife cancer: a conservation perspective. Nature Reviews Cancer 9 (7): 517–526.

Michael S , Lambert PF and Strati K (2013) The HPV16 oncogenes cause aberrant stem cell mobilization. Virology 443 (2): 218–225.

Moore PS and Chang Y (2002) Kaposi's Sarcoma‐associated Herpesvirus. In: Knipe DM and Howley PM (eds) Fields' Virology, 4th edn, pp. 2803–2833. Philadelphia, PA: Lippincott Williams & Wilkins.

Moore PS and Chang Y (2010) Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nature Reviews Cancer 10 (12): 878–889.

Musacchio A (2011) Spindle assembly checkpoint: the third decade. Philosophical Transactions of the Royal Society of London B Biological Science 366 (1584): 3595–3604.

Nam HJ , Naylor RM and van Deursen JM (2014) Centrosome dynamics as a source of chromosomal instability. Trends Cell Biology. DOI: 10.1016/j.tcb.2014.10.002.

Neuveut C , Wei Y and Buendia MA (2010) Mechanisms of HBV‐related hepatocarcinogenesis. Journal of Hepatology 52 (4): 594–604.

Padgett BL , Walker DL , ZuRhein GM , et al. (1971) Cultivation of papova‐like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 297 (7712): 1257–1260.

Pattle SB and Farrell PJ (2006) The role of Epstein–Barr virus in cancer. Expert Opinion on Biological Therapy 6 (11): 1193–1205.

Pfeiffer V and Lingner J (2013) Replication of telomeres and the regulation of telomerase. Cold Spring Harbor Perspectives in Biology 5 (5): a010405.

Prusty BK , zur Hausen H , Schmidt R , Kimmel R and de Villiers EM (2008) Transcription of HERV‐E and HERV‐E‐related sequences in malignant and non‐malignant human haematopoietic cells. Virology 382 (1): 37–45.

Rickinson A and Kieff E (2002) Epstein‐Barr virus. In: Knipe DM and Howley PM (eds) Fields' Virology, 4th edn, pp. 2575–2627. Philadelphia, PA: Lippincott Williams & Wilkins.

Rozenblatt‐Rosen O , Deo RC , Padi M , et al. (2012) Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 487 (7408): 491–495.

Sato Y and Tsurumi T (2013) Genome guardian p53 and viral infections. Reviews in Medical Virology 23 (4): 213–220.

Spurgeon ME and Lambert PF (2013) Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology 435 (1): 118–130.

Truyen U and Löchelt M (2006) Relevant oncogenic viruses in veterinary medicine: original pathogens and animal models for human disease. Contributions to Microbiology 13: 101–117.

Vitre BD and Cleveland DW (2012) Centrosomes, chromosome instability (CIN) and aneuploidy. Current Opinion in Cell Biology 24 (6): 809–815.

Vogt PK (2012) Retroviral oncogenes: a historical primer. Nature Reviews Cancer 12 (9): 639–648.

Weitzman MD and Weitzman JB (2014) What's the damage? The impact of pathogens on pathways that maintain host genome integrity. Cell Host & Microbe 15 (3): 283–294.

Yan C , Vonetta W , Maria F , et al. (2014) Viral carcinogenesis: Factors inducing DNA damage and virus integration. Cancers 6 (4): 2155–2186.

zur Hausen H (2002) Papillomaviruses and cancer: from basic studies to clinical application. Nature Reviews Cancer 2 (5): 342–350.

Further Reading

Afonso PV , Zamborlini A , Saib A , et al. (2007) Centrosome and retroviruses: the dangerous liaisons. Retrovirology 4: 27.

Buchkovich NJ , Yu Y , Zampieri CA , et al. (2008) The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K‐Akt‐mTOR signalling pathway. Nature Reviews Microbiology 6 (4): 266–275.

DeCaprio JA , Ludlow JW , Figge J , et al. (1988) SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54 (2): 275–283.

Forgues M , Difilippantonio MJ , Linke SP , et al. (2003) Involvement of Crm1 in hepatitis B virus X protein‐induced aberrant centriole replication and abnormal mitotic spindles. Molecular and Cellular Biology 23 (15): 5282–5292.

Leao M , Anderton E , Wade M , et al. (2007) Epstein‐Barr virus‐induced resistance to drugs that activate the mitotic spindle assembly checkpoint in Burkitt's lymphoma cells. Journal of Virology 81 (1): 248–260.

Moore PS and Chang Y (2014) The conundrum of causality in tumor biology: the cases of KSHV and MCV. Seminars in Cancer Biology 26: 4–12.

Morales‐Sánchez A and Fuentes‐Pananá EM (2014) Human viruses and cancer. Viruses 6: 4047–4079.

Smolders L and Teodoro JG (2011) Targeting the anaphase promoting complex: common pathways for viral infection and cancer therapy. Expert Opinion on Therapeutic Targets 15 (6): 767–780.

Topham CH and Taylor SS (2013) Mitosis and apoptosis: how is the balance set? Current Opinion in Cell Biology 25 (6): 780–785.

zur Hausen H and de Villiers EM (2014) Cancer “causation” by infections – individual contributions and synergistic networks. Seminars in Oncology 41 (6): 860–875.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bedi, Manmeet S, and Ploubidou, Aspasia(Jun 2015) Virus‐Induced Human Oncogenesis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021851.pub2]