L06 - Viruses & Cancer Flashcards
List 6 type 1 carcinogenic viruses.
Give an example of a cancer caused by each virus.
1 - Epstein-Barr virus → Burkitt’s lymphoma
2 - Kaposi sarcoma-associated herpes virus → Kaposi sarcoma
3 - Hepatitis B virus → Hepatocellular carcinoma
4 - Human T-cell lymphotropic virus type 1 → Adult T-cell leukaemia
5 - HIV type 1 → Lymphoma
6 - HPV 16 and 18 → Squamous cell carcinomas (almost all cases of cervical cancer are caused by HPV)
What is the difference between a direct carcinogen and an indirect carcinogen with regards to carcinogenic viruses?
- Direct carcinogens cause cancer through viral oncogenes that directly contribute to cancer cell transformation
- Indirect carcinogens cause cancer through chronic infection, inflammation and immunosuppression, leading to carcinogenic mutations in the host
List 3 direct carcinogenic viruses.
Direct carcinogenic viruses:
1 - Human papilloma virus
2 - Epstein-Barr virus
3 - Kaposi sarcoma-associated herpes virus
Give an example of an indirect carcinogenic virus.
HIV
Why is it difficult to establish causality in virus-associated human cancers?
1 - There is a long latency period between primary infection and tumour development
2 - Only a small proportion of virus-infected individuals develop a tumour
3 - The pathogenesis of tumour development due to infection is complex and has many cofactors
4 - The viral genome can be disrupted in the cancer
5 - There are no experimental animal models for the human cancers
To which family of viruses does EBV belong?
Give an example of a condition caused by EBV.
- EBV is a herpesvirus
- Infectious mononucleosis (glandular fever) is caused by EBV
- 95% of the world’s population is infected with EBV (EBV is usually latent for life)
What mutation is commonly found in cancers associated with EBV?
In cancers associated with EBV, the MYC oncogene is often translocated to an immunoglobulin promotor region, which is highly active in immune cells
What is the most common cause of merkel cell carcinoma and what is the average life expectancy of patients with this cancer?
- The most common cause of merkel cell carcinoma is merkel cell polyomavirus
- This is actually a common infection but only a small proportion cause tumours
- The average life expectancy of patients with merkel cell carcinoma is 9 months or less
How does the mechanism of polyomavirus infection differ in cases where the virus causes cancer compared to when it does not cause cancer?
When polyomavirus causes cancer, it incorporates its genetic material into the host cell’s DNA (whereas it usually does not)
What 2 viral oncoprotein are coded by HPV?
1 - E6
2 - E7
Describe the mechanism by which HPV increases the risk of developing cancer.
- The HPV virus infects the deep basal cells of the epithelium, as the basal cells are mitotically active
- As the epithelial cells become specialised and mitotically inactive as they become more superficial, the HPV forces the cells back into the cell cycle. It does this using E6 and E7 proteins:
1 - E7 activates the genes of the host cell that are necessary for DNA replication by interacting with pRb protein
2 - In response to this inappropriate inactivation of oncogenes, the cell responds by inducing apoptosis via p53
3 - However, E6 combines with a host cell factor known as E6AP to degrade p53 and prevent apoptosis
- Deregulation of both pRb and p53 tumour suppressor pathways promotes host genome instability, increasing the risk of acquiring an oncogenic mutation (which can then be induced by cofactors, e.g. smoking)
To which family of transcription factors does pRb bind to prevent continuation of the cell cycle?
What causes pRb to release from this family of transcription factors, and what happens once it is released?
- pRb binds to the E2F transcription factor family
- pRb releases E2F when it is phosphorylated
- E2F translocates to the nucleus, where it activates genes necessary for continuation of the cell cycle
How does E7 protein interact with pRb to cause oncogene activation?
- E7 binds with high affinity to pRb and degrades it
- This causes the inappropriate release of E2F
- This activates progression from G1 into S phase
How does the HPV vaccine work?
- HPV vaccine is developed from isolated L1 protein from HPV
- This is sufficient to assemble virus-like particles (VLP) without viral genome contents, which stimulates production of neutralising antibodies
- Vaccines are prophylactic rather than therapeutic, so must be given before HPV is contracted (generally before the start of sexual activity)
