HPV tumourigenesis Flashcards
What amount of the global cancer burden is due to infection?
20%
Which hepatitis viruses cause cancer?
B and C
What HPV viral protein inhibits Rb?
E7
Which HPV viral protein inhibits p53?
E6
What are the proteins on the outside of HPV and what is their role?
L1 and L2 - late proteins 1 and 2 which defines which type of HPV is present (16 or 18).
Which strains of HPV cause verrucas?
HPV-1 and HPV-2
which HPV strains cause recurrent respiratory papillomatosis?
HPV-6 and HPV-11
Which HPV strains cause cervical/anal/oropharyngeal cancer?
HPV-16 and HPV-18
What is the role of E1 and E2 proteins?
DNA replication
What is the role of E4 and E5 proteins?
DNA amplification of the viral genome in the upper layers of the epithelium
What is the role of E6 and E7 proteins?
Oncogenic in high risk HPV types
What is the HPV life cycle leading to infection
Entry occurs following micro-injury. This allows infection of the basal cell layer. Productive infection occurs in this layer. As the basal cells differentiate and move towards the cell surface, other viral proteins begin to be expressed with the aim to produce more viral particles (E1, E2) then at the epithelial surface L1 and L2 which packages the virus and releases it, allowing for spread of infection.
How does the HPV life cycle change in cancer?
Instead of the productive life cycle there is a latent infection. This is caused by high expression of E6 and E7 which causes episomal infection or integration. You get loss of p53 and RB which leads to epithelial proliferation.
What break point in the HPV genome is commonly seen in cancer?
At E2. This prevents the expression of E2 which would normally downregulate E6/7 expression. If this integrates into host DNA then E6/E7 will be highly expressed which will be cancer inducing
How does E6 lead to the loss of p53 function?
Associates with an E3 ubiquitin ligase which tags p53 for degradation
How does E7 lead to the loss of RB
Associates with an ubiquitin ligase complex which tags RB1 for degradation - can no longer associate with E2F…
What is CIN 1
Mild dysplasia
What is CIN 2?
Moderate dysplasia
What is CIN 3?
Severe dysplasia to carcinoma in situ
Why are HPV positive tumours normally WT for TP53?
Tumour gains no benefit from mutations in p53 because E6 degradation of p53 is occurring
What becomes overexpressed in HPV positive cancers? What is the result of this?
p16INK4A, results in low expression of cyclin-D.
Why is there disruption of the HPV16 life cycle in HNSCC development?
For immune evasion
How does HPV infection change when you are HIV positive.
Persist for longer. Makes more HPV strains (not just 16 and 18) to be able to cause cancer.
