Infection and Cancer: Viral Oncogenesis Flashcards
What is transformation?
loss of control in vitro
What are the characteristics associated with transformation?
loss of contact inhibition; loss of telomere-induced growth limit; loss of anchorage dependece; reduced need fro growth factors
What is oncogenesis?
loss of growth control in vivo
What is the significance of loss of anchorage dependece in transformation?
ability to metastasise
What are the factors that determine an association of a virus with cancer?
is the tumour associated with infection by pathogen- epidemiology; is the virus/genome found in the tumour- is it monoclonal?; is it found in all cells of the tumour- or a defined subset; are viral genes expressed or viral products found?
What are the factors which help determine causation of a virus causing cancer?
do expressed viral genes show oncogenic activity? Is virus necessary for the tumoue; does remission correlate with loss of pathogen; does it cause tumours when introdcued; is viral immunity protective?
What is the baltimore classification based on?
classifying viruses according to their genomes
What are the prodominant Baltimore classes associated with viral oncology?
class 1- dsDNA and class 6- retroviral (hepB and hepC are different)
How much of total cancer incidence worlwide is due to infecitous agents?
15%
Give an example of an animal virus carrying an oncogene?
rous sarcoma virus was found to have picked up v-Src gene into its retroviral genome
What is the function of SV40 large T antigen?
modulates Rb and p53 function - don’t get p21 being produced; preents binding of E2F to Rb
What is the result of SV40 large T antigen?
unregulated progression through the S phase
What is fundamental about the survival of viruses in terms of causing cancer?
must be able to presistent in rapidly dividing cancer cells- keep its genome in the diving cells
How do EBV and HPV maintain their genome in cancer cells?
episomally- independent of the human genome like extra chromosome
How do HBV and HCV maintain their genome?
through chronic replication
What is often required for viruses who maintain their viruses through episomes?
have very specific functions for maintenance e.g EBV replicates during S phase and has a protein to hook its genome onto the sister chromatids during separation
What determines the type of cancer caused by the virus?
reflects the virus life cycle
Why do viruses cause cancer more often in the immunsuppressed?
viruses are immunogenic- immunsuppression prevents proper control
What shows that no virus life-cycle requires oncogensis?
ALV >95% of chickens are positive whereas <3% of old birds develop leuakaemia
When do viruses usually cause cancer in the host?
with low efficiency and a long time after infection
What is the difference in chronicity between HBV and HCV?
10% of HBV infections become chronic vs 80% in HCV
What is the difference in deaths caused by HBV and HCV?
HBV- HCC whereas HCV is more likely to cause cirrhossi
What is the difference between chronic hepatitis and an asymptomatic carrier?
in chronic hepatitis the immune system is aware of the infection and there is chronic inflammation
How does HBV cause cancer in asymptomatic carriers?
direct oncogenesis
What is the mechanism by which hepatitis viruses cause cancer?
through tumour-promoting inflammation- drives tissue damage
Which 2 forms of HPV cause cervical cancer?
16 and 18
What is the general life cycle of HPV?
there is alesion which allows HPV to infect the basal epithelial layer, as epithelial cells differentiate, the virus expressed different genes and increases viral replication, when cell dies, there is viral release
What are the early genes expressed by HPV?
E6, E7, E1, E2
What are the late genes expressed with HPV?
L1, L2 and L4
What is the result of 80% of HPV infection?
clearance
What are the steps in the virus leading to carcinoma with HPV?
integration and E6/E7 over-expression; MHC-1 loss and then increased telomerase and tumour-suppressor gene loss
What may be the reason that 16 and 18 are more assocaited with cancer?
they have high risk E6 which causes degradation of p53 vs low risk E6 which blocks p53 transcription activation so some still happens
What are the functions of E6 and E7?
E6- interacts with p53, E7- prevents Rb binding to E2F
Why do HPV and other viruses target p53 and Rb?
DNA viruses rely on the S phase environment in order to replicate their genome effectively; interactions with p53 and Rb prevent their suppression of this phase
What is seen with p53 mutations in cervical cancer?
in HPV neg- p53 is mutant whereas in HPV pos, p53 is wild type
How does HPV integration act as an oncogenic mechanism?
it is circular genome, when integrates becomes linear. E2 governs the promoter of E6 and E7, when integrated E2 is dysregulated
What is seen with episomal tumour HPV?
have promoter mutations in E6 and E7 resulting in the same consequence as E2 disruption with integration
What principle of viral oncogenesis does the dysregulation of E2 with integration demonstrate?
virus only causes cancer once the viral genome is damaged
How has the efficacy of the HPV vaccines been monitored?
reduction in genital warts
What virus produced T antigen?
merkel cell polyomavirus
How many human cancers is EBV implicated in?
approx 1%
How much of the human population has EBV?
asymptomatic and persistent infection in >90%
What is latenency III programme of EBV?
all EBNAs and LMP1 and 2
When is latency III expressed in EBV?
in the B blast
What is the function of EBNA1?
ensures virus is segragated into all daughter cells
When is latency II expressed?
in the geminal centre- EBNA1 and LMP1 and 2
when is latency 0 expressed?
in memory B cells
What happens if the memory B cell becomes a plasma cell in EBV?
undergos lytic reactivation
What expression programme is hodgkins lymphoma associated with?
latency II- GC phenotype
What expression programme is burkitts lymphoma associated with?
usually latency I
What cancer is associated with latency stage III?
lmmunblasatic lymphomas
What EBV proteins are very effectively shown on MHC-I?
EBNA3
Why is immunoblastic lymphoma associated with immunodeficiency?
there is reduced recognition of EBNA3 proteins by CTLs- reduced pressure to immune escape into memory B cells ?
Where is nasopharyngeal cancer particularly prevalent?
south east asia- particularly s. china –unknown why
Where is burkitt lymphoma particularly seen?
sub-saharan africa
Why is there an increased rate of burkitts lymphoma in sub saharan africa?
synergism between EBV and malaria
What genetic translation is seen with burkitt lymphoma
Myc translocation- Myc is put under control of Ig locus
What do AID mutations result in?
increased genomic instability
What proportion of hodgkins disease is EBV positive?
40%
Which cells is EBV foudn in in Hodgkins?
malignant multi-nucleated Reed-sternberg cells
What is the origin of reed sternberg cells?
post-germinal centre origin
What happens when EBNA3B knocked out in mice?
EBV is more oncogenic- splenomegaly and tumour formation
What is thought to be the function of EBNA3B in EBV?
tumour suppressor- promotes interaction with the immune system
Are EBNA3B mutations associated with EBV oncogenesis?
related to some LCLs ; BL and HL
Why is it odd that EBNA3B mutations would be associated with BL and HL?
EBNA3B isn’t normally expressed in the gene programme assocaited with those cancers
How does EBNA3 act as a tumour suppressor?
restricts proliferation; stimulates CXCL10 production- attract immune cells and control
What is the viral mutation assocaited with merkel cell carcinomas?
truncation of small T antigen
What is the hypothesis of viral mutation are needed to cause pathogenesis?
where viruses have a long evolutionary history with their host, chronic or life-threatening disease occurs through a break-down of the host-pathogen relationship
Why is cancer bad for the virus?
represents a dead end
When was a viral aetiology of cancer first demonstrated?
when Peyton Rous injected cell-free filtrate from a chicken sarcoma into health chickens and induced tumour
What is a common feature of viruses causing cancer?
propensity to persist as chronic infections
What proportion of HCC is caused by HBV?
54%
What type of virus is HPV?
dsDNA
What factors are assocated with reduced clearance of HPV?
immunsuppression e.g HIV; smoking; co-infections e.g HSV; frequency of sexual intercourse and number of sexual partners
What is koilocytosis?
structural changes in squamous epithelium indicative of HPV infewction
Why is there particular development of chronic infection from HBV acquired during the perinatal period?
during period in which the immune system is learning to recognise and tolerate self, may be due to recognition and tolerance of HBV antigens as self
What was the first human cancer virus discovered ?
EBV- when discovered to be associated with Brukitt lymphoma
What does EBV infection result in in severe immunsuppression?
oral hairy leukoplakia
What is a major risk factor for post-transplant lymphoproliferative disase?
primary EBV infection as a result of organ tranplsantation
What was the first retrovirus to be associated with cancer?
HTLV-1 when isolated from a patient with cutaneous T cell lymphoma
How does immunsuppression link to the risk of merkel cell carcinoma?
increases the likelihood that the viral DNA will mutate and integrate into the host cell
What demonstrates the important multifactorial causes of the viral oncogenic process?
higher prevalnce of EBv-associated tumours in the developing world and in immunsupressed patietns
What is the thought to be the role of EBV in the pathogenesis of epithelial tumours?
unclear but the aberrant establishment of latent viral infection in petihleial cells with existing premalignant genetic changes
What does EBNA stand for?
Epstein-Barr nuclear antigne
What latency programme do all epithelial maliganncies associated with EBV express?
latency II
What happens when EBNA2 is deleted?
EBV is unable to transform B cells in vitro
What does EBNA2 mimic?
a consitutively activated NOTCH receptor
What are the functions of BART miRNAs?
maintain latency by targeting EBV lytic genes, modulating LMP1 expression; targeting pro-apoptotic proteins; inactivating tumour-suppressors
What gene is responsible for the latent to lytic cyle switch in EBV?
BZLF1
What other gene aside from BZLF1 is involved in inducing the expression of multiple early lytic genes?
BRLF1
What is the function of BNLF2a- an EBV lytic gene?
inhibits the transporter of antigen processing
What is the function of BILF1- an EBV lytic gene?
induces MHC-I internalisation and degradation
How is malaria thought to contibute to the formation of BL ?
induces an intense polyclonal B cell activation and loss of T cell control of EBV- increase the pool of EBV-infected BL progenitors; can icnrease expression of AID which induces BL-causing mutations including classic Myc translocation
Why are Myc abnormalities considered the hallmark of BL?
they are also found in EBV-negative BL and are required to sustain the high rate of proliferation characteristic of BL
How do EBNA3A and EBNA3C contribute to anti-apoptosis?
downregulate the pro-apoptotic molecule BIM
What is the function of BHRF1 encoded by EBV?
it is a viral Bcl-2 homologue (Bcl-2 is involved in apoptosis
Waht is the germinal centre model?
EBV initially infects B cells and expressed latency III to drive B cell proliferation, then enter GC and express default programme (II) and LMP1 and LMP2 mediate survival and exit as memory cells
Why would memory B cells express latency I?
during proliferation to ensure genome in daughter cells (EBNA1)
Which cells do burkitt lymphoma cells derived from?
GC B cells
Why is adoptive CTL therapy for PTLD particularly effective against EBV lymphomas expressing latency III?
will be expressing the highly immunogenic EBNA3 family membrers
What does the mutation in SAP reuslt in X-linked lymphoproliferative disease 1?
defective signalling lymphocyte activation moleucle- have impaired T and NK cell engagement of B cells
What are crippling mutations?
mutations that destroy the coding capacity of orginially functional immunglobulin genes
What are hodgkin reedsternberg cells thought to arise from?
GC b cells taht lack a functional BCR and have escaped apoptosis
What suggests that EBV contributes to hodgkins lymphoma?
crippling immunoglobulin mutations are found almost exclusively in EBV-pos patients and EBV can efficeintly immortalise BCR-neg GC B cells
How is EBV thought to contribute to BL pathogenesis?
when Myc is tranlocated, it is activated resulting in cell growth and prolfieration, there is a fail safe mechanism which induces cell death by apoptosis or senescence. EBV gene products probably counterac tthe proliferation-resitrcting activities of deregulated Myc
Why is BL thought to occur early in HIV infection when CD4 T cell are normal?
expanded germinal centre activity resulting in chronic B cell stimulator that increases the pool of EBV-infected B cells carrying the accidental Myc translocations- like malaria
What EBV gene increases AID?
EBNA3C
What other cells apart from B cells can EBV infect?
T and NK cells; epithelial cells
whcih strains of EBV preferentially infect primary T cells in vitro?
EBV type 2 strains
What is a gold-standard biomarker for staging patients with nasopharyngeal carcinoma?
circulating cell-free EBV DNA (in epithelial cell- lytic stage)
What indicates the EBV infection must have occurred before the expansion of the malignant cell clone in nasopharyngeal carcinoma?
tumour cells carry monoclonal viral genomes
What suggests that HBZ plays a vital role in the pathogenesis of ATL?
mRNA is detected in 100% of ATL cells and possess proliferation functions- suppressiong results in less prolfieration
Why was Tax thought to be critical for leukemogenesis and viral persistence?
interactions with host genes responsible for cell prolfieration, DNA repair; cell cycle control and apoptosis
What is hte current opinion on the roles of Tax and HBZ in leukemogeneiss?
Tax is involved in the initiation of ATL and HBZ maintains the transformed phenotype
