Viruses and Cancer Flashcards
Association of viral infection with cancer, characteristics required for viral oncogenesis
Ranges from 15% - 100%
- cervical cancer 100%
- HCC 90% (other causes e.g. alcohol, chemicals)
- oropharyngeal cancer 15% (smoking, alcohol)
Contributory (+/- necessary e.g. CA cervix) but not sufficient for carcinogenesis i.e. **majority of infected individuals don’t develop cancer
Characteristics of viral oncogenesis
- ability to INFECT BUT NOT KILL host cells (not producing lytic infection)
- establish persistent infection and evade host immune surveillance
Multistep process requiring additional cofactors, host immunity, chronic inflammatory states, cellular mutations
Cancer usually develops many years after initial infection
Known human tumour viruses and associated cancers
EBV (herpesviridae) –> NPC, Burkitt’s lymphoma, Post-transplant lymphoma, Hodgkin/Non-hodgkin, CA stomach
HBV (hepadnaviridae) –> HCC
HPV (papillomaviridae) –> cervical, oropharyngeal, anogenital cancer
HTLV-1 –> adult T cell leukaemia/lymphoma (rare in HK)
HHV8 (herpesviridae) –> Kaposi sarcoma, primary effusion lymphoma
Mechanism of viral oncogenesis and examples
Exposure
- infection and acute inflammation
Initiation
- most infection cleared but some remain persistent
Promotion
- viral persistence leads to chronic inflammation which may activate iNOS to cause DNA damage
- some viruses have special oncogenes that allow them to bypass the chronic inflammation stage
Progression (uncontrolled cell proliferation)
- chronic inflammation also leads to angiogenesis (VEGF) and cell transformation
- viral oncogenes bypass chronic inflammation and directly cause cell growth/angiogenesis/inhibit apoptosis
E.g.
- HCV causes chronic inflammation
- HBV causes chronic inflammation or may release oncogene HBx
- HPV dsDNA integrate into host genome and express E6/E7 oncogenes
- HTLV-1 ssRNA integrates and expresses TAX oncogene
- EBV/HHV8 episomal genome express oncogenes
HBV and HCV - contribution to HCC, prevention
Neither necessary or sufficient for HCC
(other causes of HCC e.g. cirrhosis due to AFLD, NAFLD, Wilson’s, haemochromatosis, DM, aflatoxins)
Prevention:
- primary - universal childhood HBV vaccination in areas of high prevalence e.g. HK
- secondary - identify carriers by viral markers (HBsAg, HCV Ab) for antiviral treatment to suppress infection and early detection cancer
EBV - primary infection, reactivation, mechanisms of oncogenesis, prevention
Common childhood infection
- primary infection mostly asymptomatic
- fever/tonsilitis/hepatitis/rash in adolescent
- lifelong latency
Reactivation in immunocompromised
Replicative infection of PHARYNGEAL EPITHELIUM
- (rare latent infection in cells that fail to replicate virus)
–> + genetic predisposition, dietary carcinogens (SE Asia) –> cellular genetic changes
==> NPC
Latent infection in B lymphocytes
+ Immunosuppression –> continued growth ==> Post-transplant lymphoma
OR
+ chronic malaria (Africa) –> chromosomal translocation (IGH-MYC) with C-myc activation ==> Burkitt lymphoma
OR
+ co-factors –> cellular genetic changes ==> Hodgkin, non-Hodgkin lymphoma
Prevention:
- primary: no vaccine available
- secondary: EBV based screening for early detection of NPC – IgA against EBV VCA/EA or plasma EBV DNA
HPV - associated cancers, pathogenesis, risk types, natural history
Cervical cancer - 100%
Anal cancer - 90%
Vagina, vulva, penile cancers - 40%
Oropharyngeal cancer - 15% (Asia); up to 75% in Europe
Pathogenesis:
- integration of HPV DNA leads to loss of E2 gene which normally inhibits E6 and E7
- increase E6 = p53 suppression = inhibit apoptosis
- increase E7 = Rb suppression = affect cell cycle progression
High risk type: HPV16/18 –> Ca cervix
Low risk type: HPV6/11 –> genital warts (condyloma)
Natural history of HPV
- 80% asymptomatic transient infections (regress in 1-2yrs)
- 20% persistent and progress to LSIL in 2-5 yrs
- 20% LSIL progress to HSIL in 4-5 yrs
- 20% HSIL progress to CA cervix in 9-15 yrs
Transmission of HPV
Sexual contact
- intercourse
- genital/manual/oral
- genital HPV rare in virgins but may result from non-penetrative sexual contact
- condom may help reduce risk but not fully protective
- SEXUAL TRANSMISSION DOESN’T MEAN PROMISCUOUS! (infection common among normal individuals; persists and remain asymptomatic for long time)
Non sexual routes
- vertical transmission
- fomites (undergarments, surgical instruments/gloves)
HPV prevention
Primary
- bi-valent vaccine (16,18)
- quadrivalent vaccine (16,18,6,11)
- nonavalent vaccine
Secondary
- SCREENING: cytology (pap smear) – 50% sensitivity, requires regular repeat testing
- HPV test (potential benefits with higher sensitivity, higher NPV)
- usually only screen >25 since infection is common and screening results can’t distinguish transient/persistent infection (risk of overinterpretation)
