viruses and cancer

Question 1

describe main structure of virus

Answer 1

• All comprise of genetic material (either DNA or RNA), a protein capsid and a membrane envelope

Question 2

describe requirements of virus from host and how this links to which viruses are oncogenic

Answer 2

• They are unable to replicate independently of a host cell and require a host cell for:
  o Translation of viral mRNA
  o Genome transcription
  o Genome replication
• Some viruses are able to encode their own transcription machinery whereas others need to utilise host cell replication factors
• It is these more dependent viruses that are more likely to push the cell into a more proliferative state leading to the development of cancer

Question 3

Viruses alone can cause cancer T/F

Answer 3

False, viruses are part of a chain of changes

that have to accumulate in the cell to drive cancer, first genetics so inactivation of TSGs (pRB and p53) and activation of oncogenes (myc) then virus, diet and chemicals which together lead to tumour cell

Question 4

viruses intend to cause cancer T/F

Answer 4

F it is an unintended consequence

Question 5

What percentage of cancers are attributable to infection and what to virus specifically

Answer 5

• High global burden of infectious agents associated cancers
• Around 20% of total cancer incidence worldwide
• Around 11% is attributable to viruses

Question 6

What are the three micro-organisms classes which oncogenic

Answer 6

• Viruses
• bacteria e.g. H pylori
• Liver flukes: schistoma haematobium, opisthorcis viverrini, clonorchis sinensis

Liver flukes are

Question 7

what is a liver fluke

Answer 7

A liver fluke is a parasitic worm.

Infections in humans usually occur after eating contaminated raw or undercooked freshwater fish or watercress.

After liver flukes have been ingested, they travel from your intestines to your bile ducts in your liver where they then live and grow.

Question 8

Do men or women have more virally induced cancers and why?

Answer 8

• Women typically have higher incidence of virally induced cancers - this is largely due to HPV and cervical cancer

Question 9

why do less delveoped countries have more viral induced cancers

Answer 9

• Less developed countries have much higher rates of these cancers
• This is due to multifactorial reasons such as screening
• Also malaria is linked to EBV leading to cancer as malaria it induces B cell proliferation and so somatic hypermutation by activating AID

Question 10

list the 6 types of oncogenic viruses and at least one disease associated with it

Answer 10

• There is a diverse range of cancers caused by viruses ranging from epithelial cancers but also mesenchymal cancers
• EBV – nasopharyngeal carcinoma, Burkitt’s lymphoma, immune-suppression related NHL, Hodgkin’s lymphoma, gastric carcinoma, extranodal NK/T cell lymphoma
• Hepatitis B/C virus – hepatocellular carcinoma
• KSHV (Kaposi sarcoma-associated herpes virus) – Kaposi’s sarcoma, primary effusion lymphoma
• HTLV-1 – adult T cell leukaemia and lymphoma
• HIV1 – NHL, Hodgkin’s lymphoma (from EBV), cervical cancer (HPV), anal, conjunctiva
• High risk HPV types (16, 18, 45) – carcinoma of cervix, vulva, vagina, penis, anus, oropharyngeal tract

Question 11

state the 4 Koch’s postulates

Answer 11

Koch’s postulates for identifying an infectious agent as the cause of a
specific disease (Robert Koch, German physician, 1843-1910)
1. The infectious agent is regularly found in the lesions of the
disease.
2. The infectious agent can be isolated in cultures from fluids or
tissues of an organism with the disease.
3. Inoculation of this culture into a susceptible host produces
the same disease.
4. The disease can be indefinitely transmitted by the
recovered infectious agent.

Question 12

give 5 reasons why koch’s postultates and so causation does not apply for viruses

Answer 12

• Difficult to establish because of:
• Long latency period between primary infection and tumour development cancer
• Small percentage of virus-infected individuals develop the tumour due to differing immune function
• Complex multi-step pathogenesis - virus infection is one link in a chain of cancer developing factors e.g. immunosuppressed patients still have long progression of disease
• No experimental animal models for the human cancers as these viruses are often human specific and will not replicate in other cells

Question 13

describe difference with examples of direct vs indirect viral carcinogens

Answer 13

Direct carcinogens:
Viral oncogenes directly contribute to cancer cell transformation e.g. HPV, EBV, KSHV

Indirect Carcinogens:
Viruses that cause cancer through chronic infection, inflammation and immuno-suppression – lead to carcinogenic mutations in host e.g. HIV-1 and immune suppression and beta HPV virus types that block apoptosis of UV damaged skin cells and so linked to non melanoma skin cancer

Some hard to place like HCV, HBV, HTLV-1

Question 14

Describe progression and epidiemiology of EBV

Answer 14

• 95% of the word population infected but it is only associated with cancer in immunocompromised individuals
• It is usually asymptomatic during childhood and may lead to infectious mononucleosis – glandular fever – this is post puberty
• Results in lifelong silent (latent) infection
• EBV has been linked to a range of lymphatic and epithelial cancers - see above
• Multifactorial – as only a small percentage of people will develop a cancer indicating that infection alone is insufficient:
• It is a DIRECT CARINOGEN that encodes oncogenes

Question 15

describe burkit’s lymphoma factors

Answer 15

Burkitt’s Lymphoma:

• A form of non-Hodgkin’s lymphoma in which cancer starts in B-cells – highly aggressive
• Burkitt’s lymphoma is much more prevalent in equatorial African countries
• Characterized by the translocation and deregulation of the c-MYC gene on chromosome 8 to Ig enhancer → cell proliferation
• Pre-existent malaria infection + EBV → more likely to get Burkitt’s lymphoma as it promotes somatic hypermutation by activation of AID in the germinal cells

caused by EBV

Question 16

Describe factor for nasopharyngeal carcinoma

Answer 16

Nasopharyngeal Carcinoma:

• Much higher rates in South-East Asian countries
• Eating salted fish (high in nitrosamines)/genetic polymorphisms = ↑ nasopharyngeal carcinoma chances

caused by EBV

Question 17

Describe epidemiology/ history of discovery of kaposi sarcoma virus and why it is important

Answer 17

• KS illustrates the importance of epidemiology in determining causation
• Classical KS is rare and usually presents in elderly Mediterranean men
• Kaposi’s sarcoma virus infection however is more common and affects a wider demographic–> karposi sarcoma and primary effusion lymphoma
• It was shown patients with AIDS more at risk and with more aggressive version
• also those who homosexual
• as homosexual made think it is sexually transmitted disease and so infectious and therefore must be infectious agent
• so this inspured Research led to the isolation of a herpes virus sequence which was later defined as Kaposi sarcoma herpes virus or HHV8
• This was done by representation difference analysis (RDA) - identified sequences that were present in tumours but not in normal tissue cells

hence without homosexual link would not have thought to look for virus

Question 18

Describe an example of new oncogenic virus and who it affects and how virus becomes oncogenic

Answer 18

Merkel cell carcinoma – neuroectodermal tumour arising from
mechanoreceptor Merkel cells in skin
- Very aggressive form of skin cancer 9 month or less
- Rare but incidence is increasing
- tripled over 2 decades in US
Tumours found to contain a new virus – Merkel Cell Polyomavirus (MCPV)
- Evident in immunosuppressed people
- MCPV is a very common skin infection
-But only a small proportion of infected individual will develop
Merkel cell carcinoma – immune surveillance
- Structure of MCPV genome is often altered in cancer cells
– clonal integration of viral genome (normally not integrated)

Question 19

What is HPV and why does it cause cancer

Answer 19

• Human Papillomavirus – DIRECT CARCINOGEN
• Small dsDNA virus infects squamous epithelium causing genital and oropharyngeal cancers and was first isolated from cervical tumours in the early 2000s
• HPV encoded oncoproteins E6 and E7 → co-operate to resist apoptosis in the host cell
• Micro-abrasions/cuts in the skin → HPV can now affect the mitotically active cells in the skins basal layer → these infected basal cells migrate to the surface of the skin but in doing so normally should lose their proliferative potential → HPV counters this problem as if in G0 not making host cell factors for genome replication–>by producing E6/E7 which induces proliferation of the mitotically inactive suprabasal cells → allows for HPV replication

Question 20

Describe the synergistic mechanism action of E6 and E7

Answer 20

• E7 binds to RB so get accumulation of E2F group of TFs which will push cell cycle into S phase from G1

↑ cell proliferation due to E7 → body responds by producing p53 (guardian of the genome) → HPV produces E6 which binds to E6AP degrading p53 → continued cell proliferation

This is because p53 inhibits cyclin D which required to lead to phosphorylate pRB relesaing binding to E2F

• Therefore the two major tumour suppressor genes within the epithelial cells have been removed leading to the induction of proliferation and resistance of cell death associated with persistent
• Deregulation of these pathways promotes host genome instability
• Persistent HPV infection + co-factors like smoking → genomic instability → cells more susceptible to cancer
• HPV not only causes cancer but helps maintain it too

Question 21

State some methods of controlling oncogene viruses

Answer 21

1. vaccines e.g. HBV vaccine

2. screening e.g. cervical screening which looks for distortions of the histology

Question 22

Describe the HPV prophylactic vaccine and types

Answer 22

• the vaccine prevents infection and so give before sexual contact as this when exposed both for boys and girls
  The HPV vaccine was developed when it was found that isolated L1 major capsid protein was sufficient to assemble the full virus structure without the viral genome contents and so present the virus stimulating immune system
• There are 2 HPV vaccines currently in use:
  1. GSK produces a vaccine called Cervarix against HPV16 and HPV18 - the two most prevalent cancer-causing types (70% of HPV cervical cancers)
  2. Merck also produces a vaccine called Gardasil against HPV16 and HPV18 as well as HPV6 and HPV11 that are associated with genital warts, so better than cervarix

Question 23

What are the common characteristics of viral oncogenes

Answer 23

1.Common persistent infections in the general population
-Only small % of virus-infected individuals develop the tumour
- Long latency period between primary infection and tumour
development (5-50 years)

2. incidence increases if immunocompromised
3. complex multi step pathogenesis

• Requirement of cofactors in development of
  virus-associated cancers e.g. smoking and cervical cancer (HPV),
  salted fish and nasopharyngeal carcinoma (EBV)

4. virus infection is one link in chain
   - Viral genes that control cell proliferation, cell survival,
   immune regulation important in tumour development
   - Break the link with prophylactic vaccines