Viral Carcinogenesis

Dr. Tariq S. H. Al Jabry

Department of Genetics
College of Medicine and Health Sciences (COMHS)

tariqaljabry@squ.edu.om
 Infectious Agents
• Approximately 30% of cancers are caused by infectious agents.
• The World Health Organisation’s International Agency for Research on Cancer
(IARC) classifies ten infectious agents as well-established (Group 1) carcinogenic
agents:
1) Helicobacter pylori (H. pylori)
2) Opisthorchis viverrini (O. Viverrini)
3) Clonorchis sinensis (C. sinensis)
4) Schistosoma haematobium (S. haematobium)
5) Human Papillomavirus (HPV; high risk types)
6) Hepatitis B Virus (HBV)
7) Hepatitis C Virus (HCV)
8) Human T-cell lymphotropic virus type 1 (HTLV-1)
9) Epstein–Barr virus (EBV)
10) Human Herpesvirus type 8 (HHV-8)

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 Infectious Agents
• H. pylori are a type of bacteria that can infect the
digestive tract and survive within the digestive system.

Horeman, 2014
• O. viverrini and C. sinensis are food-borne (fish) parasitic
flatworms known as flukes.
• They belong to the class of Trematoda (from the Greek H. Pylori
word trēmatōdēs meaning “pierced with holes”) under the
phylum of Platyhelminthes (Platy- meaning "flat" and
helminth- meaning "worm").

Sohn, 2012
• S.haematobium is another type of trematode known as a O. viverrini
blood fluke, which can infect the urinary tract and lead to
bladder cancer.
 Infection-Related Cancers
• There are infectious agents with well-established causal links with cancers:
• These cancers include:
- Non-cardia and cardia gastric carcinoma, gastric non-Hodgkin lymphoma (H. pylori)
- Cholangiocarcinoma (Opisthorchis viverrini and Clonorchis sinensis)
- Bladder carcinoma (Schistosoma haematobium).
- Carcinoma of the oral cavity, oropharynx including tonsil and base of tongue, larynx, Anus squamous cell carcinoma, cervix,
vulva, vagina, and penis (HPV)
- Hepatocellular carcinoma (HBV)
- Hepatocellular carcinoma and other non-Hodgkin lymphomas (HCV)
- Adult T-cell leukaemia and lymphoma (HTLV-1)
- Hodgkin lymphoma, Burkitt lymphoma, Nasopharyngeal carcinoma (EBV)
- Kaposi sarcoma (HHV-8)

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 Viruses
• Viruses are sub-microscopic non-living infectious agents that consist of a
protein coat and an enclosed nucleic acids.

• Some viral nucleoproteins are also surrounded by an additional lipid bilayer.

• Viral genomes are either DNA or RNA but never both, and are relatively small
when compared to cellular organisms (i.e. living organisms).

Human Papillomavirus (HPV)

 Viruses
• Viral genomes can range from 2 Kb to over 1 Mb.
• Viruses can only replicate in the host cell, as they rely on the host’s cellular
machinery to replicate.

• The outermost proteins of a viral particle determine what type of host cell it can
infect.

Human Papillomavirus (HPV)

 Viruses
• Viruses are classified based on their manner of
replication or their type of genetic material (i.e. DNA or
RNA).
• The HPV and EBV are both DNA viruses that replicate in
the host cell’s nucleus, but only EBV encodes its own
DNA-dependent DNA polymerase.
• The human immunodeficiency virus (HIV) and HCV are
both RNA viruses, but they differ in their mode of
replication.
• HCV encodes an RNA-dependent RNA polymerase and
replicates in the cytoplasm, whereas HIV first generates a
DNA intermediate by reverse transcription followed by
genome integration into the host’s DNA.
• HIV then uses the host RNA polymerase to generate
virion RNA.
 Viral Carcinogenesis
• Most viral infections with an impact on
health cause immediate disease (e.g. Ebola
haemorrhagic fever, influenza, measles, and
mumps).

• With such cases it is very easy to establish

an association between the disease And the
viral infection.

• When it comes to viral carcinogenesis, the

association might not be as obvious, as the
disease caused by the infection is not
immediate.

Müller-Coan et al, 2018

 Viral Carcinogenesis
• The first experimental demonstration of an infectious cause of
cancer is attributed to Ellerman and Bang.

• Working on leukaemia in chicken (1908) they demonstrated

that a filterable extract could transmit leukemia among
chickens.

• Two years later, Francis Peyton Rous demonstrated that what

is term now as “Rous’ Sarcoma,” is caused by an oncogenic
retrovirus which carries the activated viral oncogene v-SRC.
 Viral Carcinogenesis
• The discovery of oncogenic viruses in chicken is no
coincidence, as chickens were of immense commercial value.

• On the other hand, the first indications that a DNA virus could
cause cancer were obtained by Richard Shope and Francis
Peyton Rous in the 1930s.

• They observed warts in wild rabbits and showed that cell-free

extracts from these lesions could induce new lesions, and what
is now termed Frank carcinomas, when inoculated into other
rabbits.
 Human Papillomavirus (HPV)

Dimmock et al. 2007

• The papilloma viruses are double-stranded
DNA viruses that belong to the
Papillomaviridae family.
• They infect the multipotent basal layer of
epithelial cells in the skin, which may be
exposed after some type of trauma.
• Once within the cell; the viral capsid
(consists of protein capsomers) is degraded,
whereas the circular viral plasmid (episome)
remains dormant.
• As the basal layer of cells differentiate into
the upper layer of stratified epithelium, the
papilloma viruses begin to replicate.
• They depend on the host cell’s DNA
replication machinery to replicate
Kahn, 2009
 Human Papillomavirus (HPV)

• They possess two oncogenes known as E6 E7

and E7
• Once expressed within the infected cell, the
E6 protein binds and inactivates P53,
whereas the E7 protein binds and
inactivates the RB protein.
• Inactivation of RB by E7 liberates the
transcription factor E2F, which drives the E6
cell into S-phase.
• The Degradation of P53 via
ubiquitinylation by the E6-Associated
Protein (E6-AP) prevents the sensing of
improper S-phase entry and apoptosis.
 Human Papillomavirus (HPV)

E7
• A consequence of improper entry into S-phase is
the upregulation of the cell cycle inhibitor, Cyclin
Dependent Kinase iNhibitor 2A (CDKN2A).
• CDKN2A, also known as P16, inhibits cell cycle
progression by preventing RB phosphorylation
and deactivation by CDK4.
• In this case, this inhibition is ineffective as the RB
protein has been deactivated by the viral E7
oncoprotein. E6
• Almost all HPV-associated cancers show highly
elevated levels of CDKN2A expression.
• Detection of CDKN2A is a clinically useful
biomarker for cervical cancer and HPV head
and neck cancer, more so than the detection of
the E6 or E7 oncoproteins themselves.
 Human Papillomavirus (HPV)
• In 9 out of 10 infected cells, reactivation of
the HPV after a dormant phase leads to
viral replication, virion formation, virus
egress (escape from the cell), and eventual
destruction of the infected cell.

• In a small fraction of cells, the circular

HPV episome integrates into the host
genome.

• The integration event disrupts the

regulatory region or open reading frame of
the viral E2 transcriptional suppressor.

Kahn, 2009
 Human Papillomavirus (HPV)
• E2 negatively regulates E6 and E7
transcription during dormancy.
• In an abortively infected cell, E6 and E7 are
transcribed under conditions where virion
formation is not possible.
• This leads to improper replication under
conditions of inactive P53.
• As result there is an accumulation of
secondary genetic changes, some of which
lead to transformation and tumour
formation.
• In head and neck cancer, mutations of TP53
is inversely correlated with the presence of
HPV.

Kahn, 2009
 Human Papillomavirus (HPV)
• There are over 100 different HPV types.
• Only a subset consist of ‘high-risk’ types that
are associated with cancer: 16, 18, 31, 33, 35,
39, 45, 51, 52, 56, 58, 59, 68, 73.
• E6 and E7 oncoproteins of ‘high-risk’, but
not ‘low-risk’ HPVs, are able to immortalise
primary human keratinocytes by virtue of
specific amino acid sequences.
• These ‘high-risk’ HPVs are able to
efficiently inactive RB and P53.
• HPV is predominantly associated with
cervical cancer.

Kahn, 2009
 Vaccinations Against HPV
• HPV is particularly prevalent in low- and middle-income countries
• Three HPV vaccines are now being marketed throughout the world:
- Bivalent vaccine (Effective against HPV types 16 and 18)
- Quadrivalent vaccine (Effective against HPV types 6, 11, 16, and 18)
- Nonavalent vaccine (Effective against HPV types 6, 11, 16, 18, 31, 33, 45, 52,
and 58)
• All three vaccines are highly efficacious in preventing infections with the ‘high-
risk’ HPV types 16 and 18.
• HPV type 16 and 18 are together responsible for approximately 70% of cervical
cancer cases globally.
 Vaccinations Against HPV

• These vaccines are also highly efficacious in preventing precancerous cervical

lesions caused by HPV.

• The quadrivalent and nonavalent vaccines are also highly efficacious in

preventing anogenital warts, a common genital disease which usually caused
by HPV types 6 and 11 infections (not ‘high-risk’ types).

• The additional protection provided by the nonavalent vaccine is against

‘high-risk’ types.

• However, it does not cover all ‘high-risk’ types.

 Vaccinations Against HPV

• The primary target group that is recommended for HPV vaccinations for most
coutries are young adolescent girls aged 9-14.
• The vaccination schedule depends on the age of the vaccine recipient for the three
vaccines:
- Females younger that 15 years at the time of the first dose: a 2-dose schedule is
recommended (0, 6 months).
- If the interval between doses is shorter than 5 months: A third dose is
recommended at least 6 months after the first dose.
- Females ≥15 years at the time of the first dose: A 3-dose schedule is
recommended (0, 2, 6 months).
Questions?
Human Papillomavirus (HPV)

Kahn, 2009