Epstein–Barr virus (EBV), hepatitis B virus (HBV), human T-lymphotropic virus 1 (HTLV-1), human papillomaviruses (HPVs), hepatitis C virus (HCV), Kaposi sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV-8)) and Merkel cell polyomavirus

1. ONCOGENIC
VIRUS
Dr Rahul Acharya
1

2. Distinguishing
Characteristics of Viruses
Obligate intracellular
parasites
Extreme genetic
simplicity
Contain DNA or RNA
Replication involves
disassembly and
reassembly
Replicate by "one-step
growth”
2

3. Viruses enter the body of the host
in a variety of ways, for example...
3

4. Routes of entry:
sexual
Inhalation
inoculation
Blood
organ t/plant
ingestion
Congenital / vertical
4

5. WHO Estimates
Worldwide, the WHO International
Agency for Research on Cancer estimated
that in 2002, 20% of human cancers were
caused by infection, of which 10–15% are
caused by one of seven different viruses.
The importance of this is that some of
these cancers might be easily prevented
through vaccination
5

6. What is Cancer
Cancer results from alterations in critical
regulatory genes that control cell
proliferation, differentiation, and survival.
Studies of tumor viruses revealed that
specific genes (called oncogenes) are
capable of inducing cell transformation,
thereby providing the first insights into
the molecular basis of cancer.
6

7. How virus causes Cancers:
 The viral agents causing cancer in eukaryotic
animals by integrating in host genome
*A virus associated with malignancies in natural host,
experimental animals or cell cultures.
*viruses which modified proto-oncogene, obligatory
host specific, with the ability immortalization,
possess genes which stimulate growth and cause
cancer.
7

8. Early History
The theory that cancer could be caused
by a virus began with the experiments
of Oluf Bang and Vilhelm Ellerman in
1908 who first show that avian
erythroblastosis (a form of chicken
leukemia) could be transmitted by cell-
free extracts. This was subsequently
confirmed for solid tumors in chickens
in 1910-1911 by Peyton Rous. 8

9. Research History
In 1908, Ellerman &
Bang first discovered
virus, producing
leukemia in chicken.
In 1911 Peyton Rous 1st
shows the presence of
filterable sarcoma
material that induce the
CANCER.
9

10. 3/12/2023 Dr.T.V.Rao MD 10

11. Relationship of viruses with
malignancy
Ellerman & Bang (1908) – leukemia in
fowls
Rous (1911) – fowl sarcoma
Shope isolated Rabbit fibroma virus
(1932), papilloma virus (1933)
Bittner (1936) –Breast Ca in mice
11

12. Understanding Cancer
CANCER
Cancer is an overgrowth of cells bearing
cumulative genetic injuries that confer growth
advantage over the normal cells [Nowell’s
Law]
Cancer cells can be characterized as
antisocial, fairly autonomous units that
appear to be indifferent to the constraints
and regulatory signals imposed on normal
cells [Robbin’s]
12

13. Oncovirus
An oncovirus is a virus that can cause
cancer. This term originated from
studies of acutely-transforming
retroviruses in the 1950–60s, often
called oncornaviruses to denote their
RNA virus origin. It now refers to any
virus with a DNA or RNA genome
causing cancer and is synonymous with
"tumor virus" or "cancer virus". 13

14. by transforming cells
cancer
• When a virus infects a cell, it
expresses proteins that cause the
cell to proliferate and/or block
apoptosis
• Cancer is multi-factorial: Oncogenic
viruses are very common, only a small
% of people infected actually get
cancer
14

15. Classification
15
Oncovirus
DNA oncogenic
viruses
RNA oncogenic
viruses

16. Oncogenic viruses may be RNA or DNA
 20% of human
cancers believed to be
of viral origin
 These include:
 Cervical cancer
 Burkitt’s lymphoma
 Hepatocarcinoma
 Kaposi’s sarcoma
 Virus is not only
factor
16

17. Major human Oncogenic Viruses
17
DNA Viruses
Small DNA tumor viruses
- Adenovirus
- SV40
- Human Papilloma virus (HPV)
Herpesviruses (large)
- Epstein Barr virus (EBV)
- Kaposi’s Sarcoma Herpesvirus (KSHV)
Other
- Hepatitis virus B
RNA viruses
Human T-cell Leukemia Virus 1 (HTLV1)
Hepatitis virus C

18. Viruses Associated With The
Development Of Human Neoplasia
VIRUSES NEOPLASMS
DNA VIRUSES
Human papilloma virus Cervical Ca, warts, ano-
genital carcinoma
Herpes simplex virus II Cervical carcinoma
Epstein-Barr virus NPCa, African Burkitt’s
Human Herpes virus 8 Kaposi’s sarcoma
Hepatitis B virus Hepatocellular Ca
Herpes simplex virus 6 Certain B cell
lymphomas
(HBLV)
Molluscipoxvirus molluscum 18

19. Viruses Associated With The
Development Of Human Neoplasia
VIRUSES NEOPLASMS
RNA VIRUSES
Human T-cell leukemia virus I Some T-cell leukemia,
Lymphoma
Human T-cell leukemia virus II Some cases of hairy
cell leukemia
Human immunodeficiency virus Lymphoma; Kaposi’s
sarcoma
Hepatitis virus Hepatocellular
carcinoma
19

20. • Oncogenic viruses
 Oncogenesis is the result of
genetic changes that alter the
expression or function of
proteins that play critical roles
in the control of cell growth
and division
 •Oncogenic viruses cause
cancer by inducing changes
that affect cell growth and
division
20

21. Oncogenic Retroviruses
 More than 40 different highly oncogenic retroviruses
have been isolated from a variety of animals, including
chickens, turkeys, mice, rats, cats, and monkeys. All of
these viruses, like RSV, contain at least one oncogene
In some cases, different viruses contain the same
oncogenes, but more than two dozen distinct
oncogenes have been identified among this group of
viruses
21

22. Changes in cell that are at the roots of
cancer
22
Genetic and epigenetic alterations:
• Mutations
• Deletions
• Recombination's
• Transpositions
• Epigenetic alterations (DNA methylation,
imprinting)
• Acquisition of viral genetic material
• Various combinations of these lead to the development
of cancers - some viruses contribute single hits while
others contribute multiple hits.

23. 23
• Integrations that cause activation or
inactivation of oncogenes or tumor
suppressors (e.g. RNA viruses)
• Expression of genes that alter key
signal transduction pathways - this is our
focus
• Chronic activation of
inflammatory responses
How do Viruses contribute to
cancer?

24. Viral transformation can induce
cellular changes including
tumourigenicity
3/12/2023 Dr.T.V.Rao MD 24

25. 25

26. Transformation and poential
tumorigenesist
 Transformation - alteration in a cell’s properties that leads to
immortalization and different growth patterns that result
from alteration in cell cycle
 Loss of anchorage dependence
 Loss of contact inhibition (foci)
 Decreased requirements for growth factors
 Tumorigenesis (oncogenicity) - in vivo development of
tumors
26

27. 27

28. Cancer
 Cancer arises from
a combination of
dominant gain of
function mutations
in proto-
oncogenes and
recessive loss of
function mutations
in tumor
suppressor genes 28

29. CANCER CELLS AND NORMAL CELLS
29
CANCER CELLS NORMAL CELLS
Loss of contact inhibition
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
Oncogene expression is rare
Intermittent or co-ordinated
growth factor secretion
Presence of tumor suppressor
genes
Normal
cell
Few
mitoses
Frequent
mitoses
Nucleus
Blood vessel
Abnormal
heterogeneous cells

30. CHARACTERISTICS OF CANCER
Clonality
Cancer is a genetic disease at the cellular
level.
Genetic mutations play a critical role in
pathogenesis of cancer.
Consequences of genetic instability:
Phenotypic heterogeneity
Tumor progression
Proto-oncogenes and oncogenes
Dominant and recessive mutations 30

31. Cancer Genetics
Tumors arise as clones from a single cell. At
the cellular level, cancer is a genetic disease.
The development of the malignant clone is
due to mutations in DNA due to:
Random replication errors
Exposure to carcinogens
Faulty DNA repair process
31

32. Cancer Genes
Proto-oncogenes – normally promote
normal cell growth; mutations convert
them to oncogenes.
Tumor suppressor genes – normally
restrain cell growth; loss of function
results in unregulated growth.
Mutator or DNA repair genes – when
faulty, result in an accumulated rate of
mutations.
32

33. ONCOGENE FAMILY
+ oncogenes
Oncogenes
 promote cell proliferation
 dominant & highly conserved
 types: viral oncogenes [v-oncs]
cellular oncogenes [c-oncs]
Proto-oncogene  “Mutation”  Oncogene
Mouse fibroblast cell line NIH 3T3 can take up foreign D
Mouse fibroblast cell line NIH 3T3 can take up foreign DNA,
incorporate them into their genome and express them
•DNA extracted from human tumour cells can transform NIH 3T3
•Such transforming genes have been shown to be identical with cellular
oncogenes
14NA, incorporate them into their genome and express them
•DNA extracted from human tumour cells can transform NIH 3T3
•Such transforming genes have been shown to be identical with cellular
oncogenes
14
33

34. Viral Carcinogenesis
Viral carcinogens are classified
into RNA and DNA viruses.
Most RNA oncogenic viruses
belong to the family of
retroviruses that contain
reverse transcriptase
mediates transfer of viral RNA
into virus specific DNA.
34

35. 35
Two Major Classes of Tumor Viruses
DNA Tumor Viruses
DNA viral genome
Host RNA
polymerase
Viral mRNA
Viral protein
DNA-dependent
DNA polymerase
(Host or viral)

36. 36
RNA Tumor Viruses
Viral RNA genome
Reverse transcriptase (Virus-
encoded)
Viral DNA genome (integrated)
DNA-dependent RNA
polymerase (Host RNA pol II)
Viral genomic RNA
Splicing (Host splicing enzymes)
messenger RNA
viral protein
Virus
Important: Use HOST
RNA polymerase
to make its genome
An enzyme that normally
makes mRNA
IMPORTANT

37. Viruses causing human
malignancies
Hepatitis B & C viruses: Hepatocellular
Cancer.
E-B virus: Nasopharyngeal Ca, Burkitt’s
lymphoma
HPV 16 & 18: Ca Cx
HTLV: Adult T cell leukemia
HHV 8: Kaposi’s sarcoma
37

38. DNA Tumor Viruses In Human
Cancer
38
Adenoviruses
Highly oncogenic in animals
Only part of virus integrated
Always the same part
Early functions
E1A region: 2 T antigens
E1B region: 1 T antigen
E1A and E1B = Oncogenes

39. Retroviruses:
1.Avian leukosis
viruses
2.Murine leukosis
viruses
3.Murine mammary
tumor virus
4.Leukosis-sarcoma
viruses
5.Human T cell
leukemia virus
39

40. Retroviridae
 Any virus capable of
inducing tumors. The
RNA tumor viruses
(family Retroviridae),
which are well defined
and rather
homogeneous, or the
DNA viruses, which
contain a number of
viruses capable of
inducing
40

41. 41
• Adenovirus
• Human virus but only causes cancer in non-
human cells
• SV40
• Mesothelioma
• HPV
• Cervical Cancer
• Squamous cell anal carcinoma
• Penile cancer
• Oral cancers
Small DNA tumor viruses

42. DNA Tumor Viruses In Human Cancer
42
Papilloma Viruses
urogenital cancer
wart malignant squamous cell
carcinoma
Papilloma viruses are found in 91% of women with cervical cancer
Squamous cell carcinoma:
Larynx
Esophagus All histologically similar
Lung
10% of human cancers may be HPV-linked

43. DNA Tumor Viruses In Human Cancer
43
Herpes Viruses
Considerable evidence for role in human cancer
• Some very tumorigenic in animals
• Viral DNA found in small proportion of tumor
cells: “hit and run”
• Epstein-Barr Virus
• Burkitt’s Lymphoma
• Nasopharyngeal cancer
• Infectious mononucleosis
• Transforms human B-lymphocytes in

44. DNA Tumor Viruses In Human
Cancer
Hepatitis B continued
44
Epidemiology:
Strong correlation
between HBV and
hepatocellular
carcinoma

45. DNA Tumor Viruses In Human Cancer
45
Papilloma Viruses
• 51 types identified - most common
are types 6 and 11
• most cervical, vulvar and penile
cancers are ASSOCIATED with types
16 , 18 & 31 (70% of penile cancers)

46. Human Papillomavirus (HPV)
 Human Papillomavirus
(HPV) is a double-
stranded DNA virus of
the family Papovaviridae.
It infects only epithelial
cells in humans such as
skin and mucus
membranes. It can affect
the lower genital tract
including the vulva,
vagina, urethra, penis,
46

47. Human Papilloma virus
 (HPV), causes transformation in cells
through interfering with tumor
suppressor proteins such as p53.
Interfering with the action of p53 allows
a cell infected with the virus to move into
a different stage of the cell cycle,
enabling the virus genome to be
replicated. Forcing the cell into the S
phase of the cell cycle could cause the
cell to become transformed types of HPV
47

48. 3/12/2023 Dr.T.V.Rao MD 48

49. quadrivalent recombinant vaccine
against HPV types 6, 11, 16 and 18
 To prevent cervical cancers in children aged 9–15 years and
women from 16-26 years
 expected to prevent up to 70% of
 nearly 100 percent effective in preventing precancerous
cervical lesions, precancerous vaginal and vulvar lesions and
genital warts caused by infection with the HPV types 6, 11, 16
or 18 in women between the ages of 16 and 26.
49

50. Epstein Barr virus
50
Pathologies in immuno-competent individuals
• Infectious mononucleosis
• Burkitt’s Lymphoma
• Hodgkin’s lymphoma
• Nasopharyngeal carcinoma
Pathologies in immuno-compromised indiviuals
• Post-transplant lymphoproliferative diseases (PTLD)
• Hodgkin’s lymphoma
• A variety of non-Hodgkin’s lymphoblastic malignancies

51. Epstein-Barr virus (Human
herpes virus 4)
 EBV is most strongly associated with
cancer. It infects primarily lymphocytes
and epithelial cells. In lymphocytes, the
infection is usually non-productive, while
virus is shed (productive infection) from
infected epithelial cells.
51

52. Burkitt's lymphoma
 Burkitt's lymphoma in the tropics, where it is more
common in malaria-endemic regions
 Nasopharyngeal cancer, particularly in China and SE
Asia, where certain diets may act as co-carcinogens
 B cell lymphomas in immune suppressed individuals
(such as in organ transplantation or HIV)
 Hodgkin's lymphoma in which it has been detected
in a high percentage of cases (about 40% of affected
patients)
 X-linked lymphoproliferative Disease (Duncan's
syndrome)
52

53. Infectious mononucleosis
EBV also causes infectious mononucleosis,
otherwise known as glandular fever. This is
a self-resolving infection of B-lymphocytes
which proliferate benignly. Often infection
goes unnoticed (it is sub-clinical) and about
half of the population in western countries
has been infected by the time they reach 20
years of age. Why this virus causes a benign
disease in some populations but malignant
disease in others is unknown 53

54. 54
Kaposi’s Sarcoma Herpes
Virus - HHV-8
Hematologic malignancies
• Primary effusion lymphoma
• Multicentric Castleman's disease
(MCD) – a rare lymphoproliferative
disorder (AIDS)
• MCD-related
immunoblastic/plasmablastic lymphoma
• Various atypical lymphoproliferative
disorders
Kaposi’s sarcoma

55. Human Herpes Virus 8 (HHV-8,
Kaposi's Sarcoma Herpes Virus)
 HHV-8 infects lymphocytes and epithelial/endothelial
cells and is the causative agent of Kaposi's sarcoma. It
has also been associated with hematologic
malignancies, including primary effusion lymphoma,
Multicentric Castleman's (also Castelman's) disease
(MCD), MCD-related immunoblastic/plasmablastic
lymphoma and various atypical lymphoproliferative
disorders
55

56. Kaposi's sarcoma-associated
herpesvirus
Kaposi's sarcoma-associated
herpesvirus (KSHV or HHV-8) is
associated with Kaposi’s sarcoma, a
type of skin cancer. Epstein-Barr virus
(EBV or HHV-4) is associated with four
types of cancers Merkel cell
polyomavirus – a polyoma virus – is
associated with the development of
Merkel cell cancer 56

57. RNA oncogenic viruses
 Retroviridae
 Human T cell leukemia viruses
 (HTLV-1 and HTLV-2)
 Causes
 Adult T – cell leukemia
 Lymphoma
 Feline leukemia virus (FeLV)
 Contagious
 Causes leukemia and lymphoma in cats
 Related to presence of reverse transcriptase
 Some contain promoters that turn on other oncogenes
57

58. RNA Tumor Viruses
58
Groups of Retroviruses
• Oncovirinae
Tumor viruses and similar
• Lentiviruses
Long latent period
Progressive chronic disease
Visna HIV
• Spumavirinae
important
important

59. VIRAL AGENTS: DNA viruses
Human Papillomavirus [HPV types 16, 18, 31, 33 & 35]
Interruption of the E1/E2 ORF
E2 is not expressed
Over-expression of E6 & E7
59

60. VIRAL AGENTS: DNA viruses
Epstein-Barr Virus [EBV]
 in Burkitt’s, B-cell & Hodgkin’s lymphomas + NP ca
 tropism: CD21+ cells [e.g., B cells, epithelial cells]
 mechanism: viral entry  episomal existence  latency
 (+) LMP-1, EBNA-1, EBNA-2  immortalization
Hepatitis B virus [HBV]
 induction of chronic hepatocyte injury  (+) HBx
 HBx activates protein kinase c for transformation
60

61. Hepatitis B
 DNA virus with RNA
intermediate
 In tumors virus is
integrated with little
gene expression
 Believed to be from
chronic liver
damage/loss and
replacement causing
increased mutations
 (similar to SOS
response?) 61

62. DNA Tumor Viruses In Human Cancer
62
Hepatitis B Virus
DNA genome
RNA polymerase II
RNA Provirus
Reverse transcriptase
DNA genome
Host enzyme
Viral enzyme

63. HEPADNAVIRIDAE
HEPATITIS B VIRUS
 Hepatitis B virus is very different from the other DNA
tumor viruses. Indeed, even though it is a DNA virus, it is
much more similar to the oncornaviruses (RNA tumor
viruses) in its mode of replication. The DNA is transcribed
into RNA not only for the manufacture of viral proteins but
for genome replication. Genomic RNA is transcribed back
into genomic DNA. This is called reverse transcription. The
latter is not typical of most DNA tumor viruses but reverse
transcription is a very important factor in the life cycles of
RNA-tumor viruses
63

64. Hepatocellular carcinoma
 Hepatocellular carcinoma (HCC, also called malignant
hepatoma) is a primary malignancy (cancer) of the liver.
Most cases of HCC are secondary to either a viral hepatic
infection (hepatitis B or C) or cirrhosis (alcoholism being the
most common cause of hepatic cirrhosis).In countries where
hepatitis is not endemic, most malignant cancers in the liver
are not primary HCC but metastasis (spread) of cancer from
elsewhere in the body, e.g., the colon.
64

65. RNA Tumor Viruses
65
• Human T cell lymphotropic virus -2 (HTLV-2)
Hairy cell leukemia
Retroviruses known to cause human cancer
• Human T cell lymphotropic virus -1 (HTLV-1)
Adult T cell leukemia, Sezary T-cell leukemia
Africa, Caribbean, Some Japanese Island
• HIV?

66. Proto-oncogenes
66
Heterozygote Homozygote
Allele 1 Allele 2 Allele 1 Allele 2
Normal Mutant Mutant Mutant
Function gained Function gained
Dominant
mutations
Binds under
special
circumstance
s
Mutant
always
binds
Mutant
always
binds
Mutant
always
binds
Always binds Always binds

67. Anti-Oncogenes
67
Rb Gene Mutant Rb Mutant Rb
Rb
Rb
Rb
protein
Binds and controls cell cycle No binding - Growth continues
Mutant Rb
Recessive mutations
Function lost
Mutation growth
Heterozygote Homozygote

68. Anti-Oncogenes
68
Retinoblastoma gene has normal
regulatory function in many cells
Involved in
Retinoblastoma
Lung carcinomas
Breast carcinomas

69. RNA Tumor Viruses
69
What do oncogenes encode?
Proteins that are involved in growth control and
differentiation
Growth factors
Growth factor receptors
Signal transduction proteins
Transcription factors

70. Anti-Oncogenes
70
Retinoblastoma gene has normal regulatory
function in many cells
Involved in
Retinoblastoma
Lung carcinomas
Breast carcinomas

71. Anti-Oncogenes
71
Rb Gene
Rb
Rb protein
Rb
Stops replication
Rb
Adenovirus E1A
Cell cycle continues
Retinoblastoma
105kD

72. Anti-Oncogenes
72
P53
Inactivated by
• deletion
• point mutation
In a series of colorectal cancers all showed:
• Allele 1: partial or complete deletion
• Allele 2: Point mutation

73. Anti-Oncogenes
73
p53
P53 gene P53 gene P53 gene
P53
P53
DNA
Stops replication
Hepatitis C
P53
replication replication
Papilloma
proteolysis
P53
Papilloma