1. Neoplasia
Neoplasia literally means the process of new
growth.
British oncologist, Willis defined neoplasm as an
abnormal mass of tissue, the growth of which
exceeds and is uncoordinated with that of the
normal tissues and persists in the same excessive
manner after cessation of the stimuli which
evoked the change.
The persistence of tumors, even after the inciting
stimulus is gone, results from heritable genetic
alterations that are passed down to the progeny
of the tumor cells.
2. Nomenclature
The term tumor is now equated with
neoplasm.
Oncology is the study of tumors or
neoplasms.
Cancer is the common term for all
malignant tumors.
Basic components of tumour:
Parenchyma: proliferating neoplastic
cells Stroma: made up of connective
tissue and blood vessels that support the
parenchymal cells.
3. Nomenclature
Benign Tumors. In general, benign
tumors are designated by attaching the
suffix -oma to the cell of origin. Tumors of
mesenchymal cells generally follow this
rule. For example, a benign tumor arising
from fibroblastic cells is called a fibroma, a
cartilaginous tumor is a chondroma, and a
tumor of osteoblasts is an osteoma.
In contrast, nomenclature of benign
epithelial tumors is more complex. They
are variously classified, some based on
their cells of origin, others on microscopic
architecture, and still others on their
macroscopic patterns.
4. Nomenclature
Adenoma is the term applied to a benign
epithelial neoplasm that forms glandular
patterns as well as to tumors derived from
glands but not necessarily reproducing
glandular patterns. On this basis, a benign
epithelial neoplasm that arises from renal
tubular cells growing in the form of
numerous tightly clustered small glands
would be termed an adenoma, as would a
heterogeneous mass of adrenal cortical
cells growing in no distinctive pattern.
5. Nomenclature
Papillomas: Benign epithelial neoplasms
producing microscopically or macroscopically
visible finger-like projections from epithelial
surfaces.
Cystadenomas: form large cystic masses.
Papillary cystadenomas: Tumors that produce
papillary patterns that protrude into cystic
spaces.
Polyp: a neoplasm, benign or malignant,
producing a macroscopically visible projection
above a mucosal surface and projects into a
lumen. The term polyp is preferably restricted to
benign tumors. Malignant polyps are better
designated polypoid cancers.
6. Nomenclature
Malignant Tumors
Sarcomas: Malignant tumors arising
in mesenchymal tissue e.g.,
fibrosarcoma, liposarcoma,
leiomyosarcoma for smooth muscle
cancer, and rhabdomyosarcoma for a
cancer that differentiates toward
striated muscle.
7. Nomenclature
Carcinomas: Malignant neoplasms
of epithelial cell origin. Carcinomas
with glandular growth pattern are
termed adenocarcinomas, one
producing squamous cells is termed
a squamous cell carcinoma. If the
tumour does not resemble any
known tissue, it is referred to as
being poorly differentiated or
undifferentiated malignant tumor.
8. Nomenclature
The great majority of neoplasms,
even mixed tumors, are composed of
cells representative of a single germ
layer.
Teratomas, in contrast, are made
up of a variety of parenchymal cell
types representative of more than
one germ layer, usually all three.
They arise from totipotent cells and
so are principally encountered in the
gonads.
9. Nomenclature
* Tumours of more than one neoplastic cell
type mixed tumors, usually derived from
one germ cell layer: e.g. Pleomorphic
adenoma (mixed tumor of salivary origin)
and Wilms tumor
*Tumours of more than one neoplastic cell
type derived from more than one germ
cell layer-Teratogenous. Totipotential cells
in gonads or in embryonic rests, e.g.
Mature teratoma, dermoid cyst, Immature
teratoma, teratocarcinoma
10. Nomenclature
Some exceptions do occur in the
nomenculature. For example, melanoma,
seminoma and hepatoma (hepatocellular
carcinoma) are malignant tumours of
melanocytes, testicle and hepatocytes
respectively despite the fact that they end
with the suffix-oma.
Choristoma-ectopic rest of normal tissue
Hamartoma-aberrant growth of
indigenous tissue.
11. The nomenclature of tumors is
important because specific
designations have specific clinical
implications, even among tumors
arising from the same tissue.
12. Biology of Tumor Growth
The natural history of most malignant
tumors can be divided into four
phases:
*Malignant change in the target cell
(transformation).
*Growth of the transformed cells.
*Local invasion
*Distant metastases
13. DIFFERENTIATION AND
ANAPLASIA
Differentiation refers to the extent to which neoplastic cells
resemble comparable normal cells, both morphologically
and functionally
Anaplasia refers to lack of differentiation. Well-
differentiated tumors are composed of cells resembling the
mature normal cells of the tissue of origin of the neoplasm.
Poorly differentiated or undifferentiated tumors have
primitive-appearing, unspecialized cells. In general, benign
tumors are well differentiated
Malignant neoplasms, in contrast, range from well
differentiated to undifferentiated. Lack of differentiation, or
anaplasia, is considered a hallmark of malignant
transformation. Anaplasia literally means "to form
backward. There is substantial evidence, however, that
most cancers do not represent "reverse differentiation" of
mature normal cells but, in fact, arise from stem cells that
are present in all specialized tissues.
14. Morphologic features of anaplasia
Pleomorphism.-variation in size and shape.
Abnormal nuclear morphology.
-hyperchromasia.
-Increased nucleus-to-cytoplasm ratio which may approach 1:1
instead of the normal 1:4 or 1:6. The nuclear shape is very
variable, and the chromatin is often coarsely clumped and
distributed along the nuclear membrane. Large nucleoli are
usually present in these nuclei.
Mitoses. More important as a morphologic feature of malignant
neoplasia are atypical, bizarre mitotic figures, sometimes
producing tripolar, quadripolar, or multipolar spindles.
Loss of polarity. dysplasia.
Other changes. Another feature of anaplasia is the formation of
tumor giant cells
In many anaplastic tumors, large central areas undergo ischemic
necrosis.
15. RATES OF GROWTH
It can be readily calculated that the original transformed
cell (approximately 10 μm in diameter) must undergo at
least 30 population doublings to produce 109 cells
(weighing approximately 1 gm), which is the smallest
clinically detectable mass.
In contrast, only 10 further doubling cycles are required to
produce a tumor containing 1012 cells (weighing
approximately 1 kg), which is usually the maximal size
compatible with life. By the time a solid tumor is clinically
detected, it has already completed a major portion of its life
cycle. This is a major impediment in the treatment of
cancer, and underscores the need to develop diagnostic
markers to detect early cancers.
16. The rate of growth of a tumor is
determined by three main factors:
the doubling time of tumor cells
the fraction of tumor cells that are in
the replicative pool
the rate at which cells are shed and
lost in the growing lesion. In reality,
total cell-cycle time for many tumors
is equal to or longer than that of
corresponding normal cells.
17. during the early, submicroscopic phase of
tumor growth, the vast majority of
transformed cells are in the proliferative
pool. As tumors continue to grow, cells
leave the proliferative pool in ever-
increasing numbers owing to shedding,
lack of nutrients, or apoptosis; by
differentiating; and by reversion to G0.
Most cells within cancers remain in the G0
or G1 phases. Thus, by the time a tumor
is clinically detectable, most cells are not
in the replicative pool.
18. Fast-growing tumors may have a
high cell turnover, implying that
rates of both proliferation and
apoptosis are high. Obviously, for
the tumor to grow, the rate of
proliferation should exceed that of
apoptosis
19. The proportion of cells within the tumor
population that are in the proliferative pool is
referred to as the growth fraction. Clinical and
experimental studies suggest that.
The growth fraction of tumor cells has a profound
effect on their susceptibility to cancer
chemotherapy.
Most anticancer agents act on cells that are in
cycle.
One strategy employed in the treatment of
tumors with low growth fraction (e.g., cancer of
colon and breast) is first to shift tumor cells from
G0 into the cell cycle.
20. LOCAL INVASION
Nearly all benign tumors grow as cohesive
expansile masses that remain localized to
their site of origin and do not have the
capacity to infiltrate, invade, or
metastasize to distant sites, as do
malignant tumors.
Next to the development of metastases,
invasiveness is the most reliable feature
that differentiates malignant from benign
tumors
21. METASTASIS
Metastases are tumor implants
discontinuous with the primary
tumor. Metastasis unequivocally
marks a tumor as malignant.
However, gliomas and basal cell
carcinomas do not metastasize.
22. Pathways of Spread
Direct seeding of body cavities or
surfaces.
Lymphatic spread.
Hematogenous spread.
23. Comparisons Between Benign and
Malignant Tumors
Characteristics:
Differentiation/anaplasia: Well differentiated; structure
may be typical of tissue of origin(benign);
Some lack of differentiation with anaplasia; structure is
often atypical(malignant)
Rate of growth: Usually progressive and slow; may come
to a standstill or regress; mitotic figures are rare and
normal (benign)
Erratic and may be slow to rapid; mitotic figures may be
numerous and abnormal(malignant)
24. Local invasion: Usually cohesive and
expansile well-demarcated masses that do
not invade or infiltrate surrounding normal
tissues (benign); Locally invasive,
infiltrating the surrounding normal tissues;
sometimes may be seemingly cohesive
and expansile (malignant).
Metastasis: Absent (benign)
Frequently present (malignant).
The larger and more undifferentiated the
primary, the more likely are metastases
25. GEOGRAPHIC AND ENVIRONMENTAL
FACTORS
Remarkable differences can be found
in the incidence and death rates of
specific forms of cancer around the
world. Although racial predispositions
cannot be ruled out, it is generally
believed that most of the geographic
differences are the consequence of
environmental influences.
26. AGE
Most carcinomas occur in the later years
of life (≥ 55 years). Cancer is the main
cause of death among women aged 40 to
79 and among men aged 60 to 79.
GENETIC PREDISPOSITION TO CANCER
Evidence now indicates that for a large
number of cancer types, including the
most common forms, there exist not only
environmental influences but also
hereditary predispositions.
27. Genetic predisposition to cancer
can be divided into three categories
Autosomal Dominant Inherited Cancer
Syndromes. Inherited cancer syndromes include
several well-defined cancers in which inheritance
of a single mutant gene greatly increases the risk
of developing a tumor.
The inherited mutation is usually a point
mutation occurring in a single allele of a tumor
suppressor gene. The defect in the second allele
occurs in somatic cells, generally as a
consequence of chromosome deletion or
recombination.e.g. retinoblastoma
28. Defective DNA Repair Syndromes.
Besides the dominantly inherited
precancerous conditions, a group of
cancer-predisposing conditions is
collectively characterized by defects in
DNA repair and resultant DNA instability.
These conditions generally have an
autosomal recessive pattern of
inheritance. Included in this group are
xeroderma pigmentosum, ataxia-
telangectasia, and Bloom syndrome
29. Familial Cancers. Besides the inherited syndromes of cancer
susceptibility, cancer may occur at higher frequency in certain
families without a clearly defined pattern of transmission. Virtually
all the common types of cancers that occur sporadically have also
been reported to occur in familial forms. Examples include
carcinomas of colon, breast, ovary, and brain, as well as
melanomas. Features that characterize familial cancers include
early age at onset, tumors arising in two or more close relatives of
the index case, and sometimes, multiple or bilateral tumors.
Familial cancers are not associated with specific marker
phenotypes. For example, in contrast to the familial adenomatous
polyp syndrome, familial colonic cancers do not arise in pre-
existing benign polyps. The transmission pattern of familial
cancers is not clear. In general, siblings have a relative risk
between two and three (two to three times greater than unrelated
individuals).
30. Interactions Between Genetic
and Non-Genetic Factors
The interaction between genetic and non-genetic
factors is particularly complex when tumor
development depends on the action of multiple
contributory genes. Furthermore, the genotype
can significantly influence the likelihood of
developing environmentally induced cancers.
Inherited variations (polymorphisms) of enzymes
that metabolize procarcinogens to their active
carcinogenic forms can influence the
susceptibility to cancer. Of interest in this regard
are genes that encode the cytochrome P-450
enzymes.
31. NON HEREDITARY
PREDISPOSING CONDITIONS
Because cell replication is involved in neoplastic
transformation, regenerative, hyperplastic, and
dysplastic proliferations are fertile soil for the
origin of a malignant tumor. There is a well-
defined association between certain forms of
endometrial hyperplasia and endometrial
carcinoma and between cervical dysplasia and
cervical carcinoma. The bronchial mucosal
metaplasia and dysplasia of habitual cigarette
smokers are ominous antecedents of
bronchogenic carcinoma. About 80% of
hepatocellular carcinomas arise in cirrhotic livers,
which are characterized by active parenchymal
regeneration
32. Precancerous Conditions
Certain non-neoplastic disorders-the
chronic atrophic gastritis of
pernicious anemia, solar keratosis of
the skin, chronic ulcerative colitis,
and leukoplakia of the oral cavity,
vulva, and penis- have such a well-
defined association with cancer that
they have been termed precancerous
conditions.
33. Molecular Basis of Cancer
Nonlethal genetic damage lies at the
heart of carcinogenesis.
34. A tumor is formed by the clonal expansion
of a single precursor cell that has incurred
the genetic damage (i.e., tumors are
monoclonal). Clonality of tumors can be
assessed. For tumors with a specific
translocation, such as in myeloid
leukemias, the presence of the
translocation can be used to assess
clonality. Immunoglobulin receptor and T-
cell receptor gene rearrangements serve
as markers of clonality in B- and T-cell
lymphomas, respectively.
35. Four classes of normal regulatory
genes
the growth-promoting
protooncogenes,
the growth-inhibiting tumor
suppressor genes,
genes that regulate programmed cell
death (apoptosis),
genes involved in DNA repair-are the
principal targets of genetic damage.
36. Mutant alleles of proto-oncogenes are
considered dominant because they
transform cells despite the presence of a
normal counterpart.
In contrast, both normal alleles of the
tumor suppressor genes must be
damaged for transformation to occur
However, some tumor suppressor genes
lose their suppressor activity when a
single allele is lost or inactivated. This loss
of function of a recessive gene caused by
damage of a single allele is called
haploinsufficiency.
37. Carcinogenesis is a multistep process at
both the phenotypic and the genetic
levels. A malignant neoplasm has several
phenotypic attributes, such as excessive
growth, local invasiveness, and the ability
to form distant metastases. These
characteristics are acquired in a stepwise
fashion, a phenomenon called tumor
progression. At the molecular level,
progression results from accumulation of
genetic lesions that in some instances are
favored by defects in DNA repair.
38. ESSENTIAL ALTERATIONS FOR
MALIGNANT TRANSFORMATION
* Cancer-related genes can be
considered in the context of seven
fundamental changes in cell
physiology that together determine
malignant phenotype.
* Another important change for tumor
development is the escape from
immunity and rejection.
39. Self-sufficiency in growth signals
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Defects in DNA repair
Limitless replicative potential: associated
with maintenance of telomere length and
function.
Sustained angiogenesis:
Ability to invade and metastasize:
Mutations in genes that regulate these
cellular traits are seen in every cancer.
41. Genes that promote autonomous cell growth in
cancer cells are called oncogenes.
oncogenes are characterized by the ability to
promote cell growth in the absence of normal
mitogenic signals. Their products, called
oncoproteins, resemble the normal products of
protooncogenes. Their production in the
transformed cells is constitutive, that is, not
dependent on growth factors or other external
signals.
42. Under physiologic conditions, cell proliferation follows the
following steps:
The binding of a growth factor to its specific receptor
generally located on the cell membrane
Transient and limited activation of the growth factor
receptor, which, in turn, activates several signal-
transducing proteins on the inner leaflet of the plasma
membrane
Transmission of the transduced signal across the cytosol to
the nucleus via second messengers or by signal
transduction molecules that directly activate transcription
Induction and activation of nuclear regulatory factors that
initiate DNA transcription
Entry and progression of the cell into the cell cycle,
ultimately resulting in cell division
43. Protooncogenes, Oncogenes, and Oncoproteins
Tthe discovery of protooncogenes was not
straightforward. These cellular genes were first
discovered in their mutated or "oncogenic" forms
as "passengers" within the genome of acute
transforming retroviruses by the 1989 Nobel
laureates Harold Varmus and Michael Bishop.
These retroviruses cause rapid induction of
tumors in animals and can also transform animal
cells in vitro. Mapping of their genomes revealed
the presence of unique transforming sequences
(viral oncogenes [v-onc]) not found in the
genomes of nontransforming retroviruses.
44. Molecular hybridization revealed that the v-onc
sequences were almost identical to sequences
found in normal cellular DNA. Because they were
discovered initially as viral genes, these
protooncogenes were named after their viral
homologues. Each v-onc is designated by a
three-letter word that relates the oncogene to the
virus from which it was isolated. Thus, the v-onc
contained in feline sarcoma virus is referred to as
v-FES, whereas the oncogene in simian sarcoma
virus is called v-SIS. The corresponding
protooncogenes are referred to as FES and SIS,
dropping the prefix
45. The viral oncogenes are not present in several
cancer-causing RNA viruses. One such example is
a group of so-called slow transforming viruses
that cause leukemias in rodents after a long
latent period. The mechanism by which they
cause neoplastic transformation implicates
protooncogenes. Molecular dissection of the cells
transformed by these leukemia viruses revealed
that the proviral DNA is always integrated
(inserted) near a protooncogene. One
consequence of proviral insertion near a
protooncogene is to induce a structural change in
the cellular gene, thus converting it into a cellular
oncogene (c-onc, or onc). This mode of
protooncogene activation is called insertional
mutagenesis.
46. EVASION OF APOPTOSIS
The discovery of BCL-2, the prototypic
gene in this category, began with the
observation that approximately 85% of B-
cell lymphomas of the follicular type carry
a characteristic t(14;18)(q32;q21)
translocation, in which the BCL-2 gene
from 18q21 is translocated to the
immunoglobulin heavy-chain locus on
14q32. (Recall that the immunoglobulin
heavy-chain locus is also involved in
translocation-of the MYC gene-in Burkitt
lymphoma.)
47. INVASION AND METASTASIS
Invasion and metastasis are biologic
hallmarks of malignant tumors. For tumor
cells to break loose from a primary mass,
enter blood vessels or lymphatics, and
produce a secondary growth at a distant
site, they must go through a series of
steps
48. Organ tropism in metastasis
may be related to the following mechanisms:
Because the first step in extravasation is adhesion to the
endothelium, tumor cells may have adhesion molecules whose
ligands are expressed preferentially on the endothelial cells of the
target organ. Indeed, it has been shown that the endothelial cells
of the vascular beds of various tissues differ in their expression of
ligands for adhesion molecules.
Chemokines have a very important role in determining the target
tissues for metastasis. For instance, some breast cancer cells
express the chemokine receptors CXCR4 and CCR7. The
chemokines that bind to these receptors are highly expressed in
tissues to which breast cancers commonly metastasize.
Some target organs may liberate chemoattractants that tend to
recruit tumor cells to the site. Examples include insulin-like
growth factors I and II.
In some cases, the target tissue may be an unpermissive
environment- For example, although well vascularized, skeletal
muscles are rarely the site of metastases.
49. Molecular Genetics of Metastasis
Development
Membrane-cytoskeleton component
ezrin, appears to be necessary for
metastases in rhabdomyoscarcoma
and osteosarcoma. Several genes
have been proposed as suppressors
of metastasis. They include NM23
and the KAI-1 and KiSS genes.
50. DNA transfection experiments
revealed that no single oncogene can
fully transform non-immortalized
cells in vitro, but that such cells can
generally be transformed by
combinations of oncogenes.
51. TUMOR PROGRESSION AND
HETEROGENEITY
It is well established that over a
period of time many tumors become
more aggressive and acquire greater
malignant potential. In some
instances (e.g., colon cancer), there
is an orderly evolution from
preneoplastic lesions to benign
tumors and, ultimately, invasive
cancers. This phenomenon is
referred to as tumor progression.
52. CHEMICAL CARCINOGENESIS
Although John Hill first called
attention to the association of
"immoderate use of snuff" and the
development of "polypusses"
(polyps), we owe largely to Sir
Percival Pott our awareness of the
potential carcinogenicity of chemical
agents. In the 18th century Pott
astutely related the increased
incidence of scrotal skin cancer in
chimney sweeps to chronic exposure
to soot.
53. Some of the most potent (e.g., the
polycyclic aromatic hydrocarbons) have
been extracted from fossil fuels or are
products of incomplete combustions.
Some are synthetic products created by
industry or for the study of chemical
carcinogenesis. Some are naturally
occurring components of plants and
microbial organisms. Most important, a
significant number (including, ironically,
some medical drugs) have been strongly
implicated in the causation of cancers in
humans.
54. Steps Involved in Chemical
Carcinogenesis
Initiation; an initiated cell is altered, making it
potentially capable of giving rise to a tumor . Initiation
alone, however, is not sufficient for tumor formation.
Initiation causes permanent DNA damage
(mutations). It is therefore rapid and irreversible and
has "memory.
Promoters can induce tumors in initiated cells, but
they are nontumorigenic by themselves. Furthermore,
tumors do not result when the promoting agent is
applied before, rather than after, the initiating agent.
This indicates that, in contrast to the effects of
initiators, the cellular changes resulting from the
application of promoters do not affect DNA directly
and are reversible
55. Initiation of Chemical
Carcinogenesis
They fall into one of two categories:
direct-acting compounds, which do not require
chemical transformation for their carcinogenicity,
and
indirect-acting compounds or procarcinogens,
which require metabolic conversion in vivo. Most
direct-acting and ultimate carcinogens have one
property in common: They are highly reactive
electrophiles (have electron-deficient atoms) that
can react with nucleophilic (electron-rich) sites in
the cell. These reactions are nonenzymatic and
result in the formation of covalent adducts
(addition products) between the chemical
carcinogen and a nucleotide in DNA.
56. Most of the known carcinogens are
metabolized by cytochrome P-450-
dependent mono-oxygenases
57. The genes that encode these enzymes
are quite polymorphic, and the activity
and inducibility of these enzymes have
been shown to vary among different
individuals. Because these enzymes are
essential for the activation of
procarcinogens, the susceptibility to
carcinogenesis is regulated in part by
polymorphisms in the genes that
encode these enzymes
58. Molecular Targets of Chemical
Carcinogens
Malignant transformation results from
mutations that affect
*oncogenes,
*tumor suppressor genes,
*genes that regulate apoptosis,
*and genes involved in DNA repair
59. For the change to be heritable, the
damaged DNA template must be
replicated. Thus, for initiation to
occur, carcinogen-altered cells must
undergo at least one cycle of
proliferation so that the change in
DNA becomes fixed or permanent.
62. Promoters of Chemical
Carcinogenesis
Perhaps more serious, because they are difficult
to control, are endogenous promoters such as
hormones and bile salts. E.g. estrogens serve
in animals as promoters of liver tumors. The
prolonged use of diethylstilbestrol is implicated
in the production of postmenopausal endometrial
carcinoma and in the causation of vaginal cancer
in offspring exposed in utero Intake of high
levels of dietary fat has been associated with
increased risk of colon cancer. This may be
related to an increase in synthesis of bile acids,
which have been shown to act as promoters in
experimental models of colon cancer. Alcohol
consumption increases the risk of development of
cancers of the mouth, pharynx, and larynx by
more than tenfold, probably by acting as a
promoting agent
63. RADIATION CARCINOGENESIS
Radiant energy, whether in the form of the UV
rays of sunlight or as ionizing electromagnetic
and particulate radiation, can transform virtually
all cell types in vitro and induce neoplasms in
vivo in both humans and experimental animals.
UV light is clearly implicated in the causation of
skin cancers, and ionizing radiation exposure
from medical or occupational exposure, nuclear
plant accidents, and atomic bomb detonations
have produced a variety of forms of malignant
neoplasia.
64. Increased incidence of breast cancer has
become apparent decades later among
women exposed during childhood to the
atomic bomb of Hiroshima and Nagasaki
Japan.
Radiation has additive or synergistic
effects with other potential carcinogenic
influences
The effects of UV light on DNA differ from
those of ionizing radiation.
65. The degree of risk depends on the
type of UV rays, the intensity of
exposure, and the quantity of light-
absorbing "protective mantle" of
melanin in the skin.
66. The UV portion of the solar spectrum can
be divided into three wavelength ranges:
UVA (320 to 400 nm),
UVB (280 to 320 nm), and
UVC (200 to 280 nm).
Of these, UVB is believed to be
responsible for the induction of cutaneous
cancers. UVC, although a potent mutagen,
is not considered significant because it is
filtered out by the ozone shield around the
earth (hence the concern about ozone
depletion).
67. The carcinogenicity of UVB light is
attributed to its formation of pyrimidine
dimers in DNA. This type of DNA damage
is repaired by the nucleotide excision
repair (NER) pathway. There are five steps
in NER: (1) recognition of the DNA lesion,
(2) incision of the damaged strand on
both sites of the lesion, (3) removal of the
damaged nucleotide, (4) synthesis of a
nucleotide patch, and (5) its ligation.
68. The molecular basis of the degenerative
changes in sun-exposed skin and
occurrence of cutaneous tumors rests on
an inherited inability to repair UV-induced
DNA damage. Xeroderma pigmentosum is
a genetically heterogeneous condition,
with at least seven different variants. Each
of these is caused by a mutation in one of
several genes involved in NER.
69. Ionizing radiation ( x-rays, γ rays, α,
β- particles, protons, neutrons), are
known to cause thyroid cancers,
leukaemias/ lymphomas in exposed
individuals
70. MICROBIAL CARCINOGENESIS
Certain forms of human cancer are of viral origin
(DNA and RNA viruses) and
Infection by the bacterium Helicobacter pylori
(gastric tumors).
Of the various human DNA viruses, five
(papillomaviruses [HPV], Epstein-Barr virus
[EBV], hepatitis B virus [HBV], merkel cell
polyoma virus and Kaposi sarcoma herpes virus
[KSHV]) are of particular interest because they
have been implicated in the causation of human
cancer. Hepatitis C virus (HCV), and Human T-
Cell Leukemia Virus Type 1(HTLV-1) which are
RNA viruses are also associated with cancer.
71. The genomes of oncogenic DNA
viruses integrate into and form
stable associations with the host cell
genome. The virus is unable to
complete its replicative cycle because
the viral genes essential for
completion of replication are
interrupted during integration of viral
DNA. Thus, the virus can remain in a
latent state for years.
72. Helicobacter pylori
The disease-causing strains contain a
"pathogenicity island" containing the
CagA (cytotoxin associated gene A)
gene and a secretory system, which
injects the CagA protein into the host
cells. Another gene associated with
virulence is VacA, which encodes a
vacuolating toxin that causes
apoptosis.
73. The infection is associated with gastric
adenocarcinomas of the intestinal type
through a sequence that involves chronic
gastritis, multifocal atrophy with lower
gastric acid secretion, intestinal
metaplasia, dysplasia, and carcinoma
It is also associated with MALTomas-
mucosa assoc. lymphoid tissue tumours
