1. Prof. M.C.Bansal
MBBS,MS,MICOG,FICOG
Professor OBGY
Ex-Principal & Controller
Jhalawar Medical College & Hospital
Mahatma Gandhi Medical College, Jaipur.

2.  The number of cells in a normal tissue is tightly
regulated by a balance between cell
proliferation and death.
 The final common pathway for cell division
involves distinct molecular switches that control
cell cycle progression from G1 to S phase of DNA
synthesis.
 Dysregulation of cellular proliferation is the main
hallmark of cancer.
 There may be increased activity of genes
involved in cellular proliferation(oncogenes) or
loss of growth inhibitory(tumor suppressor) genes
or both.

5.  Cancer is a complex disease that arises
because of genetic and epigenetic alterations
that disrupt cellular proliferation, senscence
& death
 The malignant phenotype is also
characterized by its ability to invade
surrounding tissues and metastasize.

6.  Hippocrates was the first to use the word “cancer” to
describe tumors
 Cancer is derived from the Greek word “karkinos”
which means crab
 It is thought Hippocrates was referring to the
appearance of tumors. The main portion of the
tumor being the crabs body and the various
extensions of the tumor appear as the legs and claws
of the crab.

7.  Changes to the DNA of a cell
(mutations) lead to cellular
damage
 Mutations enable cancer cells
to divide continuously,
without the
need for normal signals
 In some cancers the
unchecked growth results in a
mass, called a tumor
 Cancerous cells may invade
other parts of the body
interfering with normal body
functions

8.  Although cancer is often
referred to as if it were a single
disease, it is really a diverse
group of diseases that affects
many different organs and cell
types
 The likelihood of developing
any particular cancer depends
on an individual’s genetics,
environment, and lifestyle.
 The occurrence of some
cancers may be
prevented/reduced by wise
lifestyle choices.

9.  Cancer arises from one cell, Transformation from
a normal cell to multistage process, typically
progression from a pre cancerous lesion to
malignant tumor.
 The changes are the result of interaction
between a person’s genetic factors and the
environmental factor and carcinogenic agents.
 This unguarded tissue growth is responsible for
high morbidity and mortality.

10.  Atleast three different pathways of cell
death have been characterized, including
apoptosis, necrosis, autophagy
 All three pathways may be ongoing
simultaneously within a tumor.

11.  The apoptosis derives from Greek and alludes
to a process akin to leaves dying and falling
off a tree.
 Apoptosis is a active energy dependent
process that involves cleavage of DNA by
endonucleases and proteins by proteases
called CASPASES.

12.  Morphologically apoptosis is characterized by
condensation of chromatin, nuclear and
cytoplasmic blebbing & cellular shrinkage.
 The molecular signals that affect apoptosis in
response to various stimuli are complex and
have only been partially elucidated, but
several reliable markers of apoptosis have
been discovered including ANNEXIN V,
CASPASE 3 ACTIVATION, and DNA
FRAGMANTATION.

13.  The intrinsic apoptosis pathway is regulated
by a complex interaction of pro and anti
apoptotic proteins in mitochondrial
membranes that affects its permeability.
 The TP53 tumor suppressor gene is a critical
regulator of cell cycle arrest and apoptosis in
response to DNA damage.

15.  Necrosis is a process that is distinct from
apoptosis and is a result of bioenergetic
compromise.
 Necrosis is less well regulated process that
leads to spillage of protein contents, and this
may incite a brisk immune response.
 This is in contrast to silent elimination of
cells by apoptosis, which typically elicits a
minimal immune response.

16.  Thereis evidence that some drugs may
enhance necrotic death in tumors, and this
may stimulate beneficial antitumor immune
response.

17.  Atophagy is a potentially reversible process
in which a cell that is stressed EATS itself.
 Atophagy is characterized by the formation
of cytoplasmic AUTOPHAGIC VESCICLES into
which cellular protein and organelles are
sequestered.
 Several cancer therapeutic agents have been
shown to induce autophagy, while targeted
disruption of genes such as ATG5 that are
involved in autopaghy can inhibit cell death.

18.  Normal cells are only capable of undergoing
division a finite number of times before
becoming senescent.
 Cellular sescence is regulated by a biological
clock related to progressive shortening of
repetitive DNA sequence(TTAGGG) called
telomers that cap the end of each
chromosome.

19.  Telomers are thought to be involved in
chromosome stabilization and preventing
recombination during mitosis.
 At birth chromosomes have long telomeric
sequence( 150,000 bases) that become
shorter by 50- 200 bases each time the cell
divides.
 Telomeric shortening is a biological clock
that triggers senescence.

20.  Telomeric activity is detectable in a high
fraction of many cancers, including
ovarian(8,9), cervical(10,11), and
endometrial cancers(12).
 It has been suggested that deletion of
telomerase might be useful for early
diagnosis of cancer, but lack of specificity is
a significant issue.

21.  Human cancers arise because of series of
genetic and epigenetic alterations that leads
to disruption of normal of normal
mechanism that govern cell growth, death
and senescence.
 Genetic damage may be inherited or arise
after birth as a result of either exposure to
exogenous carcinogens or endogenous
mutagenic process within the cell.

22.  Itis thought that at least 3-6 alterations are
required to fully transform the cell.
 Most cancer cells are genetically unstable
and leading to an accumulation of substantial
number of secondary changes that play a role
in evolution of malignant phenotype with
respect to growth, invasion, metastasis and
response to therapy amongst characterstics

23.  Genetic instability also result in evolution of
heterogeneous clones within a tumor.
 There is some evidence that progenitor
cells(stem cell) exist within a tumor that
may be relatively resistant to therapy.

24.  Although most cancers arise sporadically in
the population because of acquired genetic
damage, inherited mutations in cancer
susceptibility genes are responsible for some
cases.
 Families with these mutations exhibit a high
incidence of specific type of cancers
 The age of cancer onset is younger in these
families and it is not unusual for a person to
be affected with multiple primary cancers.

25.  Many of the genes involved in hereditary
cancer syndrome have been identified.
 The most common forms of hereditary
cancers syndrome predispose to breast or
ovarian(BRAC1,BRAC2) and colon or
endometrial(HNPCC genes) cancers.
 Tumor suppressor genes have been
implicated most frequently in hereditary
cancer syndromes, followed by DNA repair
genes.

26.  The familial cancer syndrome described
above result from rare mutation that occur
in 1% of the population.
 In addition low penetranc common genetic
polymorphism may also affect cancer
susceptibility, albeit less dramatically.
 There are more than 10 million polymorphic
genetic loci in human genome.
 Many of these polymorphism are common,
with rarer allele occurring in more than 5% of
individuals.

27.  Althoughgenetic polymorphism would not be
expected to increase the risk sufficiently to
produce familial cancer clustering, they
could account for significant fraction of
cancers currently classified as sporadic
because of there high prevalence

31.  The etiology of acquired genetic damage
seen in cancers also has been elucidated to
some extent.
 For ex. Strong casual link exists between
cigarette smoke and cancers of airodigestive
tract and between ultraviolet radiation and
skin cancers.
 For many common forms of cancers (colon,
breast, endometrium, ovary) a strong
association with specific carcinogens doesn’t
exists.

32.  Several families of highly effective DNA
damage surveillance and repair genes exist,
but some mutations may elude them
 The efficiency of these DNA damage-
response systems varies between individuals
because of genetic and other factors and
may affect susceptibility to cancers.

33.  Epigenetic changes are heritable changes
that do not result from alteration in DNA
sequence.
 Methylation of cytosines residues that reside
next to guanine residues is the primary
mechanism of epigenetic regulation, and this
process is regulated by a family of DNA
methyl transferases.
 Most cancers have globally reduced DNA
methylation, which may contribute to
genomic instability.

34.  Conversely, selective hypermethylation of
cytosines in the promoter regions of tumor
suppressor genes may lead to their inactivation,
and this may contribute to carcinogenesis.
 There is a family of imprinted genes in which
either the maternal or paternal copy is normally
completely silenced because of methylation.
 Loss of imprinting in the genes that stimulate
proliferation, such as insulin-like growth factor
2, may provide an oncogenic stimulus by
increasing proliferation

35.  Acetylation and methylation of the histon
protein that coat DNA represent another
level of epigenetic regulation that is altered
in cancer.

36.  Alteration in genes that stimulate cellular
growth(oncogenes) can cause malignant
transformation.
 Many genes that are involved in normal
growth regulatory pathwayscan elicit
transformation to overactive form when
altered to overactive forms via amplification,
mutation, or translocation.

37.  Peptide growth factors- such as those of
epidermal growth factor, platlet growth
factor, and fibroblast growth factor families
stimulate a cascade of molecular events that
leads to proliferation by binding to cell
membrane receptors.
 Growth factors in the extracellular space can
stimulate a cascade of molecular events that
leads to proliferation by binding to celll
membrane receptors.

38.  There is little evidence to suggest that
overproduction of growth factors is a
precipitating event in development of most
cancers.
 Cell membrane receptors that bind peptide
growth factors are composed of an
extracellular ligand binding domain, a
membrane spanning region, and a
cytoplasmic tyrosine kinase domain.

39.  Binding of growth factor to extracellular
domain results in aggregation and
conformational shifts in receptor and
activation of inner tyrosine kinase.
 This kinase phosphorylate tyrosine residue
both on the growth factor receptor itself
(autophosphorylation) and on molecular
targets in the cell interior , leading to
activation of secondary signals.

40.  Growth of some cancers is driven by
overexpression of receptor tyrosine kinase
receptors.
 Therapeutic strategies that target receptor
tyrosine kinase have been an active area of
investigation.
 Trastuzumab is a monoclonal antibody that
blocks the HER-2/neu receptor, and it is
widely used in the treatment of breast
cancers that overexpress this tyrosine kinase
(20).

41.  Cetuximab is a monoclonal antibody that
targets the epidermal growth factor receptor
(EGFR), whereas gefitinib is a direct inhibitor
of the EGFR tyrosine kinase (21).
 Lapatinib is a dual EGFR/HER-2 kinase
inhibitor. Imatinib antagonizes the activity of
the BCR-ABL, c-kit, and PDGF receptor
tyrosine kinases and has proven effective in
treatment of chronic myelogenous leukemias
and gastrointestinal stromal tumors.

43.  Following the interaction of peptide growth
factors and their receptors, secondary molecular
signals are generated to transmit the growth
stimulus to the nucleus .
 This function is served by a multitude of complex
and overlapping signal transduction pathways
that occur in the inner cell membrane and
cytoplasm.
 Many of these signals involve phosphorylation of
proteins by enzymes known as nonreceptor
kinases (22). These kinases transfer a phosphate
group from ATP to specific amino acid residues of
target proteins.

44.  The kinases that are involved in growth
regulation are of two types: those that are
phosphorylate tyrosine residues on proteins,
including those of the SRC family (23); and
others that are specific for serine or
threonine residues such as AKT (24).
 The activity of kinases is regulated by
phosphatases such as PTEN

45.  Guanosine-triphosphate-binding proteins (G
proteins) represent another class of molecules
involved in transmission of growth signals .
 They are located on the inner aspect of the cell
membrane and have intrinsic GTPase activity
that catalyzes the exchange of
guaninetriphosphate (GTP) for guanine-
diphosphate (GDP).
 In their active GTP-bound form, G proteins
interact with kinases that are involved in
relaying the mitogenic signal, such as those of
the MAP kinase family.

46.  Conversely, hydrolysis of GTP to GDP, which
is stimulated by GTPase-activating proteins
(GAPs), leads to inactivation of G proteins.
 The ras family of G proteins is among the
most frequently mutated oncogenes in
human cancers.
 BRAF mutations occur in many cancers that
lack ras mutations, and most of these
mutations involve codon 599 in the kinase
domain .

47.  Therapeutic approaches to interfering with
ras signaling are being developed, including
farnesyltransferase inhibitors that block
attachment of ras to the inner cell
membrane, antisense oligonucleotides, and
RNA interference.

48.  If proliferation is to occur in response to signals
generated in the cell membrane and cytoplasm,
these events must lead to activation of nuclear
transcription factors and other genetic products
responsible for stimulating DNA replication and
cell division.
 Expression of several genes that encode nuclear
proteins increases dramatically within minutes of
treatment of cells with peptide growth factors.
 Once induced, the products of these genes bind
to specific DNA regulatory elements and induce
transcription of genes involved in DNA synthesis
and cell division.

49.  Examples include the fos and jun oncogenes,
which dimerize to form the activator protein 1
(AP1) transcription complex.
 When inappropriately overexpressed, however,
these transcription factors can act as oncogenes.
 Among the nuclear transcription factors involved
in stimulating proliferation, amplification or
overexpression of members of the myc family
has most often been implicated in the
development of human cancers (27).
 Many of the nuclear regulatory genes such as
myc that control proliferation also affect the
threshold for apoptosis.

50.  Thus, there is overlap in the molecular
pathways that regulate the opposing
processes of proliferation and apoptosis.
 Genes involved in chromatin remodeling also
that have been implicated as oncogenes, but
primarily in hematologic malignancies rather
than solid tumors.
 Finally, as discussed previously, genes
encoding nuclear proteins that inhibit
apoptosis (e.g., bcl-2) can act as oncogenes
when altered to constituitively active forms.

51.  Loss of tumor suppressor gene function also plays
a role in the development of most cancers.
 This usually involves a two-step process in which
both copies of a tumor suppressor gene are
inactivated.
 In most cases, there is mutation of one copy of a
tumor suppressor gene and loss of the other copy
because of deletion of a segment of the
chromosome where the gene resides.
 There is also evidence that some tumor
suppressor genes may be inactivated because of
methylation of the promoter region of the gene .

52.  The promoter is an area proximal to the
coding sequence that regulates whether the
gene is transcribed from DNA into RNA. When
the promoter is methylated, it is resistant to
activation, and the gene is essentially
silenced despite remaining structurally
intact.
 This two-hit paradigm is relevant to both
hereditary cancer syndromes, in which one
mutation is inherited and the second
acquired, and sporadic cancers, in which
both hits are acquired.

53.  The retinoblastoma gene was the first tumor
suppressor gene discovered.
 The Rb gene plays a key role in the
regulation of cell cycle progression.
 Mutations in the Rb gene have been noted
primarily in retinoblastomas and sarcomas.

55.  Beyond simply inhibiting proliferation,
normal p53 is thought to play a role in
preventing cancer by stimulating apoptosis of
cells that have undergone excessive genetic
damage. In this regard, p53 has been
described as the ―guardian of the genome‖.

56.  Although many tumor suppressor genes—
including TP53, Rb, and p16—encode nuclear
proteins, some extranuclear tumor
suppressors have been identified.
 Inactivation of APC leads to malignant
transformation, and inherited mutations in
this gene are responsible for familial
adenomatous polyposis syndrome. The
transforming growth factor-beta (TGF-β)
family of peptide growth factors inhibit
proliferation of normal epithelial cells and
serve as a tumor suppressive pathway.

57.  Prominent intracellular targets include a
class of molecules called Smads that
translocate to the nucleus and act as
transcriptional regulators.
 In addition to primary disregulation of
oncogenes and tumor suppressor genes,
altered expression of microRNAs that
regulate the expression of these genes occurs
in many cancers .
 MicroRNA genes consist of a single RNA strand
of approximately 21 to 23 nucleotides that
does not encode proteins.

58.  Theybind to messenger RNAs that contain
complementary sequences and can block
protein translation.

59.  Metastasis is a process by which cancer cells
spread from the primary tumor to distant
sites .
 It is now appreciated at a molecular level
that metastasis is dependent on a balance
between stimulating factors from both the
tumor and host cells versus inhibitory signals.
 To produce metastasis, the balance must be
weighted toward the stimulatory signals.

60.  Cancer progression is a product of an
evolving crosstalk between different cell
types within the tumor and its surrounding
supporting tissue, the tumor stroma .
 The tumor stroma contains a specific
extracellular matrix as well as cellular
components such as fibroblasts, immune and
inflammatory cells, and blood-vessel cells.
 The interactive signaling between tumor and
stroma contributes to the formation of a
complex multicellular organ..

61.  The organ microenvironment can markedly
change the gene-expression patterns of
cancer cells and therefore their behavior and
growth potential .
 Recent studies regarding chemokines and
their receptors provide important clues
regarding why some cancers metastasize to
specific organs.
 For example, breast cancer cells frequently
express chemokine receptors CXCR4 and
CCR7 at high levels.

62.  The specific ligands for these receptors,
CXCL12 and CCL 21, are found at high levels
in lymph nodes, lung, liver, and bone
marrow, which are common sites for breast
cancer metastasis.

63.  Fig 1.6

64.  Angiogenesis occurs as a result of a shift in
balance toward proangiogenic factors within
the tumor microenvironment along with
down regulation of antiangiogenic influences.
 One of the primary mediators of angiogenesis
is vascular endothelial growth factor A
(VEGF-A), which increases vascular
permeability, stimulates endothelial cell
proliferation and migration, and promotes
endothelial cell survival.

65.  Other mediators of angiogenesis include
tumor-derived factors and host stromal
factors including interleukin-8, alpha v-beta
3 integrin, the tyrosine kinase receptor
EphA2, and matrix metalloproteinases.
 Antiangiogenesis therapies such as
Bevicizumab that target the VEGF pathway
are showing promise in ovarian cancer and
have already entered phase III clinical trials.

66. A critical first step in metastasis, and the
primary feature that defines malignancy, is
invasion through the basement membrane.
 This requires interplay between cancer cells
and a permissive underlying stroma .
 Invasion of malignant cells through the
basement membrane and endothelial cell
migration for angiogenesis require
degradation of the extracellular matrix.

67.  Thisprocess is facilitated by a group of
enzymes called matrix metalloproteinases
(MMPs), which are a family of zinc-
dependent endopeptidases that digest
collagen and other extracellular matrix
components.
 They also stimulate proliferation and induce
release of VEGF. Ovarian tumors overexpress
MMP-2 and MMP-9, and this increased
expression correlates with aggressive clinical
features .

68.  Tumor cell adhesion to the extracellular
matrix within tissues greatly influences the
ability of a malignant cell to invade and
metastasize.
 Given the shedding nature of ovarian cancer,
adhesion molecules such as focal adhesion
kinase, integrins, and E-cadherin have been
evaluated for their role in peritoneal
metastasis.

69.  Cadherins are another group of cell-cell
adhesion molecules that are involved in
development and maintenance of solid
tissues.
 E-cadherin is uniformly expressed in ovarian
cancer, in low-malignant-potential tumors, in
benign neoplasms, and—notably—in inclusion
cysts of normal ovaries, but not in the
normal surface epithelium.

70.  The cytoplasmic tails of cadherins exist as a
macromolecular complex with β-catenin, which
is involved in the wnt signaling pathways that
regulate both adhesion and growth.
 Regulation of β-catenin activity also depends on
the APC gene product and others in the wnt
pathway.
 Mutations in the APC gene that abrogate its
ability to inhibit β-catenin activity are common
in both the hereditary adenomatous polyposis
coli syndrome and sporadic colon cancers.
 Likewise, mutations in the β-catenin gene that
result in

72.  Within the tumor microenvironment, other
cell types also play a critical role in tumor
growth and progression.
 For example, recent studies indicate that
certain types of inflammatory cells, including
macrophages and mast cells, and their
associated cytokines confer an unfavorable
prognosis and increased tumor growth.
 Conversely, the presence of an adaptive
immune response characterized by cytotoxic
T cells is associated with improved clinical
outcome.

73.  In addition, cancer cells may evade immune
recognition and destruction by various
means, such as Fas ligand production to
induce lymphocytice apoptosis and HLA-G
secretion to inhibit natural-killer cell
activity.
 Moreover, cytokine production by cancer
cells promotes growth and inhibits apoptosis.

74.  Themechanistic relationships between the
microenvironment and tumor growth remain
only partially understood, but
immunomodulating strategies that target the
cancer-promoting properties of both innate
and adaptive immune cell populations are
being developed.

75.  Cancer is leading causes of death worldwide.
 It accounts for 7.4 million deaths e.g. 13% of
all deaths worldwide in 2004.
The Common types of Cancer in general
population are-
 Lung - 1.3 million deaths per year
 Stomach - 803000 deaths per year
 Colorectal- 639000 deaths per year
 Liver - 610000 deaths per year
 Breast - 519000 deaths per year
 Female Genital Tract - 467000 deaths per
year
(Source – WHO-2008 Burden of disease 2004 update)

76.  Cancer
 Cerebro vascular diseases
 Motor vehicle Accidents
 Chronic Obstructive lung diseases
 Diabetes
 Pneumonia and influenza

77.  Breast – 20.27 per lac population
 Female Genital Cancer – 22.42 per lac
population
 Colorectal – 6.74 lac population
 Lungs – 6.62 per lac population
 Liver – 4.55 per lac population
(ICMR 2004 – Assessment of burden of non communicable diseases)

78.  Lungs and Bronchus – 25%
 Breast Cancer – 16%
 Colorectal Cancer – 11%
 Ovarian Cancer – 5%
 Cancer Cervix - 4%

79. • Lungs and Bronchus – 6.45 per lac Population
• Breast Cancer – 5.52 per lac population
• Colorectal Cancer – 6.83 per lac population
• Female Genital Tract – 4.94 per lac population
• Liver – 13.49 per lac population
 (ICMR – 2004)

80.  Cancer Cervix – 75-80%
 Cancer Endometrium –
15-20%
 Cancer Ovary – 5%
 Vulval Cancers – 3.5%
 Chorio-carcinoma -
1:20000- 14000
Pregnancy

81.  Gynecologic cancers vary with respect to
grade, histology, stage, response to
treatment, and survival.
 It is now appreciated that this clinical
heterogeneity is attributable to differences
in underlying molecular pathogenesis.
 Some cancers arise in a setting of inherited
mutations in cancer susceptibility genes, but
most occur sporadically in the absence of a
strong hereditary predisposition.

82.  The spectrum of genes that are mutated
varies between cancer types.
 There also is significant variety with respect
to the spectrum of genetic changes within a
given type of cancer
 The molecular profile may prove valuable in
predicting clinical behavior and response to
treatment.

83.  Epidemiologic and clinical studies of endometrial
cancer have suggested that there are two
distinct types of endometrial cancer .
 Type I cases are associated with unopposed
estrogen stimulation and often develop in a
background of endometrial hyperplasia.
 Obesity is the most common cause of unopposed
estrogen and is part of a metabolic syndrome
that also includes insulin resistance and
overexpression of insulin-like growth factors that
may also play a role in carcinogenesis.. r

84.  Type I cancers are well differentiated,
endometrioid, early stage lesions and have a
favorable outcome.
 In contrast, type II cancers are poorly
differentiated or nonendometrioid (or both) and
are more virulent. They often present at an
advanced stage, and survival is relatively poor.
 A small minority of endometrial cancers occur in
women with a strong hereditary predisposition
because of germ-line mutations in DNA repair
genes in the context of HNPCC syndrome

85. A higher rate of proliferation in response to
estrogens may lead to an increased
frequency of spontaneous mutations.
 Progestins oppose the action of estrogens by
both down regulating estrogen receptor
levels and decreasing proliferation and
increasing apoptosis.

86.  Approximately 3% to 5% of endometrial
cancers arise because of inherited mutations
in DNA repair genes in the context of
hereditary nonpolyposis colon cancer
(HNPCC) syndrome.
 HNPCC typically manifests as familial
clustering of early onset colon cancer.

87.  The identification of the DNA mismatch
repair genes responsible for HNPCC has
facilitated the development of genetic
testing .
 Most HNPCC cases result from alterations in
MSH2 and MLH1.
 MSH6 mutations also are associated with an
increased incidence of endometrial cancer .
 PMS1 and PMS2 have been implicated in a
small number of these cancers as well.

88.  Loss of mismatch repair leads to a ―mutator
phenotype‖ in which genetic mutations
accumulate throughout the genome,
particularly in repetitive DNA sequences
called microsatellites.
 Examples of microsatellite sequences
include mono-, di-, and trinucleotide repeats
(AAAA, CACACACA, and CAGCAGCAGCAG).
The propensity to accumulate mutations in
microsatellite sequences is referred to as
microsatellite instability (MSI).

89.  Analysis of cancers for microsatellite instability
has been proposed as a genetic screening test
for HNPCC.
 Among families with germ-line mutations in
mismatch repair genes, MSI is seen in greater
than 90% of colon cancers and approximately 75%
of endometrial cancers .
 Another screening approach for HNPCC is
immunohistochemical staining of tumors to
determine where there has been a loss of MSH2
or MLH1 protein .
 Currently, mutational analysis of the responsible
genes remains the gold standard for diagnosis of
HNPCC.

90.  Endometrial cancer is the most common
extracolonic malignancy is women with
HNPCC. The risk of a woman developing
endometrial cancer has ranged from 20% to
60%.
 The most striking clinical feature of HNPCC-
related cancers is early onset, typically at
least ten years earlier than sporadic cases.
 Transvaginal ultrasound has been proposed as
a screening test for endometrial and ovarian
cancer, but it appears to be relatively
ineffective .

91.  There is no evidence that CA125 or other blood
markers facilitate early detection of endometrial
cancer, but CA125 can be justified as a means of
screening for HNPCC-associated ovarian cancer.
 Endometrial biopsy may be the only screening
test with sufficient sensitivity.
 prophylactic hysterectomy demonstrated that
there were no cases of endometrial cancer in 61
HNPCC carriers who underwent prophylactic
hysterectomy, whereas endometrial cancer
developed in 69 of 210 (33%) who did not
undergo surgery.

92.  Some women in HNPCC families elect to
undergo prophylactic colectomy.
 In view of the increased risk of ovarian
cancer in HNPCC syndrome, concomitant
prophylactic salpingo-oophorectomy should
be strongly considered.
 Postmenopausal estrogen-replacement
therapy in the general population
substantially decreases colon cancer risk.

94.  Approximately 80% of endometrial cancers have
a normal diploid DNA content as measured by
ploidy analysis.
 Aneuploidy occurs in 20% and is associated with
advanced stage, poor grade, nonendometrioid
histology and poor survival (87). The frequency
of aneuploidy (20%) is relatively low in
endometrial cancers relative to ovarian cancers
(80%).
 Finally, patterns of genetic expression have been
described using microarrays that distinguish
between normal and malignant endometrium and
between various histologic types of cancer.

95.  Inactivation of the TP53 tumor suppressor
gene is among the most frequent genetic
events in endometrial cancers .
 Overexpression of mutant p53 protein occurs
in approximately 20% of endometrial
adenocarcinomas and is associated with
several known prognostic factors, including
advanced stage, poor grade, and
nonendometrioid histology .
 Overexpression occurs in some 10% of stages
I and II and 40% of stages III and IV cancers.

96.  Numerous studies have confirmed the strong
association between p53 overexpression and
poor prognostic factors and decreased
survival.
 In some of these studies, p53 overexpression
has been associated with worse survival even
after controlling for stage.
 This suggests that loss of p53 tumor
suppressor function confers a particularly
virulent phenotype

97.  Mutations in the PTEN tumor suppressor gene
occur in approximately 30% to 50% of
endometrial cancers , and this represents the
most frequent genetic alteration described thus
far in these cancers.
 Deletion of the second copy of the gene is also a
frequent event, which results in complete loss of
PTEN function.
 Most of these mutations are deletions,
insertions, and nonsense mutations that lead to
truncated protein products, whereas only about
15% are missense mutations that change a single
amino acid in the critical phosphatase domain.

98.  The PTEN gene encodes a phosphatase that
opposes the activity of cellular kinases.
 For example, it has been shown that loss of
PTEN in endometrial cancers is associated
with increased activity of the PI3 kinase with
resultant phosphorylation of its downstream
substrate Akt.
 Mutations in the PTEN gene are associated
with endometrioid histology, early stage and
favorable clinical behavior .
 Well differentiated, noninvasive cases have
the highest frequency of mutations.

99.  Inaddition, PTEN mutations have been
observed in 20% of endometrial hyperplasias,
suggesting that this is an early event in the
development of some endometrioid type I
endometrial cancers.
 Synchronous endometrioid cancers are
sometimes encountered in the endometrium
and ovary that are indistinguishable
microscopically.
 Endometrial cancer is the second most
common malignancy observed in women with
HNPCC.

100.  Cancers that arise in these women with HNPCC
syndrome are characterized by mutations in
multiple microsatellite repeat sequences
throughout the genome.
 This microsatellite instability also has been seen
in approximately 20% of sporadic endometrial
cancers .
 Endometrial cancers that exhibit microsatellite
instability tend to be type I cancers.
 Loss of mismatch repair in these cases usually
results from silencing of the MLH1 gene by
promoter methylation .

101.  Methylation of the MLH1 promoter also has been
noted in endometrial hyperplasias and normal
endometrium adjacent to cancers, suggesting
that this is an early event in the development of
some of these cancers .
 Several other tumor suppressor genes may play a
role in the development of some endometrial
cancers.
 The Par-4 gene is a proapoptotic factor, and loss
of expression of this gene occurs in some human
cancers.
 Reduced expression occurs in approximately 40%
of endometrial cancers and may be attributable
to methylation of the promoter region of the
gene.

102.  The Cables gene is a putative tumor suppressor
involved in regulating phosphorylation of cyclin-
dependent kinase 2 in a manner that restrains
cell cycle progression.
 Cables mutant mice develop endometrial
hyperplasia at an early age, and exposure to low
levels of estrogen causes endometrial cancer.
 Cables expression is up regulated by estrogen
and decreases following progestin treatment.
 Loss of Cables expression also occurs in human
endometrial hyperplasias and cancers.

103.  Finally, mutations in the CDC4 gene, which
is involved in regulating cyclin E expression
during cell cycle progression, have been
noted in 16% of endometrial cancers.

104.  Alterations in oncogenes have been
demonstrated in endometrial cancers, but these
occur less frequently than inactivation of tumor
suppressor genes .
 Increased expression of the HER-2/neu receptor
tyrosine kinase initially was noted in only 10% of
endometrial cancers and was associated with
advanced stage and poor outcome.
 Recently, it has been suggested that HER-2/neu
overexpression may be more prevalent in
patients with papillary serous endometrial
cancers.

105.  These data also suggest that therapies that
target HER-2/neu may have a role in the
treatment of papillary serous endometrial
carcinomas.
 The fms oncogene encodes a tyrosine kinase
that serves as a receptor for macrophage-
colony stimulating factor (M-CSF).
 Expression of fms in endometrial cancers
was found to correlate with advanced stage,
poor grade, and deep myometrial invasion.

106.  The ras oncogenes undergo point mutations in
codons 12, 13, or 61 that result in constitutively
activated molecules in many types of cancers.
 K-ras mutations also have been identified in
some endometrial hyperplasias, which suggests
that this may be a relatively early event in the
development of some type I cancers.
 The PTEN tumor suppressor gene, which
normally acts to restrain PI3K activity, is
frequently inactivated in type I endometrial
cancers. Conversely, the PIK3CA gene is
oncogenically activated in some cases.

107.  Studies confirm that PIK3CA activating
mutations are common in endometrial
cancers.
 Both inactivation of PTEN or unrestrained
PIK3CA can lead to activation of AKT, which
in turn leads to up regulation of the
mammalian target of rapamycin (mTOR).
 Recent studies have suggested that mTOR
inhibitors may have a role in the in the
management of progesterone refractory
hyperplasia and treatment of type I
endometrial cancer.

108.  Alterations in the wnt pathway involving E-
cadherin, APC, and β-catenin, the product of
the CTNNB1 gene, have been noted in some
endometrial cancers.
 E-cadherin is a transmembrane glycoprotein
involved in cell-cell adhesion, and decreased
expression in cancer cells is associated with
increased invasiveness and metastatic
potential.
 APC mutations have not been described in
endometrial cancers
 β-catenin gene is considered an oncogene.

109.  β-catenin mutations have been observed in
several types of cancers, including
hepatocellular, prostate, and endometrial
cancers.
 Mutation of β-catenin occurs in
approximately 10% to 15% of endometrial
cancers.
 Mutations have also been observed in the
fibroblast growth factor receptor 2 (FGFR2)
gene in approximately 10% of endometrial
cancers.

110.  Several
studies have suggested that myc may
be amplified in a fraction of endometrial
cancers.

111.  Approximately 10% of ovarian cancers arise in women
who carry germ-line mutations in cancer
susceptibility genes—predominantly BRCA1 or BRCA2.
 Reproductive events that decrease lifetime ovulatory
cycles (e.g., pregnancy and birth control pills) are
protective against ovarian cancer .
 Five years of oral contraceptive use provides a 50%
risk reduction while only decreasing total years of
ovulation by less than 20%.
 Epithelial ovarian cancers are heterogeneous with
respect to behavior (borderline versus invasive) and
histologic type (serous, mucinous, endometrioid,
clear cell).
 Many endometrioid and clear cell cancers likely
develop in deposits of endometriosis.

112.  Low-grade tumors are generally confined to the
ovary at diagnosis and include low-grade serous
carcinoma, mucinous, endometrioid, and clear
cell carcinomas.
 They are genetically stable and characterized by
mutations in a number of genes including K-ras,
BRAF, PTEN, and β-catenin.
 High-grade cancers typically present at an
advanced stage and are predominantly serous
but also include carcinosarcoma and
undifferentiated cancers.
 This group of tumors has a high level of genetic
instability and is characterized by mutation of
TP53.

114.  It
had long been suspected based on
epidemiologic and family studies that
approximately 10% of epithelial ovarian
cancers are attributable to inheritance of
mutations in high-penetrance cancer
susceptibility genes.
 The BRCA1 gene was identified on
chromosome 17q in 1994, and BRCA2 was
identified on chromosome 13q in 1995.
Inherited mutations in these two breast and
ovarian cancer susceptibility genes are
responsible for approximately 6% and 3% of
ovarian cancers, respectively.

115.  BRCA mutations were found in 28% and 17% of
women with fallopian tube cancer. Likewise,
germ-line BRCA mutations have been reported in
some studies in approximately onethird of those
with primary peritoneal cancer.
 In some studies, survival of BRCA carriers with
ovarian cancer was better than that of sporadic.
 BRCA1 and BRCA2 mutations are associated with
60% to 90% lifetime risks of breast cancer, and
this begins to manifest before age 30. BRCA2
also increases the risk of breast cancer in men.

116.  The lifetime risk of ovarian cancer ranges from
20% to 40% in BRCA1 carriers and 10% to 20% in
BRCA2 carriers, but this increased risk is not
manifest until the late 30s.
 The median age of sporadic epithelial ovarian
cancer is in the early to mid-60s, compared to
the mid-40s and early 50s for BRCA1- and BRCA2-
associated cases.
 The most common founder mutations described
thus far are the BRCA1 185delAG and BRCA2
6174delT mutations that occur in approximately
1.0% and 1.4% of Ashkenazi Jews, respectively

117.  the most reliable method of detecting mutations
is complete gene sequencing.
 Testing generally has been advocated when the
family history suggests at least a 5% probability
of finding a mutation.
 In practical terms, this translates into two first-
or second-degree relatives with either ovarian
cancer at any age or breast cancer before age
50.
 When a specific mutation is identified in an
affected individual, others in the family can be
tested much more rapidly and inexpensively for
that specific mutation.

118.  Failure to identify a BRCA1 or BRCA2 mutation in a
family may be reassuring, but it must be tempered by
the realization that BRCA mutational analysis may
miss some mutations and that other undiscovered
hereditary ovarian cancer genes may exist.
 Because BRCA testing is now widely accepted and
insurance companies generally cover the costs,
results should be acknowledged in the medical
record.
 The value of screening for early stage ovarian cancer
with CA125 or ultrasound is unproven but seems
reasonable until controlled studies are available.
 Use of birth control pills as a chemopreventive also
has been advocated .

119.  Because ovarian cancer has a 70% mortality
rate, prophylactic bilateral
salpinoophorectomy (BSO) should be
discussed with all women who carry germ-
line BRCA1 or BRCA2 mutations.
 The therapeutic benefit of BSO in women
with breast cancer has long been
appreciated, and more recent studies
support the contention that this intervention
significantly reduces breast cancer risk in
BRCA carriers.

120.  Many patients elect to have the uterus removed
as part of the surgical procedure because they
have completed their family.
 Furthermore, the likelihood of future exposure
to tamoxifen, which increases endometrial
cancer risk two- to threefold, in the context of
breast cancer prevention or treatment, also
argues for concomitant hysterectomy.
 The more problematic issue in performing
prophylactic BSO is whether the risk of
malignant transformation is increased solely in
the ovaries and fallopian tubes or in the entire
field of mullerian-derived epithelia.

121.  Peritoneal papillary serous carcinoma that is
indistinguishable histologically or
macroscopically from ovarian cancer has been
described in rare instances following
prophylactic salpingo-oophorectomy.
 Careful examination of prophylactic salpingo-
oophorectomy specimens has led to the
identification of occult cancers in as many as
12% of women in some series.
 there is some evidence to suggest that the tubal
fimbria rather than the ovarian epithelium may
be the preferred site of cancer development in
BRCA1 and BRCA2 mutation carriers.

122.  Among 259 women who had undergone
prophylactic oophorectomy, 2.3% were found
to have stage I ovarian cancer at the time of
the procedure, and two women subsequently
developed papillary serous peritoneal
carcinoma.
 an international registry study of more than
1,800 subjects with median follow-up of 3.5
years found that prophylactic BSO reduced
ovarian, tubal, and peritoneal cancer risk by
only 80%, partly because of an estimated 6%
residual lifetime risk of primary peritoneal
cancer.

124.  Invasive epithelial ovarian carcinoma
generally is a monoclonal disease that
develops as a clonal expansion of a single
transformed cell in the ovary.
 advanced stage, poorly differentiated
cancers have a higher number of genetic
changes than early stage, low-grade cases.
 microarrays have demonstrated patterns of
gene expression that distinguish between
histologic types, borderline and invasive
cases and between early and advanced stage
disease .

125.  Alteration of the TP53 tumor suppressor gene
is the most frequent genetic event described
thus far in ovarian cancers.
 approximately two-thirds of early stage
serous ovarian cancers were found to have
TP53 mutations compared to only 21% of
nonserous cases.
 Overall, some 70% of advanced ovarian
cancers have either missense or truncation
mutations in the TP53 gene.

126.  Ithas been suggested that loss of functional
p53 might confer a chemoresistant
phenotype because of its role in
chemotherapy-induced apoptosis.
 TP53 mutational status was not concordant
between the original borderline tumor and
the subsequent invasive cancer.
 The cyclin-dependent kinase (cdk) inhibitors
act as tumor suppressors.

127.  In approximately 15% of ovarian cancers, p16
undergoes homozygous deletions .
 There is evidence to suggest that p16 , CDKN2B
(p15) , and some other tumor suppressor genes
such as BRCA1 may be inactivated via
transcriptional silencing because of promoter
methylation rather than mutation or deletion.
 Likewise, decreased expression of the p21 cdk
inhibitor has been noted in a significant fraction
of ovarian cancers despite the absence of
inactivating mutations .

128.  Loss of CDKN1B (p27) also may occur and
correlates with poor survival in some studies.
 It has been suggested that abberant
expression of p27 in the cytoplasm may be
most associated with poor outcome .
 Normal ovarian epithelial cells are inhibited
by the growth inhibitory peptide TGF-β.
 Thus far, it has not been convincingly
demonstrated that derangement of the TGF-
β pathway plays a role in the development of
ovarian cancers.

129.  Ovarian cancers produce and are capable of
responding to various peptide growth factors.
 For example, epidermal growth factor and
transforming growth factoralpha (TGF-α) are
produced by some ovarian cancers that also
express the receptor that binds these peptides
(EGF receptor) .
 Some cancers produce insulin-like growth factor-
1 (IGF-1), IGF-1 binding protein, and express
type 1 IGF receptor.
 Plateletderived growth factor also is expressed
by many types of epithelial cells, including
human ovarian cancer cell lines, but these cells
usually are not responsive to PDGF .

130.  In addition, ovarian cancers produce basic
fibroblast growth factor and its receptor, and
basic FGF acts as a mitogen in some ovarian
cancers .
 Ovarian cancers produce macrophagecolony
stimulating factor, and serum levels of M-CSF are
elevated in some patients . Because the M-CSF
receptor (fms) is expressed by many ovarian
cancers.
 it is possible that growth factors may primarily
act as ―necessary but not sufficient‖ cofactors
that support growth and metastasis following
malignant transformation.

131.  The HER-2/neu tyrosine kinase is a member
of a family of related transmembrane
receptors that includes the EGF receptor.
 Expression of HER-2/neu is increased in a
fraction of ovarian cancers and
overexpression has been associated with poor
survival in some studies , but not all.
 only 11% of ovarian cancers exhibit
significant HER-2/neu overexpression .
 The response rate to single-agent
trastuzumab therapy was disappointingly low
(7%).

132.  In contrast, K-ras mutations are common in
borderline serous ovarian tumors, occurring in
approximately 25% to 50% of cases.
 In addition, mutations in BRAF occur in some 20%
of serous borderline cases lacking K-ras
mutations .
 Mutations in K-ras and BRAF have also been
noted in cystadenoma epithelium adjacent to
serous borderline tumors, suggesting that this is
an early event in their development .
 K-ras mutations have been noted in
approximately 50% of mucinous ovarian cancers,
but BRAF mutations have not been found .

133.  Similar to endometrial cancers, activation of the
PIK3CA and AKT2 oncogenes occurs in some
ovarian cancers.
 The region of chromosome 3p26 that includes
the phosphatidylinositol 3-kinase (PIK3CA) is
amplified in some ovarian cancers .
 In addition, activating mutations in PIK3CA
occur in about 10% of ovarian cancers, and are
much more common in endometrioid and clear
cell cancers (20%) as compared to serous cancers
(2%).
 PTEN phosphatase, and this tumor suppressor
gene also is inactivated in about 20% of
endometrioid ovarian cancers.

134.  Mutations in the β-catenin gene are a feature
of some endometrial cancers. Similarly, β-
catenin mutations are present in some 30% of
endometrioid ovarian cancers.
 cyclin E overexpression has been was shown
to be associated with serous and clear cell
histology, advanced stage, and poor
outcome.

135.  One of the most preventable and curable
malignancies
 More than 75% cases belong to developing
countries.
 Incidence falling by about 7% per annum in
developed countries due to operational
screening programs
 Cancer cervix is twice common among Africo-
Americans as compared to white Americans
probably due to high prevalence of HPV, STD, HIV
infections, drug abuses and Smoking.

136.  Young women (<35 yrs.) have lower
survival rate then older women within the
same ca cx – staging.
 Ca cx in situ or early stage I-A is detected
more frequently in develop country as
compare to under developed (II, III stage)
 5% cases of ca cx report in stage IV in
India while majority >80% in stage II & III.

137.  Cervical cancer is a slow developing cancer that starts in the
interior lining of the cervix. Almost all cases begin with
changes caused by the human papillomavirus (HPV), a
sexually transmitted infection.
 Over time the changes caused by HPV build up and a pre-
cancerous condition called cervical intraepithelial neoplasia
(CIN) develops.
 CIN can progress to cervical cancer, but this is not always the
case.

138.  Abnormal Vaginal bleeding
 Menstrual bleeding is longer and heavier than
usual
 Bleeding after menopause or increased
vaginal discharge
 Bleeding following intercourse or pelvic exam
 Pain during intercourse
Source: American Cancer Society

139.  About 80% of Women will be infected
with
HPV in their lifetime

140. ABOUT 9-25 PER 100,000 WOMEN IN INDIA
WILL DEVELOPE CERVICAL CANCER.

141. HPV
20%
LSIL
HSIL
33%
CANCER

142.  Procedure by which cancer can be detected
in precancerous/ early stage to make the
treatment effective.
 According to WHO cervical cancer is the only
preventable cancer of female genital tract as
the precancerous changes of cervix can be
diagnosed way before the development of
cancer by the screening methods.

143.  Littleunderstanding of cervical cancer
 Limited understanding of female
reproductive organs and associated
diseases
 Lack of access to services
 Shame and fear of a vaginal exam
 Fear of death from cancer
 Lack of trust in health care system
 Lack of community and family support
 Concept of ―preventive care‖ is foreign

144.  Visualinspection of cervix
 Pap smear
 Conventional
 Liquid based cytology
 Viraltyping for high risk HPV subtypes
 Combination of Pap smear and HPV
 Colposcopy

145.  Cancer is leading cause of death worldwide :
it accounted for 7.4 million deaths all
deaths) in 2004.
 The most frequent types of cancer differ
between men and women
 More than 30% of cancer deaths can be
prevented
 HPV is the single most important risk factor
in causation of ca cx.
 Cancer arises from a change in one single
cell. The change may be started by ext and
inherited genetic factors.
 Ca cx is detectable in Pre Cancerous stage by
screening methods.
 Ca cx cost effectively preventable cancer

146.  Cervical cancer is the most common gynecologic
malignancy worldwide and accounts for more
than 400,000 cases annually.
 Molecular and epidemiologic studies have
demonstrated that sexually transmitted human
papilloma virus (HPV) infections play a role in
almost all cervical dysplasias and cancers .
 Although HPV plays a major role in the
development of most cervical cancers, only a
small minority of women who are infected
develop invasive cervical cancer.

147.  Thissuggests that other genetic or
environmental factors also are involved in
cervical carcinogenesis.
 For example, individuals who are
immunosuppressed because of either HIV
infection or immunosuppressive drugs are
more likely to develop dysplasia and invasive
cervical cancer following HPV infection.

148.  There are more than 100 HPV subtypes, but not all infect
the lower genital tract.
 HPV 16 and 18 are the most common types associated
with cervical cancer and are found in more than 80% of
cases.
 Types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82
should be considered high-risk types, and types 26, 53, and
66 should be considered probably carcinogenic.
 Low-risk types that may cause dysplasias or condyloma in
the lower genital tract, but rarely cause cancers, include
types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81.
 The advent of HPV typing now allows assessment of
whether patients carry high-risk or low-risk HPV types, and
this has proven clinically useful in the management of
patients with low-grade Pap smear abnormalities.

149.  The HPV DNA sequence consists of 7,800
nucleotides divided into ―early‖ and ―late‖ open
reading frames (ORFs).
 Early ORFs are within the first 4,200 nucleotides
of the genome and encode proteins (E1-E8) that
are important in viral replication and cellular
transformation.
 Late ORFs (L1 and L2) are found within the latter
half of the sequence and encode structural
proteins of the virion.
 In oncogenic subtypes such as HPV 16 and 18,
transformation may be accompanied by
integration of episomal HPV DNA into the host
genome.

150.  Opening of the episomal viral genome usually
occurs in the E1-E2 region, resulting in a linear
fragment for insertion.
 The location of the opening may be significant
because E2 acts as a repressor of the E6-E7
promoter, and disruption of E2 can lead to
unregulated expression of the E6/E7
transforming genes.
 HPV 16 DNA may be found in its episomal form
in some cervical cancers, however, and
unregulated E6-E7 transcription may occur
independently of viral DNA integration into the
cellular genome.

151.  The E6 and E7 oncoproteins are the main
transforming genes of oncogenic strains of HPV.
 Transfection of these genes in vitro results in
immortalization and transformation of some cell
lines.
 The HPV E7 protein acts primarily by binding to
and inactivating the Rb tumor suppressor gene
product.
 E7 contains two domains, one of which mediates
binding to Rb while the other serves as a
substrate for casein kinase II (CKII)
phosphorylation.

152.  Variations in oncogenic potential between HPV
subtypes may be related to differences in the
binding efficacy of E7 to Rb.
 High-risk HPV types contain E7 oncoproteins that
bind Rb with more affinity than E7 from low-risk
types.
 The transforming activity of E7 may be increased
by CKII mutation, implying a role for this binding
site in the development of HPV-mediated
neoplasias.
 The E6 proteins of oncogenic HPV subtypes bind
to and inactivate the TP53 tumor suppressor
gene product .

153.  HPV-negative cervical cancers are uncommon
but have been reported to exhibit
overexpression of mutant p53 protein.
 This suggests that inactivation of the p53
tumor suppressor gene either by HPV E6 or
by mutation is a requisite event in cervical
carcinogenesis.
 In some studies, the levels of E6 and E7 in
invasive cervical cancers have been found to
predict outcome, whereas HPV viral load
does not .

155.  Comparative genomic hybridization techniques
have been used to identify chromosomal loci
that are either increased or decreased in copy
number in cervical cancers.
 A strikingly consistent finding of various studies
is the high frequency of gains on chromosome 3q
in both squamous cell cancers and
adenocarcinomas .
 Other chromosomes that exhibit frequent gains
include 1q and 11q.
 The most common areas of chromosomal loss
include chromosomes 3p and 2q

156.  For the most part, with the exception of the fragile
histidine triad (FHIT) gene on chromosome 3p, it has
not been proven that these genomic gains and losses
result in the recruitment of specific oncogenes and
tumor suppressor genes in the process of malignant
transformation.
 It is conceivable that these chromosomal alterations
may be frequent sequelae of infection with oncogenic
HPVs while playing no significant role in the
pathogenesis of cervical cancers.
 Abnormalities seen in invasive cancers using
comparative genomic hybridization also have been
identified in high-grade dysplasias, however,
suggesting that these are early events in cervical
carcinogenesis .

157.  Only a small fraction of HPV-infected women
develop cervical cancer. This suggests that
additional genetic alterations are requisite
for progression to high-grade dysplasia and
cancer.
 the cyclindependent kinase inhibitor p16 is
up regulated in almost all cervical dysplasias
and cancers.
 Mutant ras genes are capable of cooperating
with HPV in transforming cells in vitro.

158.  Alterations in ras genes have not been seen
in cervical intraepithelial neoplasia,
suggesting that mutation of ras is a late
event in the pathogenesis of some cervical
cancers.
 In contrast, c-myc amplification and
overexpression may be an early event in the
development of some cervical cancers.
 The fragile histidine triad gene localized
within human chromosomal band 3p14.2 is
frequently deleted in many different
cancers, including cervical cancer.

159.  it is thought that gene silencing resulting from
promoter hypermethylation also may play a role
in cervical carcinogenesis.
 Hypermethylation of genes associated with
programmed cell death (apoptosis) or tumor
suppressor genes have also been described in
association with cervical cancer.
 Likewise, hypermethylation of HPV DNA that has
been integrated into the host genome may also
play a role in suppressing the transformation
associated with viral oncogenes until other
molecular alterations overcome this method of
epigenetic silencing .

160.  The most prominent feature of these tumors
is an imbalance of parental chromosomes. In
the case of partial moles, this involves an
extra haploid copy of one set of paternal
chromosomes, while complete moles
generally are characterized by two complete
haploid sets of paternal chromosomes and an
absence of maternal chromosomes.
 Thus far, there is no convincing evidence that
damage to specific tumor suppressor genes
or oncogenes contributes to the development
of gestational trophoblastic disease.