3. Cancer is a disease of the cell cycle
Do you agree
4. What Is the Connection Among Cancer,
the Cell Cycle, and Genetics?
Cells either grow and divide with control ...or
not!
All kinds of malignant growth that the term
"cancer" represents, all have one lethal
attribute in common:
The cells of the malignancy go through the
cell cycle without control.
These cells disobey control mechanisms that lie
with them.
5. What Is the Connection Among
Cancer, the Cell Cycle, and Genetics?
Many protein molecules involved in the cell
cycle, each is the product of a single gene.
When there is a mutation in one of these genes,
it can:
increase the likelihood that a cell will become
cancerous and eventually, through repeated,
unrestrained division, overtake the normal
cells, become malignant;
possibly spread, or metastasise throughout
the body
6. What Is the Connection Among
Cancer, the Cell Cycle, and Genetics?
Cancer can develop at almost any stage in life.
Some forms of cancer develop very early, such as
retinoblastoma (a cancer of the eye)
Others tend to develop in childhood, such as
various forms of leukaemia, a cancer of the blood
There are many forms that develop during
adulthood.
In each case, cancer is the result of a mutated gene,
or a series of mutated genes, that lead to unregulated
cell growth and haphazard controls over cell
proliferation.
7. MALIGNANT NEOPLASM
(CANCER)
• Is multifactorial disease (genetic, environmental)
– Types of genes which may mutate to cause
cancer: (tumour suppressor genes,
oncogenes, DNA repair genes, telomerase,
p53)
– Environmental agents associated with cancer
such as viruses, tobacco smoke, food,
radiation, chemicals, pollution
8. • Cancer is considered as a genetic disease;
occurs sporadically (somatic mutations), or as a
hereditary trait.
• Genes in which mutations cause cancer fall into
two distinct categories:
– Oncogenes
– Tumor suppressor genes (TSGs) fall into two
types Gatekeepers and Caretakers
GENETIC BASIS OF CANCER
9. • Oncogene is a mutant allele of a proto-oncogene,
whose altered function or expression results in
abnormal stimulation of cell division and
proliferation.
– Proto-oncogene is normal gene that has
physiologic function via its protein that regulate
cell growth (proliferation & apoptosis) and
differentiation
ONCOGENES
10. ONCOGENES
• Oncogenes facilitate malignant transformation
by stimulating proliferation or inhibiting
apoptosis.
• Oncogenes have a dominant effect at the
cellular level
– when it is activated or overexpressed, a single
mutant allele is sufficient to initiate the change
in phenotype of a cell from normal to
malignant.
11. ONCOGENES
• The mutation can be an activating gain-of-
function mutation in the coding sequence of the
oncogene itself, a mutation in its regulatory
elements, or an increase in its genomic copy
number, leading to unregulated ectopic function
of the oncogene product.
12. ONCOGENES
• Activated oncogenes encode proteins such as:
– proteins in signaling transduction pathways
for cell proliferation (K-Ras, H-Ras, N-Ras)
– receptors and cytoplasmic proteins that
transduce signals
– transcription factors that respond to the
transduced signals and control the
expression of growth-promoting genes (myc)
– inhibitors of programmed cell death
machinery
15. Proto-oncogene activation
• Point mutation: Ras oncogene point mutation
results in decreased GTPase activity.
– GTPase: enzyme that hydrolyze guanosine
triphosphate.
• Chromosomal rearrangement: (translocation and
inversion) Philadelphia chromosomes, Burkitt’s
lymphoma gene arrangement
• Gene amplification
16. • Fig 16-3. Mechanisms
of tumorigenesis by
oncogenes of various
classes. Unregulated
growth factor signaling
may be due to
mutations in genes
encoding growth factors
themselves (1), their
receptors (2), or
intracellular signaling
pathways (3).
Downstream targets of
growth factors include
transcription factors (4),
whose expression may
become unregulated.
Both telomerase (5)
and antiapoptotic
proteins that act at the
mitochondria (6) may
interfere with cell death
and lead to
tumorigenesis.
17. • TSGs are normal genes and their normal function is to
regulate cell division, so can suppress the development of
cancer
– TSGs encode a proteins which are part of the system that
regulates cell division (keeping cell division in check).
• When mutated, TSGs lose their function, and as a
result uncontrolled cell growth may occur
– This may contribute to the development of a cancer
• Both alleles need to be mutated or removed in order to
lose the gene activity.
– The first mutation may be inherited or somatic.
– The second mutation will often be a gross event
leading to loss of heterozygosity
TUMOR SUPPRESSOR GENES
(TSGS)
18. Knudsen’s “two hit” hypothesis
explain why certain tumors can occur in both hereditary and
sporadic forms
19. The Two-Hit Origin of Cancer
• For example, it was suggested that the
hereditary form of the childhood cancer
retinoblastoma might be initiated when a cell in
a person heterozygous for a germline mutation
in a tumor-suppressor retinoblastoma gene,
required to prevent the development of the
cancer, undergoes a second, somatic event that
inactivates the other allele.
20. The Two-Hit Origin of Cancer
• As a consequence of this second somatic event,
the cell loses function of both alleles, giving rise
to a tumor. The second hit is most often a
somatic mutation, although loss of function
without mutation, such as occurs with
transcriptional silencing (epigenetic changes),
has also been observed in some cancer cells.
21. The Two-Hit Origin of Cancer
• In the sporadic form of retinoblastoma, both
alleles are also inactivated (two somatic events
occurring in the same cell).
• familial polyposis coli, familial breast cancer,
neurofibromatosis type 1 (NF1), hereditary
nonpolyposis colon carcinoma, and a rare form
of familial cancer known as Li-Fraumeni
syndrome.
22. • Gatekeeper TSGs regulate the cell cycle and
control cell growth directly
– they block tumor development by regulating
the transition of cells through checkpoints
("gates") in the cell cycle or by promoting
apoptosis and, thereby, controlling cell division
and survival.
– loss-of-function mutations of gatekeeper genes
lead to uncontrolled cell proliferation.
TUMOR SUPPRESSOR GENES
(TSGS)
23. TUMOR SUPPRESSOR GENES
(TSGS)
• Gatekeeper TSGs encode:
– regulators of various cell-cycle checkpoints
– mediators of programmed cell death
24. • Caretaker TSGs are involved in repairing DNA
damage and maintaining genomic integrity.
– Loss of function of caretaker genes permits
mutations to accumulate in proto-oncogenes
and gatekeeper genes, which, in concert, go
on to initiate and promote cancer.
TUMOR SUPPRESSOR GENES
(TSGS)
25. • Caretaker TSGs encode:
– proteins responsible for detecting and repairing
mutations
– proteins involved in normal chromosome
disjunction during mitosis
– components of programmed cell death
machinery
TUMOR SUPPRESSOR GENES
(TSGS)
26. • Loss of both alleles of genes that are involved in
repairing DNA damage or chromosome breakage
leads to cancer indirectly by allowing additional
secondary mutations to accumulate either in
proto-oncogenes or in other TSGs.
TUMOR SUPPRESSOR GENES
(TSGS)
27. Gene Gene product and possible
function sporadic
DISORDERS IN WHICH THE GENE IS
AFFECTED
Gatekeepers Familial Sporadic
RB1 p110
Cell cycle regulation
Retinoblasto
ma
Retinoblastoma, small cell lung
carcinomas, breast cancer
TP53 p53
Cell cycle regulation
Li-Fraumeni
syndrome
Lung cancer, breast cancer,
many others
Selected Tumor-Suppressor Genes
Caretakers Familial Sporadic
BRCA1,
BRCA2
Brca1, Brca2
Chromosome repair in response to double-
stranded DNA breaks
Transcriptional regulation and DNA repair
Familial breast and
ovarian cancer
Breast cancer,
ovarian cancer
MLH1,
MSH2
Mlh1, Msh2
Repair nucleotide mismatches between
strands of DNA
(Microsatellite instability, a marker of
DNA mismatch repair)
Hereditary
nonpolyposis colon
cancer
Colorectal cancer
28. • The p53 protein is a DNA-binding protein that
appears to be an important component of the
cellular response to DNA damage.
• In addition to being a transcription factor that
activates the transcription of genes that stop cell
division and allow repair of DNA damage, p53
also appears to be involved in inducing apoptosis
in cells that have experienced irreparable DNA
damage.
TP53
29. TP53
• Loss of p53 function, therefore, allows
cells with damaged DNA to survive and
divide, thereby propagating potentially
oncogenic mutations. The TP53 gene can
therefore be considered to also be a
gatekeeper TSG.
30. • Different types of genetic alterations are responsible for
initiating cancer. These include mutations such as:
– activating or gain-of-function mutations, including gene
amplification, point mutations, and promoter mutations,
that turn one allele of a proto-oncogene into an
oncogene
– chromosome translocations that cause misexpression
of genes or create chimeric genes encoding proteins
with novel functional properties
– loss of function of both alleles, or a dominant negative
mutation of one allele, of TSGs.
Tumor Initiation & Progression
31. • Once initiated, a cancer progresses by accumulating
additional genetic damage, through mutations or epigenetic
silencing, of caretaker genes that encode the cellular
machinery that repairs damaged DNA and maintains
cytogenetic normality.
• A further consequence of genetic damage is altered
expression of genes that promote vascularization and the
spread of the tumor through local invasion and distant
metastasis.
Tumor Initiation & Progression
32. • Stages in the evolution of cancer. Increasing degrees of
abnormality are associated with sequential loss of tumor-
suppressor genes from several chromosomes and
activation of proto-oncogenes, with or without a
concomitant defect in DNA repair.
• Multiple lineages carrying somewhat different mutational
spectra and epigenetic changes are likely, particularly once
metastatic disease appears.
34. • Some tumor-suppressor genes directly regulate proto-oncogene function
(gatekeepers); others act more indirectly by maintaining genome integrity
and correcting mutations during DNA replication and cell division
(caretakers). Activation of an antiapoptotic gene allows excessive
accumulation of cells, whereas loss of function of apoptotic genes has the
same effect.
• Activation of oncogenes or antiapoptotic genes is dominant. Mutations in
tumor-suppressor genes are recessive; when both alleles are mutated or
inactivated, cell growth is unregulated or genomic integrity is compromised.
Loss of pro-apoptotic genes may occur through loss of both alleles or
through a dominant negative mutation in one allele.
35. Tumor Initiation & Progression
• The development of cancer (oncogenesis)
results from mutations in one or more of the vast
array of genes that regulate cell growth and
programmed cell death.
36. Tumor Initiation & Progression
• When cancer occurs as part of a hereditary
cancer syndrome, the initial cancer-causing
mutation is inherited through the germline and is
therefore already present in every cell of the
body.
• Most cancers, however, are sporadic because
the mutations occur in a single somatic cell,
which then divides and proceeds to develop into
the cancer.
37. Micro-RNA Genes
• The catalogue of genes involved in cancer also
includes genes that are transcribed into
noncoding RNAs from which regulatory
microRNAs (miRNAs) are generated.
• There are at least 250 miRNAs in the human
genome that carry out RNA-mediated inhibition
of the expression of their target protein-coding
genes, either by inducing the degradation of
their targets' mRNAs or by blocking their
translation.
38. Micro-RNA Genes
• Approximately 10% of miRNAs have been found
to be either greatly overexpressed or down-
regulated in various tumors, and are referred to
as oncomirs.
• One example is the 100-fold overexpression of
the miRNA miR-21 in glioblastoma multiforme, a
highly malignant form of brain cancer.
39. Micro-RNA Genes
• Overexpression of some miRNAs can suppress
the expression of tumor-suppressor gene
targets, whereas loss of function of other
miRNAs may allow overexpression of the
oncogenes they regulate.
• Since each miRNA may regulate as many as
200 different gene targets, overexpression or
loss of function of miRNAs may have
widespread oncogenic effects because many
genes will be dysregulated.
