MOLECULAR BASIS OF

CANCER

SFUCHAS-SECOND YEAR CLASS 2022

E.M.ELIAS (MD, MMED)
LECTURER-PATHOLOGY DEPT
Introduction
• The genetic hypothesis of cancer implies that a tumor mass results from
the clonal expansion of a single progenitor cell that has incurred genetic
damage (i.e., tumors are monoclonal)

• Such genetic damage (or mutation) may be acquired by the action of

environmental agents, such as chemicals, radiation, or viruses, or it may be
inherited in the germ line
Introduction…
Normal regulatory genes
• 4 classes
Growth-promoting proto-oncogenes,
Growth-inhibiting tumor suppressor genes,
Genes that regulate programmed cell death (i.e. Apoptosis),
Genes involved in DNA repair

• These are the principal targets of genetic damage

Introduction…
• Collectively, the genetic alterations in tumor cells confer growth and
survival advantages over normal cells

• These genetic alterations occur in

Oncogenes
Tumor suppressor genes
Introduction….
Oncogenes
• Are genes that induce a transformed phenotype when expressed in cells.
• Most oncogenes are mutated or over expressed versions of normal
cellular genes, which are called proto-oncogenes.
• Most known oncogenes encode transcription factors, growth regulating
proteins, or proteins involved in cell survival and cell–cell and cell–matrix
interactions.
• They are considered dominant because mutation of a single allele can
lead to cellular transformation
Introduction…
Tumor suppressor genes
• Are genes that normally prevent uncontrolled growth and, when mutated
or lost from a cell, allow the transformed phenotype to develop.
• Usually both normal alleles of tumor suppressor genes must be damaged
for transformation to occur

• Are classified into

Governors
Guardians.
Introduction…
Tumor suppressor genes
Governors
• Are classic tumor suppressor genes, such as RB, where mutation of the gene
leads to transformation by removing an important brake on cellular proliferation.

Guardian
• Genes are responsible for sensing genomic damage.
• Some of these genes initiate and design a complex “damage control response.”
• This response leads to the cessation of proliferation or, if the damage is too great
to be repaired, the induction of apoptosis e.g TP53
Genetic lesions in cancer
• The genetic changes that characterize cancer-associated mutations
may be
Point mutations or insertions and deletions

Large enough to produce karyotypic changes

Genetic lesions in cancer…
Point mutations
• Can either activate or inactivate the resulting protein products.
For example, point mutations in proto-oncogenes, such as RAS or EGFR,
frequently result in overactivity of the protein, usually by altering an
internal regulatory amino acid and producing a constitutively active
protein.

• However, point mutations in tumor suppressors, such as those affecting

RB or TP53 genes, reduce or disable the function of the encoded
protein
Genetic lesions in cancer…
Karyotypic changes in tumors
• If the genetic change is large enough the Karyotype changes can be
detected.
• Some cancers have a virtually normal karyotype, while others are
markedly aneuploid, with loss and gain of many entire chromosomes or
chromosomal arms.

• The common types of nonrandom structural abnormalities in tumor

cells are balanced translocations, deletions, and cytogenetic
manifestations of gene amplification.
Genetic lesions in cancer…
Karyotypic changes in tumors
Balanced translocation
• In Burkitt lymphoma the cells have a translocation, usually between
chromosomes 8 and 14, which leads to overexpression of the MYC gene on
chromosome 8 by juxtaposition with immunoglobulin heavy chain gene
regulatory elements on chromosome 14.

• In follicular B cell lymphomas, a reciprocal translocation between

chromosomes 14 and 18 leads to overexpression of the antiapoptotic
gene, BCL2, on chromosome 18, also driven by immunoglobulin gene
elements
Genetic lesions in cancer…
Karyotypic changes in tumors…
Balanced translocation
• Philadelphia (Ph) chromosome in
chronic myelogenous leukemia,
consisting of a reciprocal and
balanced translocation between
chromosomes 22 and 9
Genetic lesions in cancer…
Karyotypic changes in tumors…
Deletion
• Chromosomal deletions are the second most prevalent karyotypic
abnormality in tumor cells.
• Deletions large enough to be observed karyotypically are more common in
non-hematopoietic solid tumors e.g. retinoblastoma
• Deletion of specific regions of chromosomes may result in the loss of
particular tumor suppressor genes.
• Tumor suppressors generally require inactivation of both alleles in order for
them to contribute to carcinogenesis.
Genetic lesions in cancer…
Genetic lesions in cancer…
Karyotypic changes in tumors…
Gene Amplifications
• Proto-oncogenes may be converted to oncogenes by amplification, with
consequent overexpression, of otherwise normal proteins.

• Such amplification may produce several hundred copies of the proto-

oncogene in the tumor cell.

• The amplified genes can be readily detected by molecular hybridization

with appropriate DNA probes or microscopically
Genetic lesions in cancer…
Karyotypic changes in tumors…
Gene Amplifications…
• The most interesting cases of
amplification involve NMYC in
neuroblastoma and ERBB2(HER2/NEU) in
breast cancers
Genetic lesions in cancer…
Genetic lesions in cancer…
Karyotypic changes in tumors…
Aneuploidy
• Aneuploidy is defined as a number of chromosomes that is not a multiple of
the haploid state
For humans that is a chromosome number that is not a multiple of 23.

• Aneuploidy is remarkably common in cancers, particularly carcinomas, and

was proposed as a cause of carcinogenesis
Genetic lesions in cancer…
Karyotypic changes in tumors…
Aneuploidy
• Aneuploidy frequently results from errors of the mitotic checkpoint, the
major cell cycle control mechanism that acts to prevent chromosome
missegregation.
• The mitotic checkpoint prevents aneuploidy by inhibiting the irreversible
transition to anaphase until all of the replicated chromosomes have made
productive attachments to spindle microtubules.
• Complete absence of the mitotic checkpoint leads to rapid cell-autonomous
lethality as a consequence of massive chromosome missegregation
MicroRNAs and Cancer
• MicroRNAs (miRNAs) are noncoding, single-stranded RNAs,
approximately 22 nucleotides in length, that function as negative
regulators of genes.

• They inhibit gene expression post transcriptionally by repressing

translation or, in some cases, by messenger RNA (mRNA) cleavage

• In view of their important function to control cell growth,

differentiation, and survival, it is not surprising that accumulating
evidence supports a role for miRNAs in carcinogenesis
……
• miRNAs can participate
in neoplastic
transformation either by
increasing the
expression of oncogenes
or reducing the
expression of tumor
suppressor genes
Epigenetic Modifications and Cancer
• Epigenetics refers to reversible, heritable changes in gene expression
that occur without mutation.
• Such changes involve posttranslational modifications of histones and
DNA methylation, both of which affect gene expression.
• In normal, differentiated cells, the major portion of the genome is not
expressed.
• These regions of the genome are silenced by DNA methylation and
histone modifications.
 Epigenetic Modifications and Cancer…
• Tumor suppressor genes and
DNA repair genes also may be
silenced by epigenetic changes,
which involve reversible,
heritable changes in gene
expression that occur not by
mutation but by methylation of
the promoter
Hallmarks of cancer
Introduction…
• Be reminded that malignant neoplasms have several phenotypic attributes,
such as excessive growth, local invasiveness, and the ability to form distant
metastasis
• It is well established that over a period of time, many tumors become more
aggressive and acquire greater malignant potential.

• This phenomenon is referred to as tumor progression and is not represented

simply by an increase in tumor size but ability to be heterozygous and attain
specific potential e.g invasiveness , metastasis
• Thus even though most malignant tumors are monoclonal in origin, by the
time they become clinically evident their constituent cells may be extremely
heterogeneity
Introduction
• Each cancer gene has a specific
function, the dysregulation of
which contributes to the origin or
progression of malignancy.

• It is best, therefore, to consider

cancer related genes in the context
of several fundamental changes in
cell physiology, the so-called
hallmarks of cancer, which together
dictate the malignant phenotype
 Hallmarks of cancer….
Self-Sufficiency in Growth Signals
• Oncoproteins promote uncontrolled cell proliferation by several mechanisms:
The binding of a growth factor to its specific receptor on the cell membrane
Transient and limited activation of the growth factor receptor
Transmission of the transduced signal across the cytosol to the nucleus by
second messengers or a cascade of signal transduction molecules
 Induction and activation of nuclear regulatory factors that initiate and
regulate DNA transcription
Entry and progression of the cell into the cell cycle, resulting ultimately in cell
division
Insensitivity to Growth Inhibitory Signals

• Loss of tumor suppressor genes results to unregulated cell growth

RB Gene: Governor of the Cell Cycle

• Two mutations (hits) are required to produce retinoblastoma.
• These involve the RB gene, which has been mapped to chromosomal locus
13q14.
• Both of the normal alleles of the RB locus must be inactivated (hence the
two hits) for the development of retinoblastoma
……
• In the familial form, all
somatic cells inherit one
mutant RB gene from a
carrier parent.
• The second mutation
affects the RB locus in
one of the retinal cells
after birth.
• In the sporadic form,
both mutations at the RB
locus are acquired by the
retinal cells after birth.
…….
• Role of RB gene in cell cycle
• CELL CYCLE CHECK POINTS
PHOTO

Virtually all cancer cells show dysregulation of the G1–S checkpoint as a result of mutation in one of four genes that
regulate the phosphorylation of Rb; these genes are RB, CDK4, cyclin D, and CDKN2A [p16]. EGF, epidermal growth
factor; PDGF, platelet-derived growth factor
……..
TP53 Gene: Guardian of the Genome
• The p53-encoding tumor suppressor gene, TP53, is one of the most
commonly mutated genes in human cancers.
• The p53 protein prevents neoplastic transformation by three interlocking
mechanisms:
Activation of temporary cell cycle arrest (quiescence), induction of
permanent cell cycle arrest (senescence), or triggering of programmed cell
death (apoptosis).
• If Rb “senses” external signals, p53 can be viewed as a central monitor of
internal stress, directing the stressed cells toward one of these three
pathways.
……

TP53 Gene: Guardian of the

Genome
• The role of p53 in maintaining the
integrity of the genome

• In cells with loss or mutations of

TP53, DNA damage does not
induce cell cycle arrest or DNA
repair, and genetically damaged
cells proliferate, giving rise
eventually to malignant
neoplasms.
Evasion of Cell Death
• Accumulation of neoplastic cells may also result
from mutations in the genes that regulate apoptosis
• Mechanisms used by tumor cells to evade cell
death:
1-Reduced CD95 level.
2-Inactivation of death induced signaling complex
by FLICE protein.
3-Reduced entrace of cytochrome c from
mitochondrion as a result of upregulation of BCL2.
4-Reduced levels of pro-apoptotic BAX resulting
from loss of p53.
5-Loss of APAF-1.
6-Upregulation of inhibitors of apoptosis.
Limitless Replicative Potential
• The cells lose the capacity to divide and enter senescence.
This phenomenon has been ascribed to progressive shortening of telomeres at
the ends of chromosomes.
• Replication of somatic cells, which do not express telomerase, leads to
shortened telomeres.

• Tumor cells reactivate telomerase, thus staving off mitotic catastrophe and
achieving immortality

• Reexpression of telomerase allows the cells to escape the bridge–fusion–

breakage cycle, thus promoting their survival and tumorigenesis.
Limitless Replicative Potential…
Development of Sustained Angiogenesis
• Tumors cannot enlarge beyond 1 to 2 mm in diameter unless they are
vascularized

• Neovascularization has a dual effect on tumor growth:

Perfusion supplies needed nutrients and oxygen,
Newly formed endothelial cells stimulate the growth of adjacent tumor

• Angiogenesis is required not only for continued tumor growth but also for
access to the vasculature and hence for metastasis.
Ability to Invade and Metastasize
Therapeutic targeting hallmarks of cancer
THANKS FOR LISTENING

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