Cancer Genetics

Chapter Outline
• Cancer: A Genetic Disease

• Cancer and Genes

• Oncogenes
• Tumor Suppressor Genes

• Genetic pathways to cancer

Cancer: A Genetic Disease
• Cancer is a disease characterized by uncontrolled cell
division.

• More than 100 kinds of human cancers have been

identified.

• Classified according to the type of cell that has become

cancerous.
Named for site of origin

Carcinomas – epithelial cells; cover external & internal body

surfaces

Sarcomas – supporting tissue; bone, cartilage, fat, connective

tissue, pancreas, Liver.

Lymphoma & leukemias – blood & lymphatic tissue

(leukemia reserved for cancers that reside in bloodstream
not as solid tissue)
• Some characteristics are common to all
cancers
1. Most cancers originate in a single cell
(clonal in origin)
2. Usually a multistep process that
begins with a precancerous genetic
change—a benign growth
3. When cells have become cancerous,
their growth is described as
malignant
• Malignant cells have three common characteristics:
i. Cell division continues in an unlimited manner
ii. The cells are invasive, which means they can invade healthy
tissues
iii. The cells are metastatic, which means they can migrate to
other parts of the body and cause secondary tumors.
Changes in growth properties of
cancer cells
 Control of the Cell division

Mechanisms for controlling progress through the

cell cycle:
• Length of Telomeres
• Checkpoints
• Chemical Signals from within and outside the
cell
Length of Telomeres

telomeres

Telomeres are structures

at the ends of
chromosomes that
shorten with each cell
division. After 50
divisions, the shortened
length of telomeres
causes mitosis to stop.
Failure to Stop at Cell Cycle Checkpoints

1. Mutation in a gene Rate of cell division is

that usually slows the accelerated.
cell cycle
2. Failure to pause for Faulty DNA leads to
DNA repair unregulated cell growth.

3. Loss of control over Cancer cells have

telomere length telomerase, an enzyme
that elongates telomeres.
Cells continue to divide
after 50 mitoses.
Chemical Signals that Control the Cell Cycle

1. Cyclin and Kinase

-proteins that initiate mitosis
-requires buildup of cyclin to pair with kinase
2. Hormones
-chemical signals from specialized glands
that stimulate mitosis
3. Growth Factors
-chemical factors produced locally that stimulate mitosis
 Normal cells vs. Cancer cells
Normal cell proliferation Cancer cell proliferation

Anchorage dependent Anchorage independent

Density-dependent inhibition Can grow on top of one

another
Limited number of cell Immortal
divisions
Telomere shortening Telomere maintenance

Proliferation dependent upon Constant signal to divide

extracellular signals independent
Checkpoints activated at Loss of checkpoint
appropriate times
Apoptosis functional Apoptosis inhibited
Cancer and Genes
Oncogenes
• Have Gain-of-Function Mutations That May Affect Proteins Involved
in Cell Division Pathways
• An oncogene is an abnormally active gene that promotes cancerous
growth.
• A normal, nonmutated gene that has the potential to become an
oncogene is termed a proto-oncogene.
Oncogenes
• A gain-of-function mutation that produces an oncogene typically has
one of three possible effects:
i. The amount of the encoded protein is greatly increased.
ii. A change occurs in the structure of the encoded protein that causes it to be
overly active.
iii. The encoded protein is expressed in a cell type where it is not normally
expressed.
Oncogenes commonly encode
proteins that function in cell
growth signalling pathways
In cancer cells, the RAS gene
product is locked into its GTP-
binding shape and does not
require a signal at the Ras Proto-Oncogene
receptor in order to stimulate
cell division

In response to growth factor

binding at receptor, the Ras
gene product combines with
GTP to promote cell division
Normal Ras Protein Signaling
Mutant Ras Protein is Unregulated
Mutations that alter the amino acid
sequence of the Ras protein cause
functional abnormalities.

• Mutations that convert the normal

ras gene into an oncogene either:
• Decrease the ability of the Ras protein
to hydrolyze GTP or
• Increase the rate of exchange of bound
GDP for GTP

• These mutations keep the signalling

pathway turned on, thereby
stimulating the cell to divide
Genetic Changes in Proto-Oncogenes Convert Them to
Oncogenes
• Specific genetic alterations convert proto-oncogenes into oncogenes
by the following:
• Missense mutations
• Gene amplifications (i.e., an increase in copy number)
• Chromosomal translocations
• Viral integrations
Missense mutations
• A change in the amino acid sequence of a proto-oncogene protein
may cause it to function in an abnormal way.

• Missense mutations can convert ras genes into oncogenes

• E.g. missense mutation in rasH that changes a glycine to a valine is
responsible for the conversion of rasH into an oncogene:
 Gene Amplification
• The copy number of a proto-oncogene may be increased by gene
duplication → increase the amount of the encoded protein → malignancy.

• Myc genes have been amplified in:

• Human leukemias, Breast, stomach, lung, and colon carcinomas; and
neuroblastomas and glioblastomas.

• ErbB genes have been amplified in glioblastomas, squamous cell

carcinomas, and breast, salivary gland, and ovarian carcinomas.
 Chromosomal Translocation
• A piece of chromosome may be
translocated to another
chromosome and affect the
expression of genes at the
breakpoint site.
Active
region

• E.g. In Burkitt lymphoma, a

region of chromosome 8 is
translocated to either
chromosome 2, 14, or 22.
• The breakpoint in chromosome 8 causes the overexpression of the c-myc
gene → promoting malignancy
• E.g. The reciprocal
translocation commonly
found in people with chronic
myelogenous leukemia.

• abl gene fuses with the bcr

gene

• The combined gene (under the control of the bcr promoter) → encodes
an abnormal fusion protein that overexpresses the tyrosine kinase
function of the ABL protein and leads to leukemia
Viral Integration
• Certain viruses, such as retroviruses, integrate their genomes into the
chromosomal DNA of their host cell.

• When a virus integrates into a chromosome, it may enhance the

expression of nearby proto-oncogenes.

• In avian lymphomas, the integration of the avian leukosis virus can

enhance the transcription of the c-myc gene.
Tumor-Suppressor Genes
• Play a Role in Preventing the Proliferation of Cancer Cells

• When a tumor- suppressor gene becomes inactivated by mutation, it

becomes more likely that cancer will occur.

• It is a loss-of-function mutation in a tumor-suppressor gene that

promotes cancer.
Rb gene
Knudson’s Two-Hit
Hypothesis
• When tumor suppressor
genes are mutated, a
predisposition to develop
cancer often follows a
dominant pattern of
inheritance.

• Cancer develops only if a

second mutation in somatic
cells knocks out the
function of the wild-type
allele.
 Interactions between the Rb and E2F proteins.
Rb gene

• The Rb protein
suppresses the
proliferation of
cancer cells.
p53 Gene (Guardian of the Genome)
• Is a Master Tumor Suppressor Gene That Senses DNA Damage

• Most commonly altered gene in human cancers.

• ≈ 50% of all human cancers are associated with defects in p53

• These include malignant tumors of the lung, breast, oesophagus, liver,

bladder, and brain as well as sarcomas, lymphomas, and leukemias.
p53 Gene
• If damage is detected, p53 can promote three types of cellular
pathways aimed at preventing the proliferation of cells with damaged
DNA

1. When confronted with DNA damage, the cell can try to repair its
DNA.
• This may prevent the accumulation of mutations that activate oncogenes or
inactivate tumor-suppressor genes.
p53 Gene
2. If a cell is in the process of dividing, it can arrest itself in the cell
cycle.
• A cell has more time to repair its DNA and avoid producing two mutant
daughter cells.

• For this to happen, p53 stimulates the expression of another gene

termed p21.

• p21 protein inhibits cyclin/CDK protein complexes that are needed to

progress from the G1 phase of the cell cycle to the S phase.
 p53 Gene
3. A cell can initiate a series of events called apoptosis, or programmed
cell death.
• In response to DNA-damaging agents, a cell may self-destruct.

• Apoptosis occurs in some cells as a normal process of embryonic

development.

• It is also an important way by which an adult organism can eliminate

cells with cancer-causing potential.
p53 Gene
• Apoptosis is an active process that involves cell shrinkage, chromatin
condensation, and DNA degradation.

• Facilitated by proteases known as caspases.

• Sometimes called the “executioners” of the cell.
• Digest selected cellular proteins such as microfilaments, which are
components of the intracellular cytoskeleton.

• This causes the cell to break down into small vesicles that are
eventually phagocytized by cells of the immune system.
Central role of p53 in
preventing the
proliferation of cancer
cells
[ increase ]
p-p53
TSG’s Encode Proteins that Negatively Regulate
Cell Division or Maintain Genome Integrity

• Many tumor-suppressor genes, when defective, contribute to the

development and progression of cancer.

• They tend to fall into two broad categories:

1. Genes that negatively regulate cell division or
2. Genes that maintain genome integrity.
1. Genes that negatively regulate cell
division
• Some TSG’s encode proteins that have
direct effects on the regulation of cell
division.

• E.g. the rb gene

• The Rb protein negatively regulates E2F.
• If both copies of the rb gene are
inactivated, the growth of cells is
accelerated.

• Therefore, loss of function of these

kinds of negative regulators has a
direct effect on the abnormal cell
division rates seen in cancer cells.
2. Genes that maintain genome integrity

• Other TSG’s play a role in the proper maintenance of the integrity of

the genome.

• The term genome maintenance refers to:

• Cellular mechanisms that either prevent mutations from occurring and/or
prevent mutant cells from surviving or dividing.

• The proteins encoded by such genes help to ensure that gene

mutations or changes in chromosome structure and number do not
occur and are not transmitted to daughter cells.
• The proteins that participate in genome maintenance can be
subdivided into two classes:
i. Checkpoint proteins and
ii. Those involved directly with DNA repair.
Checkpoint proteins

• The role of many checkpoint proteins is to detect genetic

abnormalities.
• i.e. DNA breaks and improperly segregated chromosomes.

• When abnormalities are detected, the proteins participate in

regulatory pathways that prevent cell division.
Checkpoint proteins
• Called checkpoint proteins because their role is to check the integrity
of the genome and prevent cells from progressing past a certain point
in the cell cycle if genetic abnormalities are detected

• Proteins called cyclins and cyclin-dependent protein kinases (CDKs)

are responsible for advancing a cell through the four phases of the
cell cycle
Cell cycle control
• For example, an
activated G1-cyclin/
CDK complex is
necessary to
advance from the
G1 phase to the S
phase.
Checkpoint proteins
• The G1 and G2 checkpoints involve the functions of proteins that can
sense if the DNA has incurred damage.
• If so, these checkpoint proteins, such as p53, can prevent the formation of
active cyclin/CDK complexes.
• This stops the progression of the cell cycle

• Metaphase checkpoint is monitored by proteins that can sense if a

chromosome is not correctly attached to the spindle apparatus,
making it likely that it will be improperly segregated.
Checkpoint proteins
• Checkpoint proteins prevent the division of cells that may have
incurred DNA damage or harbour abnormalities in chromosome
attachment.
• This provides a mechanism to stop the accumulation of genetic abnormalities
that could produce cancer cells within the body

• The loss of checkpoint protein function makes it more likely that

undesirable genetic changes occur that could cause cancerous growth
DNA Repair Enzymes
• The repair of base damage is initiated by DNA repair enzymes called
DNA glycosylases.

• Genes encoding such enzymes are inactivated in certain forms of cancer.

• Makes it more likely for a cell to accumulate mutations that could create
an oncogene or eliminate the function of a tumor-suppressor gene.

• E.g. defects in DNA mismatch repair enzymes can contribute to

colorectal cancer.
Tumor-Suppressor Genes Can Be Silenced in
a Variety of Ways
• Three common ways that the function of tumor-suppressor genes can
be lost:

1. A mutation can occur specifically within a tumor-suppressor gene

to inactivate its function.
• E.g. a mutation could inactivate the promoter of a tumor-suppressor gene or
introduce an early stop codon in the coding sequence.
• Either of these would prevent the expression of a functional protein.
2. Tumor suppressor genes are inhibited via DNA methylation.
• DNA methylation usually inhibits the transcription of eukaryotic genes,
particularly when it occurs in the vicinity of the promoter.

• E.g. The methylation of CpG islands near the promoters of tumor-

suppressor genes has been found in many types of tumors.
• suggesting that this form of gene inactivation plays an important role in the
formation or progression of malignancy.
3. Many types of cancer are associated with aneuploidy.
• Aneuploidy involves the loss or addition of one or more
chromosomes, so the total number of chromosomes is not an even
multiple of a set.

• In some cases, chromosome loss may contribute to the progression of

cancer because the lost chromosome carries one or more tumor-
suppressor genes.
Genetic Pathways to Cancer

Cancers develop through an accumulation

of somatic (not a single) mutations in
proto-oncogenes and tumor suppressor
genes.
Multiple Mutations in Cancer
• Most malignant tumors cannot be attributed to mutation of a single
gene.

• Tumor formation, growth, and metastasis depend on the

accumulation of mutations in several different genes.

• The genetic pathways to cancer are diverse and complex.

Pathway to Metastatic Colorectal Cancer

Carcinoma-epithelial cells.
Adenoma-glandular cells.
Pathway to Androgen-Independent
Prostate Cancer
Hallmarks of Pathways to Malignant Cancer
1. Cancer cells acquire self-sufficiency in the signaling processes that
stimulate division and growth.

2. Cancer cells are abnormally insensitive to signals that inhibit

growth.

3. Cancer cells can evade programmed cell death (apoptosis).

4. Cancer cells acquire limitless replicate potential.

5. Cancer cells develop ways to grow themselves.

6. Cancer cells acquire the ability to invade other

tissues and colonize them.