Cancer is not a single disease; rather, it is a heterogeneous

group of disorders characterized by the presence of cells that

do not respond to the normal controls on division.

Cancer cells divide rapidly and continuously, creating tumors

that crowd out normal cells and eventually rob healthy tissues
of nutrients.

The cells of an advanced tumor can separate from the tumor and
travel to distant sites in the body, where they may take up
residence and develop into new tumors.
Normal cells grow, divide, mature, and die in response to a
complex set of internal and external signals. A normal cell
receives both stimulatory and inhibitory signals, being regulated
by a delicate balance between these opposing forces.

In a cancer cell, one or more of the signals has been disrupted,

which causes the cell to proliferate at an abnormally high rate.

As they lose their response to the normal controls, cancer cells

gradually lose their regular shape and boundaries, eventually
forming a distinct mass of abnormal cells—a tumor.
If the cells of the tumor remain localized, the tumor is said to be
benign;

If the cells invade other tissues, the tumor is said to be

malignant.

Cells that travel to other sites in the body, where they establish
secondary tumors, have undergone metastasis.
Cancer As a Genetic Disease
Earlier observations: Cancer might result from DNA damage.

Mutation causing agents like ionizing radiation

and chemicals also cause cancer.

Some cancers are consistenly associated with

particular abnormalities (reciprocal translocation)

Third, some specific types of cancers tend to run

in families. Retinoblastoma, a rare childhood cancer
of the retina, appears with high frequency in a few
families.
A reciprocal
translocation
between
chromosomes
9 and 22 causes
chronic
myelogenous
leukemia.
Cancer As a Genetic Disease

Although these observations hinted that genes play some

role in cancer,
Problem:----

If cancer is inherited, every cell in the body should receive

the cancer-causing gene, and therefore every cell should
become cancerous.
Cancer As a Genetic Disease

In 1971, Alfred Knudson proposed a model to explain the

genetic basis of cancer.

Knudson was studying retinoblastoma, a cancer that usually

develops in only one eye but occasionally appears in both.

In on eye affected cases, a single cell in one eye undergoes

two successive mutations. Because the chance of these two
mutations occurring in a single cell is remote, retinoblastoma
is rare and typically develops in only in one eye.
Cancer As a Genetic Disease

But in bilateral cases, all that is required for cancer to develop

is for one eye cell to undergo the second mutation.

Because each eye possesses millions of cells, there is a high

probability that the second mutation will occur in at least one
cell of each eye, producing tumors in both eyes at an early
age.
Cancer As a Genetic Disease

Multiple mutation

Cancer is the result of a multistep process that requires

several mutations. If one or more of the required mutations is
inherited, fewer additional mutations are required to
produce cancer, and the cancer will tend to run in families.
Alfred Knudson proposed that retinoblastoma results from two separate
genetic defects, both of which are necessary for cancer to develop
Cancer As a Genetic Disease

Clonal evolution
Cancer begins when a single cell undergoes a mutation that
causes the cell to divide at an abnormally rapid rate.

The cell proliferates, giving rise to a clone of cells, each of

which carries the same mutation.

Because the cells of the clone divide more rapidly than

normal, they soon outgrow other cells.
Cancer As a Genetic Disease

Clonal evolution
Eventually, they may be overtaken by cells that contain yet
more mutations that enhance proliferation.

The tumor cells acquire more mutations that allow them to

become increasingly more aggressive in their proliferative
properties.
Cancer As a Genetic Disease

A defect in DNA repair mechanism may cause mutation to

persist in all the genes.

Xeroderma pigmentosum, for example, is a rare disorder

caused by a defect in DNA repair.

People with this condition have elevated rates of skin cancer

when exposed to sunlight.
Xeroderma pigmentosum is a human disease that
results from defects in DNA repair.

Persons who have this disease also have a strong

predisposition to skin cancer, with an incidence from
1000 to 2000 times that
found in unaffected people.

Exposure to sunlight produces pyrimidine dimers in the

DNA of skin cells. Although human cells lack
photolyase, enzyme that repairs pyrimidine dimers in
bacteria. most pyrimidine dimers in humans can be
corrected by nucleotide-excision repair.

However, the cells of most people with xeroderma

pigmentosum are defective in nucleotideexcision
repair, and many of their pyrimidine dimers go
uncorrected and may lead to cancer.
Cancer As a Genetic Disease

Many cancer cells are aneuploid, and it is clear that

chromosome mutations contribute to cancer progression by
duplicating some genes (those on extra chromosomes) and
eliminating others (those on deleted chromosomes).
Environmental factor influencing cancer

Most cancers are not inherited, & many cancers are

influenced by environmental factors.

Environmental factors such as smoking, chemicals,

ultraviolet light, ionizing radiation, and viruses are known
carcinogens and are associated with variation in the
incidence of many cancers.
Environmental factor influencing cancer

The role of environmental factors in cancer is suggested by

differences in the incidence of specific cancers throughout the
world.

Migrant populations typically take on the cancer incidence of

their host country.
Genetic changes which contribute to cancer

Cell division regulation signals falls into two types:

Molecules that stimulate cell division

Molecules that inhibit cell division

Cancer can arise from mutation in either type of signal.

Genetic changes which contribute to cancer

A stimulatory gene can be made hyperactive or active at an

inappropriate times

Dominant-acting stimulatory genes that cause cancer are

termed oncogenes

Inhibitory genes in cancer are termed tumor-

suppressor genes.
Genetic changes which contribute to cancer

Although oncogenes or mutated tumor-suppressor genes or

both are required to produce cancer, mutations in DNA
repair genes can increase the likelihood of acquiring
mutations in these genes.
Genetic changes which contribute to cancer

Oncogenes were the first cancer-causing genes to be

identified.

In 1910, Peyton Rous described a virus that causes

connective-tissue tumors (sarcomas) in chickens; this virus
became known as the Rous sarcoma virus.
Genetic changes which contribute to cancer

These viruses were generally assumed to carry a cancer

causing gene that was transferred to the host cell.

The first oncogene, called src, was isolated from the Rous
sarcoma virus in 1970.
Genetic changes which contribute to cancer

In 1975, scientists began to use probes for viral oncogenes to

search for related sequences in normal cells.

They discovered that the genomes of all normal cells carry

DNA sequences that are closely related to viral oncogenes.
These cellular genes are called proto-oncogenes
Genetic changes which contribute to cancer

They are responsible for basic cellular functions in normal

cells but, when mutated, they become oncogenes that
contribute to the development of cancer.

When a virus infects a cell, a proto-oncogene may become

incorporated into the viral genome through recombination.

Within the viral genome, the proto-oncogene may mutate to an

oncogene that, when inserted back into a cell, causes rapid cell
division and cancer.
Genetic changes which contribute to cancer

In 1975, scientists began to use probes for viral oncogenes to

search for related sequences in normal cells.

They discovered that the genomes of all normal cells carry

DNA sequences that are closely related to viral oncogenes.
These cellular genes are called proto-oncogenes
Genetic changes which contribute to cancer

Tumor-suppressor genes are more difficult than

oncogenes to identify because they inhibit cancer and are
recessive;

both alleles must be mutated before the inhibition of cell

division is removed.

Defects in both copies of a tumor-suppressor gene are usually

required to cause cancer
Genetic changes which contribute to cancer
An organism inheriting one defective copy of the tumor-
suppressor gene (is heterozygous for the cancer-causing
mutation) and not have cancer, because the remaining
normal allele produces the tumor-suppressing product.

However, these heterozygotes are often predisposed to

cancer, because inactivation or loss of the one remaining
allele is all that is required to completely eliminate the
tumor-suppressor product and is referred to as loss of
heterozygosity.
Genetic changes which contribute to cancer

Sometimes the mutation or loss of a single allele of a

recessive tumor-suppressor gene is sufficient to
cause cancer.

This effect in an individual cell or organism that is

heterozygous for a normally recessive trait—is
called haploinsufficiency
Genetic changes which contribute to cancer

Haploinsufficiency is seen in some inherited

predispositions to cancer. Bloom syndrome is an
autosomal recessive disease characterized by short
stature, male infertility, and a predisposition to
cancers of many types.

Persons homozygous for mutations at the BLM locus

have a greatly elevated risk of cancer. Persons
heterozgyous for mutations at the BLM locus were
thought to be unaffected.
Changes in chromosome number and structure

Some cancers are associated with specific

chromosome mutations.

Chromosome breaks associated with a chromosome

rarrangement may occur within proto-oncogenes or
tumor suppressor genes, disrupting their normal
function and contributing to tumorogenesis.
Changes in chromosome number and structure

Chromosome rearrangements may also bring

together parts of different genes, creating a fusion
protein that stimulates some aspect of the cancer
process.

It can also cause cancer by moving a potential

cancer-causing gene to a new location where it is
activated by different set of regulatory sequences.
Changes in chromosome number and structure

Aneuploidy (extra chromosomes or missing

chromosomes) is common in cancer cells and may
contribute to the pathogenesis of cancer by altering
the dosage of oncogenes and tumor-suppressor
genes.
The cell cycle controlling genes

Genes that control the cell cycle often serve as proto-

oncogenes or tumor-suppressor genes.

The cell cycle is regulated by cyclins, whose

concentration oscillates during the cell cycle, and
cyclin-dependent kinases (CDKs), which have a
relatively constant concentration.
The cell cycle controlling genes

Genes that encode cyclins and factors that inhibit or

stimulate the formation of activated CDKs are often
oncogenes and tumor-suppressor genes,
respectively.
The cell cycle controlling genes

Mutated cyclin genes have been associated with

cancers of the immune system, breast, stomach, and
esophagus; genes, such as p16 and p21, that encode
inhibitors of CDKs are mutated or missing in many
cancer cells.
The cell cycle controlling genes

Some proto-oncogenes and tumor-suppressor genes

have roles in apoptosis.

The ability of a cell to initiate apoptosis in response

to DNA damage depends on a gene called p53, which
is inactivate in many human cancers.