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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 changea benign growth

  • 3. When cells have become cancerous, their growth is described as malignant

• Some characteristics are common to all cancers 1. Most cancers originate in a single cell

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

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

Length of Telomeres telomeres Telomeres are structures at the ends of chromosomes that shorten with each
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 cell cycle

accelerated.

  • 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 divisions

Immortal

Telomere shortening

Telomere maintenance

Proliferation dependent upon

Constant signal to divide

extracellular signals

independent

Checkpoints activated at appropriate times

Loss of checkpoint

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

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
In cancer cells, the RAS gene
product is locked into its GTP-
binding shape and does not
require a signal at the
receptor in order to stimulate
cell division

Ras Proto-Oncogene

In response to growth factor binding at receptor, the Ras gene product combines with GTP to
In response to growth factor
binding at receptor, the Ras
gene product combines with
GTP to promote cell division

Normal Ras Protein Signaling

Normal Ras Protein Signaling

Mutant Ras Protein is Unregulated

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

Mutations that alter the amino acid sequence of the Ras protein cause functional abnormalities. • Mutations

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:

Missense mutations • A change in the amino acid sequence of a proto-oncogene protein may cause

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.

E.g. In Burkitt lymphoma, a region of chromosome 8 is translocated to either chromosome 2, 14, or 22.

Active region
Active
region

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

• E.g. The reciprocal translocation commonly found in people with chronic myelogenous leukemia. • abl 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.

Rb gene Knudson’s Two -Hit Hypothesis • When tumor suppressor genes are mutated, a predisposition to

Rb gene

The Rb protein suppresses the proliferation of

cancer cells.

Interactions between the Rb and E2F proteins.

Rb gene • The Rb protein suppresses the proliferation of cancer cells. Interactions between the Rb

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

Central role of p53 in preventing the proliferation of cancer cells
[ increase ] p-p53
[ 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.

1. Genes that negatively regulate cell division • Some TSG’s encode proteins that have direct effects
  • 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.

Cell cycle control • For example, an activated G1-cyclin/ CDK complex is necessary to advance from

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

Pathway to Metastatic Colorectal Cancer Carcinoma-epithelial cells. Adenoma-glandular cells.

Carcinoma-epithelial cells.

Adenoma-glandular cells.

Pathway to Androgen-Independent Prostate Cancer

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.