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PART IV

The Genetics of Cancer

OUTLINE
4.1 Cancer: A Failure of Control over Cell Division 4.2 Common signaling molecules 4.3 Cell Cycle Regulation

The relative percentages of new cancers in the United States that occur at different sites

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Two unifying themes about cancer genetics


Cancer is a disease of genes

Multiple cancer phenotypes arise from mutations in genes that regulate cell growth and division
Environmental chemicals increase mutation rates and increase chances of cancer Cancer has a different inheritance pattern than other genetic disorders Inherited mutations can predispose to cancer, but the mutations causing cancer occur in somatic cells Mutations accumulate in clonal descendants of a single cell
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Overview of the initiation of cell division


Two basic types of signals that tell cells whether to divide, metabolize, or die Extracellular signals act over long or short distances Collectively known as hormones

Steroids, peptides, or proteins


Cell-bound signals require direct contact between cells

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An example of an extracellular signal that acts over large distances


Thyroid-stimulating hormone (TSH) produced in pituitary gland Moves through blood to thyroid gland, which expresses thyroxine

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An example of an extracellular signal that is mediated by cell-to-cell contact

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Each signaling system has four components


Growth factors Extracellular hormones or cell-bound signals that stimulate or inhibit cell proliferation Receptors Comprised of a signal-binding site outside the cell, a transmembrane segment, and an intracellular domain Signal transducers Located in cytoplasm Transcription factors Activate expression of specific genes to either promote or inhibit cell proliferation
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Hormones transmit signals into cells through receptors that span the cellular membrane

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Signaling systems can stimulate or inhibit growth

Signal transduction activation or inhibition of intracellular targets after binding of growth factor to its receptor

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RAS is an intracellular signaling molecule

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Cancer phenotypes result from the accumulation of mutations


Mutations are in genes controlling proliferation as well as other processes Result in a clone of cells that overgrows normal cells Cancer phenotypes include:

Uncontrolled cell growth


Genomic and karyotypic instability Potential for immortality Ability to invade and disrupt local and distant tissues

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Phenotypic changes that produce uncontrolled cell growth


Most normal cells Many cancer cells

Autocrine stimulation: Cancer cells can make their own stimulatory signals

a.1

Most normal cells

Many cancer cells

Loss of contact inhibition: Growth of cancer cells doesn't stop when the cells contact each other

a.2

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Phenotypic changes that produce uncontrolled cell growth (cont)


Most normal cells Many cancer cells

Loss of cell death: Cancer cells are more resistant to programmed cell death (apoptosis)

a.3

Loss of gap junctions: Cancer cells lose channels for communicating with adjacent cells

Most normal cells a.4

Many cancer cells

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Phenotypic changes that produce genomic and karyotypic instability


Defects in DNA replication machinery: Cancer cells have lost the ability to replicate their DNA accurately Increased mutation rates can occur because of defects in DNA replication machinery
b.1

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Phenotypic changes that produce genomic and karyotypic instability (cont)


Increased rate of chromosomal aberrations:

Cancer cells often have chromosome rearrangements (translocations, deletions, aneuploidy, etc)
Some rearrangements appear regularly in specific tumor types

Fig. 17.4b.2
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Phenotypic changes that enable a tumor to disrupt local tissue and invade distant tissues
Ability to metastasize: Tumor cells can invade the surrounding tissue and travel through the bloodstream
d.1

Angiogenesis: Tumor cells can secrete substances that promote growth of blood vessels

d.2

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Evidence from mouse models that cancer is caused by several mutations


Transgenic mice with dominant mutations in the myc gene and in the ras gene
(a)

Mice with recessive mutations in the p53 gene


(b)

Fig. 17.5a

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The incidence of some common cancers varies between countries

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The role of environmental mutagens in cancer


Concordance for the same type of cancer in first degree relatives (i.e. siblings) is low for most forms of cancer The incidence of some cancers varies between countries When a population migrates to a new location, the cancer profile becomes like that of the indigenous population Numerous environmental agents are mutagens and increase the likelihood of cancer

Some viruses, cigarette smoke

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Some families have a genetic predisposition to certain types of cancer


Example: retinoblastoma caused by mutations in RB gene Individuals who inherit one copy of the RB allele are prone to cancer of the retina During proliferation of retinal cells, the RB+ allele is lost or mutated Tumors develop as a clone of RB/RB cells

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Cancer is thought to arise by successive mutations in a clone of proliferating cells

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Cancer-producing mutations are of two general types

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Oncogenes act dominantly and cause increased proliferation


Oncogenes are produced when mutations cause improper activation a gene Two approaches to identifying oncogenes: Tumor-causing viruses
Many tumor viruses in animals are retroviruses
Some DNA viruses carry oncogenes [e.g. Human papillomavirus (HPV)]

Tumor DNA
Transform normal mouse cells in culture with human tumor DNA
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Cancer-causing retroviruses carry a mutant or overexpressed copy of a cellular gene


After infection, retroviral genome integrates into host genome If the retrovirus integrates near a proto-oncogene, the protooncogene can be packaged with the viral genome

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The RAS oncogene is the mutant form of the RAS proto-oncogene


Normal RAS is inactive until it becomes activated by binding of growth factors to their receptors Oncogenic forms of RAS are constitutively activated

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Oncogenes are members of signal transduction systems

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Cancer can be caused by mutations that improperly inactivate tumor suppressor genes
Function of normal allele of tumor suppressor genes is to control cell proliferation Mutant tumor suppressor alleles act recessively and cause increased cell proliferation Tumor suppressor genes identified through genetic analysis of families with inherited predisposition to cancer Inheritance of a mutant tumor suppressor allele One normal allele sufficient for normal cell proliferation in heterozygotes Wild-type allele in somatic cells of heterozygote can be lost or mutated abnormal cell proliferation
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The retinoblastoma tumor-suppressor gene

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Mutant alleles of these tumor-suppressor genes decrease the accuracy of cell reproduction

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The normal control of cell division


Four phases of the cell cycle: G1, S, G2, and M

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Some important cell-cycle and DNA repair genes

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CDKs interact with cyclins and control the cell cycle by phosphorylating other proteins
Cyclin-dependent kinases (CDKs) family of kinases that regulate the transition from G1 to S and from G2 to M Cyclin specifies the protein targets for CDK Phosphorylation by CDKs can activate or inactive a protein

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CDKs control the dissolution of the nuclear membrane at mitosis


Lamins provide structural support to the nucleus

Form an insoluble matrix during most of the cell cycle


At mitosis, lamins are phosphorylated by CDKs and become soluble

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CDKs mediate the transition from the G1 to the S phase of the cell cycle

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CDK activity in yeast is controlled by phosphorylation and dephosphorylation

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Cell-cycle checkpoints ensure genomic stability


Checkpoints monitor the genome and cell-cycle machinery before allowing progression to the next stage of cell cycle G1-to-S checkpoint DNA synthesis can be delayed to allow time for repair of DNA that was damaged during G1 The G2-to-M checkpoint Mitosis can be delayed to allow time for repair of DNA that was damaged during G2 Spindle checkpoint Monitors formation of mitotic spindle and engagement of all pairs of sister chromatids
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The G1-to-S checkpoint is activated by DNA damage

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Disruption of the G1-to-S checkpoint in p53-deficient cells can lead to amplified DNA
Tumor cells often have homogenously staining regions (HSRs) or small, extrachromosomal pieces of DNA (double minutes)

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Disruption of the G1-to-S checkpoint in p53-deficient cells can lead to many types of chromosome rearrangements

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Checkpoints acting at the G2-to-M cell-cycle transition or during M phase

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The necessity of checkpoints


Checkpoints are not essential for cell division

Cells with defective checkpoints are viable and divide at normal rates
But, they are much more vulnerable to DNA damage than normal cells Checkpoints help prevent transmission of three kinds of genomic instability Chromosome aberrations Changes in ploidy Aneuploidy
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Chromosome painting can be used to detect chromosome rearrangements


Chromosomes from normal cells Chromosomes from tumor cells

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