Somatic Mutation and the Genetics of Cancer

Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17 Outline  Overview: Initiation of Division  Cancer: A Failure of Control over Cell Division  The N

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Somatic Mutation and

the Genetics of Cancer

Week 13

2

Hartwell et al., 4th edition, Chapter 17

Outline

 Overview: Initiation of Division

 Cancer: A Failure of Control over Cell Division

 The Normal Control of Cell Division

Overview of Cell division and cell cycle

 Proliferation of cells

 In human adults: 300 different types of cells divide when

needed

• inner skin, blood, intestinal lining: daily

• liver cells rarely divide

• nerves, surface skin: never divide

 In normal conditions, cell division is under the control, in

balance and tight organization

How cancer can arise?

 Some cells divide out of control, spread (metastasize)

 excessive and inaccurate proliferation

 cells grow in invasive way

 Rarely occurs in children, common in older adults

Figure: Lung cancer cells (530x) These cells are from a tumor

located in the alveolus (air sac) of a lung

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Fig 17.1

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

 Cancer is a disease of genes:

 mutations in genes that regulate cell cycle (growth and division)

 Environmental factors (chemicals ) raises the rate mutation

 Cancer differs in two ways:

 most mutations in some somatic cells

• accumulate over time (sporadic)

• inheritant mutations  predisposition to cancer

 mutations in germline cells: mutations in all cells of all somatic tissues.

• Examples: cystic fibrosis, Huntington disease

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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,

•The mutations causing cancer occur in somatic cells

•Mutations accumulate in clonal descendants of a single cell

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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

• Steroids, peptides, or proteins

• Collectively known as hormones

 Cell-bound signals

• histocompatibility proteins

• 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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Fig 17.2a

An example of an extracellular signal that

is mediated by cell-to-cell contact

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Fig 17.2b

Each signaling system has four components

Growth factors

•Extracellular hormones or cell-bound signals that stimulate or

inhibit cell proliferation

Receptors

•Have three parts: a signal-binding site outside the cell, a

transmembrane segment, and an intracellular domain.

Signal transducers

•Located in cytoplasm, relaying the signal inside the cell

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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Fig 17.3a

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stimulate or inhibit growth

Signal transduction

-activation or inhibition of

intracellular targets after

binding of growth factor

to its receptor

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Fig 17.3b&c

RAS is an intracellular signaling molecule

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Fig 17.3d

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Outline

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

16 Cancer phenotypes result from the accumulation of mutations

Phenotypic changes that produce uncontrolled cell growth

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Autocrine stimulation:

Cancer cells can make

their own stimulatory

signals

Loss of contact inhibition:

Growth of cancer cells

doesn't stop when the

cells contact each other

a.1

a.2 Most normal cells Many cancer cells Most normal cells Many cancer cells

Fig 17.4

Phenotypic changes that produce uncontrolled cell growth (cont)

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Loss of cell death:

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

Loss of gap junctions:

Cancer cells lose channels for communicating with adjacent cells

a.3

a.4 Most normal cells Many cancer cells Most normal cells Many cancer cells

Fig 17.4

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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

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Fig 17.4

b.1

Phenotypic changes that produce genomic and karyotypic instability

Increased rate of chromosomal aberrations:

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

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Fig 17.4b.2

Phenotypic changes that produce a potential for immortality

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Loss of limitations on the number of cell divisions:

Tumor cells can divide indefinitely in culture (below) and express telomerase (not

shown)

Fig 17.4

Phenotypic changes that enable a tumor to disrupt local tissue and invade distant tissues

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Fig 17.4

Ability to metastasize:

Tumor cells can invade the surrounding tissue and travel through the bloodstream

Angiogenesis:

Tumor cells can secrete substances that promote growth of blood vessels

d.1

d.2

Multiple mutations leading to convert a normal cell into a

cancerous cell

 DNA sequencing revealed thousands of mutations in

each tumor.

 How many actually contribute to the cancer phenotype is

unclear.

 Identify and isolate a mutation of interest by

 linkage analysis of markers,

 traditional genetic mapping to a chromosome,

 and positional cloning.

 Use gene transfer experiments in mice to test

 whether a mutation in a single gene associated with

cancer is sufficient to induce a tumor.

 the mutation acts in a dominant or recessive fashion

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

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Fig 17.5a

(b) (a)

Mice with recessive mutations in the

p53 gene

Fig 17.5

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Analysis of polymorphic enzymes

encoded by the X chromosome in

female

Sample from normal tissues has

mixture of both alleles

Clones of normal cells has only one

allele

Sample from tumor has only one

allele

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Fig 17.6

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 (see Table 17.1)

• 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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The incidence of some common cancers

varies between countries

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Table 17.1

Cancer development over time

Lung cancer death rates and incidence of cancer with age

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Fig 17.7

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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Fig 17.8

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

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Fig 17.9

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Fig 17.10

Some important definitions

 Cancer genes: the mutant alleles of normal genes that

lead to cancer.

 Mutant alleles that act dominantly are known as

oncogenes;

 The wild-type genesthat become oncogenes upon

mutation are known as proto-oncogenes.

 Mutant alleles that act recessively are known as mutant

tumor-suppressor genes

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 (Fig 17.11a)

 Many tumor viruses in animals are retroviruses

 Some DNA viruses carry oncogenes [e.g Human papillomavirus

(HPV)]

•Tumor DNA (Fig 17.11b)

 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 proto-oncogene can be packaged with the viral genome and become mutated.

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Fig 17.11a

Retroviruses and their associated oncogenes

 a virus carrying one or more oncogenes infects a cell,

the oncogenes cause abnormal proliferation  cells lead

to the accumulation of more mutations  cancer.

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Table 17.2

DNA from human tumor cells is able to transform normal mouse cells into tumor cells

Human gene that is oncogenic can be identified and cloned from transformed mouse cells

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Fig 17.11b

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Normal RAS is inactive until it becomes activated by binding of growth

factors to their receptors

Oncogenic forms of RAS are constitutively activated (GTP-activated form)

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Fig 17.11c

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Table 17.3

Mutations inactivate tumor suppressor genes cause cancer

Function of normal allele of tumor suppressor genes is to control cell

proliferation

Mutant tumor suppressor alleles act recessively and cause increased cell

proliferation

One wild-type copy produces enough protein to regulate

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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Fig 17.12

The retinoblastoma tumor-suppressor gene

Mutant allele of RB gene is recessive.

How can the retinoblastoma trait be inherited in a dominant fashion

if a deletion of the RB gene is recessive to the wild-type RB allele?

Because: in many retina heterozygous cells, only one cell can have

mutation at single remaining RB allele  a clone of cancerous cells.

The recessive RB mutation that leads to retinoblastoma through the

genomic analysis of families inheriting a predisposition to the

cancer

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

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Table 17.4

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Hartwell et al., 4th edition, Chapter 17

Outline

division

Four phases of the cell cycle:

G 1 , S, G 2 , and M

44

Fig 17.13

Experiments with yeast helped identify genes that control cell division

Two kinds of used: Saccharomyces cerevisiae (budding yeast) and

Schizosaccharomyces pombe (fission yeast)

Usefulness of yeast for studies of the cell cycle

• Both grow as haploids or diploids

 Can identify recessive mutations in haploids

 Can do complementation analysis in diploids

• S cerevisiae – size of buds serves as a marker of progress

through the cell cycle

 Daughter cells arise as small buds on mother cell at end of G 1 and grow during mitosis

 Stage of cell cycle can be determined by relative appearance of buds (see Fig 17.14)

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The isolation of temperature-sensitive mutants of yeast

Mutants grow normally at permissive

temperature (22°)

At restrictive temperature (36°), mutants

lose gene function

After replica plating, colonies that grow at

22° but not at 36° have

temperature-sensitive mutation

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Fig 17.15

A temperature-sensitive cell-cycle mutant inS cerevesiae

Cells grown at permissive temperature display buds of all sizes

(asynchronous division)

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Fig 17.14b Fig 17.14a

Growth of the same cells at restrictive temperature – all have large buds

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Some important cell-cycle and DNA repair genes

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Table 17.5

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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Fig 17.16a

 CDKs function only after associating with a cyclin.

 Cyclin specifies which set of proteins a CDK

phospholylates.

 Cyclins are unstable and their levels are regulated

strictly.

 Example: CDK phosphorylate to active the nuclear

lamins

CDKs control the dissolution of the nuclear membrane at mitosis

Nuclear 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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Fig 17.16

Mutant yeast permit the cloning of a human CDK gene

Human CDKs and cyclins can

function in yeast and replace

the corresponding yeast

proteins

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Fig 17.17

CDKs mediate the transition from the G 1 to the S phase of the cell cycle

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Fig 17.18

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Fig 17.19

Cell-cycle checkpoints ensure genomic stability

Checkpoints monitor the genome and cell-cycle machinery before allowing progression to the next stage of cell cycle

G 1 -to-S checkpoint

• DNA synthesis can be delayed to allow time for repair of DNA that was damaged during G 1

The G 2 -to-M checkpoint

• Mitosis can be delayed to allow time for repair of DNA that was damaged during G 2

Spindle checkpoint

• Monitors formation of mitotic spindle and engagement of all pairs of sister chromatids

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The G 1 -to-S checkpoint is activated

by DNA damage

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Fig 17.20a

Disruption of the G 1 -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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Fig 17.20b

Disruption of the G 1 -to-S checkpoint in

p53-deficient cells can lead to many types of chromosome rearrangements

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Fig 17.20c

Checkpoints acting at the G 2 -to-M cell-cycle transition or during M phase

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Fig 17.21

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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 (Fig 17.22)

•Chromosome aberrations

•Changes in ploidy

•Aneuploidy

Fig 17.22a

Chromosome painting can be used to detect chromosome rearrangements

Chromosomes from normal cells

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Fig 17.22

Chromosomes from tumor cells

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