2. Cancer Genetics

8/13/2019 2. Cancer Genetics

1/42

The Genetics of Cancer

1

PARTIV

4.1 Cancer: A Failure of Control over Cell Division

4.2 Common signaling molecules

4.3 Cell Cycle Regulation

OUTLINE


2/42

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

Copyright The McGraw-Hill Companies, Inc. Permission required to reproduce or displayHartwell et al., 4th edition, Chapter 17

2


3/42

Two unifying themes about cancer genetics

Cancer is a disease of genes

Multiple cancer phenotypes arise from mutations ingenes that regulate cell growth and division

Environmental chemicals increase mutation rates andincrease chances of cancer

Cancer has a different inheritance pattern than other geneticdisorders

Inherited mutations can predispose to cancer, but themutations causing cancer occur in somatic cells

Mutations accumulate in clonal descendants of asingle cell


3


4/42

Overview of the initiation of cell division

Two basic types of signals that tell cells whether to divide,metabolize, or die

Extracellular signalsact over long or short distances

Collectively known as hormones

Steroids, peptides, or proteins

Cell-bound signalsrequire direct contact between cells


4


5/42

An example of an extracellular signalthat acts over large distances

Thyroid-stimulatinghormone (TSH) producedin pituitary gland

Moves through blood to

thyroid gland, whichexpresses thyroxine


5


6/42

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


6


7/42

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, atransmembrane segment, and an intracellular domain

Signal transducers

Located in cytoplasm

Transcription factors

Activate expression of specific genes to either promoteor inhibit cell proliferation


7


8/42

Hormones transmit signals into cells throughreceptors that span the cellular membrane


8


9/42

Signaling systemscan stimulate or

inhibit growth

Signal transduction -

activation or inhibition ofintracellular targets afterbinding of growth factorto its receptor


9


10/42

RAS is an intracellular signaling molecule


10


11/42

Cancer phenotypes result from theaccumulation of mutations

Mutations are in genes controlling proliferation as well asother 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


11


12/42

Phenotypic changes that produceuncontrolled cell growth


12

Au tocr ine st imulation:

Cancer cells can maketheir own stimulatory

signals

Loss of con tact inhib i t ion:

Growth of cancer cellsdoesn't stop when thecells contact each other

a.1

a.2

Most normal cells Many cancer cells



13/42

Phenotypic changes that produceuncontrolled cell growth (cont)


13

Loss o f cel l death:

Cancer cells are moreresistant to programmedcell death (apoptosis)

Loss of gap junct ions:

Cancer cells lose channelsfor communicating withadjacent cells

a.3

a.4




14/42

Phenotypic changes that producegenomic and karyotypic instability

Defects in DNA repl icat ionmachinery:

Cancer cells have lost the abilityto replicate their DNA accurately

Increased mutation rates canoccur because of defects inDNA replication machinery


14

b.1


15/42

Phenotypic changes that producegenomic and karyotypic instability (cont)

Inc reased rate of

chrom osom al aberrations:

Cancer cells often havechromosome rearrangements

(translocations, deletions,aneuploidy, etc)

Some rearrangements appearregularly in specific tumortypes


15

Fig. 17.4b.2


16/42

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


16

Ab i l i ty to m etastasize:

Tumor cells can invadethe surrounding tissueand travel through thebloodstream

Angiogenesis:

Tumor cells can secretesubstances that promotegrowth of blood vessels

d.1

d.2


17/42

Evidence from mouse models that cancer iscaused by several mutations

Transgenic mice with dominantmutations in the mycgene andin the rasgene


17

Fig. 17.5a

(b)(a)

Mice with recessive mutationsin the p53 gene


18/42

The incidence of some common cancersvaries between countries


18


19/42

The role of environmental mutagens in cancer

Concordance for the same type of cancer in first degreerelatives (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 indigenouspopulation

Numerous environmental agents are mutagens and increasethe likelihood of cancer

Some viruses, cigarette smoke


19


20/42

Some families have a genetic predispositionto certain types of cancer

Example: retinoblastoma

caused by mutations in RBgene

Individuals who inherit onecopy of the RBallele areprone to cancer of the retina

During proliferation of retinalcells, the RB+allele is lost or

mutated

Tumors develop as a cloneof RB/RB cells


20


21/42

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


21


22/42

Cancer-producing mutations areof two general types


22


23/42

Oncogenes act dominantly and causeincreased proliferation

Oncogenes are produced when mutations cause improperactivation a gene

Two approaches to identifying oncogenes:

Tumor-causing viruses

Many tumor viruses in animals are retroviruses

Some DNA viruses carry oncogenes [e.g. Humanpapillomavirus (HPV)]

Tumor DNA

Transform normal mouse cells in culture with human tumorDNA


23


24/42

Cancer-causing retroviruses carry a mutant oroverexpressed copy of a cellular gene

After infection, retroviral genome integrates into hostgenome

If the retrovirus integrates near a proto-oncogene, the proto-oncogene can be packaged with the viral genome


24


25/42

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

Normal RAS is inactive until it becomes activated bybinding of growth factors to their receptors

Oncogenic forms of RAS are constitutively activated


25


26/42

Oncogenes are members of signaltransduction systems


26


27/42

Cancer can be caused by mutations thatimproperly inactivate tumor suppressor genes

Function of normal allele of tumor suppressor genes is tocontrol cell proliferation

Mutant tumor suppressor alleles act recessively and causeincreased cell proliferation

Tumor suppressor genes identified through genetic analysisof families with inherited predisposition to cancer

Inheritance of a mutant tumor suppressor allele

One normal allele sufficient for normal cell proliferationin heterozygotes

Wild-type allele in somatic cells of heterozygote can belost or mutated abnormal cell proliferation


27


28/42

The retinoblastoma tumor-suppressor gene


28


29/42


30/42

The normalcontrol of cell

divisionFour phases of the cellcycle:

G1

, S, G2

, and M


30


31/42

Some important cell-cycle andDNA repair genes


31


32/42

CDKs interact with cyclins and control the cellcycle by phosphorylating other proteins

Cyclin-dependent kinases (CDKs)family of kinases thatregulate the transition from G1 to S and from G2 to M

Cyclinspecifies the protein targets for CDK

Phosphorylation by CDKs can activate or inactive a protein


32


33/42

CDKs control the dissolution of thenuclear membrane at mitosis

Laminsprovide structural support to the nucleus

Form an insoluble matrix during most of the cell cycle

At mitosis, lamins are phosphorylated by CDKs and becomesoluble


33


34/42

CDKs mediate the transition from the G1to theS phase of the cell cycle


34


35/42

CDK activity in yeast is controlled byphosphorylation and dephosphorylation


35


36/42

Cell-cycle checkpoints ensuregenomic stability

Checkpoints monitor the genome and cell-cycle machinerybefore 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 DNAthat was damaged during G2

Spindle checkpoint

Monitors formation of mitotic spindle and engagementof all pairs of sister chromatids


36


37/42

The G1-to-S checkpoint is activatedby DNA damage


37


38/42

Disruption of the G1-to-S checkpoint inp53-deficient cells can lead to amplified DNA

Tumor cells often have homogenously staining regions(HSRs) or small, extrachromosomal pieces of DNA (doubleminutes)


38


39/42

Disruption of the G1-to-S checkpoint inp53-deficient cells can lead to many types of

chromosome rearrangements


39


40/42


41/42

The necessity of checkpoints

Checkpoints are not essential for cell division

Cells with defective checkpoints are viable and divide atnormal rates

But, they are much more vulnerable to DNA damage

than normal cells

Checkpoints help prevent transmission of three kinds ofgenomic instability

Chromosome aberrations

Changes in ploidy

Aneuploidy


41


42/42

Chromosome painting can be used to detectchromosome rearrangements

Chromosomes from normalcells

Chromosomes from tumorcells

Date post:	04-Jun-2018
Category:	Documents
Upload:	sylvestar-darvin
View:	222 times
Download:	0 times

2. Cancer Genetics

Documents