Genetics of CancerGenetics of Cancer

Genetic Mutations that Lead Genetic Mutations that Lead to Uncontrolled Cell Growth to Uncontrolled Cell Growth

How do we define cancer?How do we define cancer?

Cancer is a group of disorders that Cancer is a group of disorders that causes cells to escape normal controls causes cells to escape normal controls on cell divisionon cell division--cancer cells divide more frequentlycancer cells divide more frequently

-cancer cells divide an unlimited number of -cancer cells divide an unlimited number of times times-cancer cells are not inhibited by contact with-cancer cells are not inhibited by contact with other cells and can form tumors other cells and can form tumors-cancer cells can invade other tissues, a -cancer cells can invade other tissues, a process called metastasis process called metastasis

Non-cancerous Non-cancerous cells form sheets.cells form sheets.

Cancer cellsCancer cellsgrow into tumors.grow into tumors.

Cancer cells canCancer cells caninvade other tissues.invade other tissues.

A series of mutations is responsible for the A series of mutations is responsible for the development of FAP colon cancer. development of FAP colon cancer.

OncogeneOncogene Tumor Tumor SuppressorSuppressor

Cancer is the result of a series of Cancer is the result of a series of mutations in genes already existing within mutations in genes already existing within the cell. Environmental agents cause a the cell. Environmental agents cause a significant number of these mutations. significant number of these mutations.

Clonal Clonal Evolution Evolution of Tumor of Tumor

CellsCells

Cells gain mutations Cells gain mutations that increase their that increase their ability to divide and ability to divide and metastasizemetastasize

Types of Mutations Causing Types of Mutations Causing CancerCancer

• Dominant Oncogenic AllelesDominant Oncogenic Alleles– Gain of function mutationsGain of function mutations– Dominant allele codes for gene product that Dominant allele codes for gene product that

stimulates cell proliferationstimulates cell proliferation– Proto-oncogene undergoes mutation or Proto-oncogene undergoes mutation or

comes under alternate control to become comes under alternate control to become an oncogene (may involve viruses)an oncogene (may involve viruses)

– Increased cell division provides an Increased cell division provides an opportunity to accumulate mutations in opportunity to accumulate mutations in additional genesadditional genes

Dominant Oncogenic AllelesDominant Oncogenic Alleles

Types of Mutations Causing Types of Mutations Causing CancerCancer

• Recessive Tumor Suppressor Recessive Tumor Suppressor AllelesAlleles– Loss of function mutationsLoss of function mutations– Recessive allele codes for gene Recessive allele codes for gene

product that fails to inhibit cell product that fails to inhibit cell proliferationproliferation

– Heterozygous individual is prone to Heterozygous individual is prone to cancer development when the single cancer development when the single copy of dominant allele is mutated to a copy of dominant allele is mutated to a recessive allelerecessive allele

Recessive Tumor Suppressor AllelesRecessive Tumor Suppressor Alleles

Applying Your KnowledgeApplying Your Knowledge

Indicate whether each statement is TRUE or FALSEIndicate whether each statement is TRUE or FALSE• Cancer cells escape the normal controls on cell Cancer cells escape the normal controls on cell

division. division. • Oncogenes are recessive mutations. Oncogenes are recessive mutations. • The growth of a cancer cell is stopped by The growth of a cancer cell is stopped by

contact with another cell.contact with another cell.• Cancer-causing mutations in tumor suppressor Cancer-causing mutations in tumor suppressor

alleles represent a loss of function.alleles represent a loss of function.

TRUE: Thumbs UpTRUE: Thumbs UpFALSE: Thumbs Down FALSE: Thumbs Down

Control of the Cell CycleControl of the Cell Cycle

Mechanisms for controlling progress Mechanisms for controlling progress through the cell cyclethrough the cell cycleExtracellular Signals Extracellular Signals

Control the timing of cell division Control the timing of cell division TransitionsTransitions

Orderly progression from one stage of cell Orderly progression from one stage of cell cycle to anothercycle to another

CheckpointsCheckpointsDelay progression to next stage if cell Delay progression to next stage if cell

must repair damage must repair damage

Extracellular SignalsExtracellular Signals Ras is a G-protein that is part Ras is a G-protein that is part of a signal transduction of a signal transduction pathway to stimulate cell pathway to stimulate cell division, in response to division, in response to growth factor binding to a growth factor binding to a transmembrane receptortransmembrane receptor

Extracellular SignalsExtracellular Signals The normal RAS protein product The normal RAS protein product is reversibly activated by a signal is reversibly activated by a signal from a growth factor and from a growth factor and stimulates cell proliferation only stimulates cell proliferation only when active.when active.

The RAS oncogene is The RAS oncogene is always activated, leading always activated, leading to uncontrolled growth.to uncontrolled growth.

Cell Cycle Transitions and CheckpointsCell Cycle Transitions and Checkpoints

G1S

G2

cytoplasm doubles

chromosomesreplicate

assembly of components for division cytokinesis

P MA

TMitosis

G1G1S S TransitionTransition

G2G2M M CheckpointCheckpoint

DNA DamageDNA DamageCheckpointCheckpoint

ApoptosisApoptosisCheckpointCheckpoint

G2G2M M TransitionTransition Spindle Spindle

AssemblyAssemblyCheckpointCheckpoint

G1G1S S CheckpointCheckpoint

SSG2G2TransitionTransition

Proteins Controlling Cell Cycle TransitionsProteins Controlling Cell Cycle Transitions • G1G1S and G2S and G2M Transitions are M Transitions are

controlled by CDK-cyclin complexescontrolled by CDK-cyclin complexes– CDK = cyclin-dependent kinaseCDK = cyclin-dependent kinase

• Enzyme that activates or inactivates a target Enzyme that activates or inactivates a target protein by phosphorylationprotein by phosphorylation

– Cyclin Cyclin • Protein that accumulates at specific stages of cell Protein that accumulates at specific stages of cell

cycle to associate with CDK and specify the cycle to associate with CDK and specify the target proteinstarget proteins

• Cyclin levels are controlled Cyclin levels are controlled by gene regulation and by gene regulation and protein degradation protein degradation

Phosphorylation of Rb Protein Mediates the Phosphorylation of Rb Protein Mediates the G1G1 S Transition S Transition

Rb = product of the retinoblastoma geneRb = product of the retinoblastoma geneE2F = transcription factorE2F = transcription factor

How Do Mutations in Rb How Do Mutations in Rb

Cause Retinal Cancer?Cause Retinal Cancer?

In heterozygotes, conversion of the RbIn heterozygotes, conversion of the Rb++ allele to Rb allele to Rb- -

by mutation leads to uncontrolled growth of retinal cells. by mutation leads to uncontrolled growth of retinal cells.

Tumor Suppressor Genes p53 and p21 Tumor Suppressor Genes p53 and p21 Control the G1Control the G1 S Checkpoint S Checkpoint

How Do Mutations in p53 How Do Mutations in p53

Cause Cancer?Cause Cancer?

In the absence of p53 function, In the absence of p53 function, cells enter S phase despite cells enter S phase despite breaks in chromosomes. This breaks in chromosomes. This can lead to chromosomal can lead to chromosomal rearrangements. rearrangements.

How Do Mutations in p53 How Do Mutations in p53

Cause Cancer?Cause Cancer?

If DNA damage cannot be If DNA damage cannot be repaired, functional p53 repaired, functional p53 protein triggers apoptosis protein triggers apoptosis (programmed cell death). (programmed cell death). Mutations in p53 allow Mutations in p53 allow defective cells to proliferate. defective cells to proliferate.

p53 gives an internal signal for apoptosis

Defects in DNA Repair Defects in DNA Repair •BRCA1 is a tumor BRCA1 is a tumor suppressor involved suppressor involved in DNA repair. Faulty in DNA repair. Faulty copies of BRCA1 copies of BRCA1 cause inherited breast cause inherited breast cancer. cancer.

•The disease Xeroderma The disease Xeroderma Pigmentosum results Pigmentosum results from a defect in from a defect in nucleotide excision nucleotide excision repair. repair.

Viral Origin of Viral Origin of Some CancersSome Cancers

Retroviruses can cause Retroviruses can cause cancer by mutating or cancer by mutating or rearranging host genesrearranging host genes

Viral Origin of Some CancersViral Origin of Some Cancers

Retroviruses can cause cancer by Retroviruses can cause cancer by changing the expression of host geneschanging the expression of host genes

Applying Your KnowledgeApplying Your Knowledge

Which description best represents theWhich description best represents the

• Cancer-causing allele for Rb protein?Cancer-causing allele for Rb protein?

• Extracellular signal for cell division? Extracellular signal for cell division?

• Cancer-causing RAS allele?Cancer-causing RAS allele?

• Component that influences cell cycle Component that influences cell cycle progress through phosphorylation of progress through phosphorylation of molecules?molecules?

1.1. Dominant Oncogenic AlleleDominant Oncogenic Allele2.2. Recessive Tumor Suppressor AlleleRecessive Tumor Suppressor Allele3.3. CDK-Cyclin ComplexCDK-Cyclin Complex4.4. Growth FactorGrowth Factor