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Genetics of CancerGenetics of Cancer
Alterations in the Cell CycleAlterations in the Cell Cycle
and Gene Mutations thatand Gene Mutations that
Cause CancerCause Cancer
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How do we define cancer?How do we define cancer?
Cancer is a group of disorders thatCancer is a group of disorders thatcauses cells to escape normal controlscauses cells to escape normal controls
on cell divisionon cell division
--cancer cells divide more frequentlycancer cells divide more frequently
--cancer cells are not inhibited by contact withcancer cells are not inhibited by contact withother cells and can form tumorsother cells and can form tumors
--cancer cells can invade other tissues, acancer cells can invade other tissues, aprocess called metastasisprocess called metastasis
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Non
Non--cancerouscancerouscells form sheets.cells form sheets.
Cancer cellsCancer cells
grow into tumors.grow into tumors.
Cancer cells canCancer cells can
invade other tissues.invade other tissues.
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Spread of Lung Cancer CellsSpread of Lung Cancer Cells
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Control of the Cell CycleControl of the Cell Cycle
Mechanisms for controlling progressMechanisms for controlling progress
through the cell cycle:through the cell cycle:
CheckpointsCheckpoints
Length of TelomeresLength of Telomeres
Chemical Signals from within andChemical Signals from within and
outside the celloutside the cell
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Cell Cycle CheckpointsCell Cycle Checkpoints
G1S
G2
cytoplasmdoubles
chromosomes
replicate
assembly of
components
for divisioncytokinesis
P M
A T
Mitosis
DNA DamageDNA Damage
CheckpointsCheckpoints
DNA DamageDNA Damage
CheckpointCheckpoint
ApoptosisApoptosisCheckpointCheckpoint
SpindleSpindle
AssemblyAssemblyCheckpointCheckpoint
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Length of TelomeresLength of Telomeres
Telomeres areTelomeres arestructures at the endsstructures at the endsof chromosomes thatof chromosomes thatshorten with each cellshorten with each cell
division. After 50division. After 50divisions, thedivisions, theshortened length ofshortened length oftelomeres causestelomeres causes
mitosis to stop.mitosis to stop.
telomerestelomeres
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Failure to Stop atFailure to Stop at
Cell Cycle CheckpointsCell Cycle Checkpoints
Mutation in a gene thatMutation in a gene that
usually slows the cellusually slows the cellcyclecycle
Rate of cell division isRate of cell division is
accelerated.accelerated.
Failure to pause forFailure to pause for
DNA repairDNA repair
Faulty DNA leads toFaulty DNA leads to
unregulated cell growth.unregulated cell growth.
Loss of control overLoss of control overtelomere lengthtelomere length
Cancer cells haveCancer cells havetelomerase, an enzymetelomerase, an enzyme
that elongates telomeres.that elongates telomeres.
Cells continue to divideCells continue to divide
after 50 mitoses.after 50 mitoses.
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Chemical Signals that Control the Cell CycleChemical Signals that Control the Cell Cycle
1.1. Cyclin and KinaseCyclin and Kinase
--proteins that initiate mitosisproteins that initiate mitosis
--requires buildup of cyclin to pair with kinaserequires buildup of cyclin to pair with kinase
2.2. HormonesHormones
--chemical signals from specialized glandschemical signals from specialized glandsthat stimulate mitosisthat stimulate mitosis
3.3. Growth FactorsGrowth Factors--chemical factors produced locally thatchemical factors produced locally thatstimulate mitosisstimulate mitosis
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Apoptosis: Cell DeathApoptosis: Cell Death
Signal arrives at
death receptor
on cell
White blood
cells destroy cell
fragments
Caspase
enzymes carry
out cell
destruction
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Applying Your KnowledgeApplying Your Knowledge
Indicate whether each statement is TRUE orFALSEIndicate whether each statement is TRUE orFALSE
Cancer cells escape the normal controls on cellCancer cells escape the normal controls on celldivision.division.
The growth of a cancer cell is stopped by contactThe growth of a cancer cell is stopped by contact
with another cell.with another cell.
Apoptosis is a process for destroying damagedApoptosis is a process for destroying damaged
cells.cells.
Structures at the ends of chromosomes areStructures at the ends of chromosomes are
called centromeres.called centromeres.
TRUE: Thumbs UpTRUE: Thumbs UpFALSE: Thumbs DownFALSE: Thumbs Down
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A series of mutations is responsible for theA series of mutations is responsible for the
development ofFAP colon cancer.development ofFAP colon cancer.
Oncogene TumorSuppressor
Gene
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Genetic Mutations ThatGenetic Mutations That
Can Cause CancerCan Cause Cancer
OncogenesOncogenes
Formed when protoFormed when proto--oncogenes thatoncogenes thatpromote cell division are improperlypromote cell division are improperlyactivated.activated.
May lead toMay lead to
increased expression of the gene in aincreased expression of the gene in a
new locationnew location production of fusion proteins with newproduction of fusion proteins with new
functionsfunctions
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Ras ProtoRas Proto--OncogeneOncogene
In response to growth factor
binding at receptor, the Ras
gene product combines with
GTP to promote cell division
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 tostimulate cell division
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Movement of a protoMovement of a proto--oncogene on chromosome 8oncogene on chromosome 8to the vicinity of a highly active gene onto the vicinity of a highly active gene on
chromosome 14 causes Burkitts lymphoma.chromosome 14 causes Burkitts lymphoma.
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The Philadelphia Chromosome found inThe Philadelphia Chromosome found inpatients with Chronic Myeloid Leukemia causespatients with Chronic Myeloid Leukemia causes
a fusion protein to be made from a combinationa fusion protein to be made from a combination
of genes on chromosomes 9 and 22.of genes on chromosomes 9 and 22.
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Genetic Mutations That Can Cause CancerGenetic Mutations That Can Cause Cancer
TumorSuppressor GenesTumorSuppressor Genes Genes that inhibit cell division areGenes that inhibit cell division are
inactivated.inactivated.
Mutation in a gene that halts the cell cycleMutation in a gene that halts the cell cyclein G1 causes retinoblastoma.in G1 causes retinoblastoma.
Mutation in p53, a gene that promotesMutation in p53, a gene that promotes
apoptosis if a cell has damaged DNA, leadsapoptosis if a cell has damaged DNA, leads
to a variety of cancers.to a variety of cancers. Mutation in BRCA1, involved in tumorMutation in BRCA1, involved in tumor
suppression and DNA repair, leads tosuppression and DNA repair, leads to
inherited breast cancer.inherited breast cancer.
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In Normal Cells, the Rb Gene ProductIn Normal Cells, the Rb Gene Product
Controls the G1Controls the G1 S TransitionS Transition
Rb = product of
Retinoblastoma gene,
inhibits action of E2F until
chemically modified
People prone to retinoblastoma have one mutated copy of the RbPeople prone to retinoblastoma have one mutated copy of the Rb
gene (Rbgene (Rb--) and one normal copy (Rb) and one normal copy (Rb++). Conversion of the Rb). Conversion of the Rb++ copycopy
to Rbto Rb--
by mutation leads to uncontrolled growth of retinal cells.by mutation leads to uncontrolled growth of retinal cells.
E2F = transcription factor
required to activate genes
for DNA synthesis
CDK-cyclin (intracellular
signal) modifies Rb so
the E2F can mediatethe G1S transition
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In Normal Cells, the p53 Gene ProductIn Normal Cells, the p53 Gene Product
Acts at the G1Acts at the G1 S Checkpoint PreventingS Checkpoint Preventing
Entry Into S Phase If DNA Is DamagedEntry Into S Phase If DNA Is Damaged
p21 inhibits intracellular signals
that would activate EF2
p53 = transcription factor that
causes p21 to be produced
Cells with
damaged DNA
do not pass the
G1S checkpoint
In cancer cells the mutated p53 gene
product no longer stimulates p21
production. Cells will pass the G1 S
checkpoint even when chromosomal
damage exists.
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In Normal Cells, the p53 Gene Product StimulatesIn Normal Cells, the p53 Gene Product Stimulates
Apoptosis If DNA Damage Cannot Be RepairedApoptosis If DNA Damage Cannot Be Repairedp53 gives an internal
signal for apoptosis
In cancer cells, a mutated p53
gene product no longer initiates
self-destruction. Cells with
damaged DNA can divide and
more DNA damage can be
accumulated.
p53 is the most frequently mutated
of all known cancer-causing genes,
contributing to many types of cancer.
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Genetic Mutations That Can Cause CancerGenetic Mutations That Can Cause Cancer
DNA Repair GenesDNA Repair Genes Genes that promote DNA repair are inactivated.Genes that promote DNA repair are inactivated.
BRCA1 is a tumor suppressor involved inBRCA1 is a tumor suppressor involved in
DNA repair. Faulty copies of BRCA1 causeDNA repair. Faulty copies of BRCA1 cause
inherited breast cancer.inherited breast cancer. The disease Xeroderma PigmentosumThe disease Xeroderma Pigmentosum
results from a defect in excision repair.results from a defect in excision repair.
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Applying Your KnowledgeApplying Your Knowledge
Indicate whether each statement isIndicate whether each statement isTRUE orFALSE:TRUE orFALSE:
Oncogenes are formed by mutations of genesOncogenes are formed by mutations of genes
that normally stimulate cell division.that normally stimulate cell division.
Cancer Cancer--causing mutations in tumor suppressorcausing mutations in tumor suppressor
genes inhibit cell divisiongenes inhibit cell division
TRUE: Thumbs UpTRUE: Thumbs UpFALSE: Thumbs DownFALSE: Thumbs Down
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Applying Your KnowledgeApplying Your Knowledge
Which description best represents theWhich description best represents the
Cancer Cancer--causing Rb mutation?causing Rb mutation?
Cancer Cancer--causing p53 mutation?causing p53 mutation?
Cancer Cancer--causing RAS mutation?causing RAS mutation?
Cancer Cancer--causing BRCA1 mutation?causing BRCA1 mutation?
Thumbs Up: OncogeneThumbs Up: Oncogene
Thumbs Down: TumorSuppressor GeneThumbs Down: TumorSuppressor Gene
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