Genetics of Cancer-0

8/3/2019 Genetics of Cancer-0

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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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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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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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Genetics of Cancer-0

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