Genetics of CancerGenetics of Cancer

Alterations in the Cell Cycle Alterations in the Cell Cycle and Gene Mutations that and Gene Mutations that Cause CancerCause Cancer

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 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.

Spread of Lung Cancer CellsSpread of Lung Cancer Cells

Control of the Cell CycleControl of the Cell Cycle

Mechanisms for controlling progress Mechanisms for controlling progress through the cell cycle:through the cell cycle:

CheckpointsCheckpointsLength of TelomeresLength of TelomeresChemical Signals from within and Chemical Signals from within and

outside the celloutside the cell

Cell Cycle Checkpoints Cell Cycle Checkpoints

G1S

G2

cytoplasm doubles

chromosomesreplicate

assembly of components for division cytokinesis

P MA

T

Mitosis

DNA DamageDNA DamageCheckpointsCheckpoints

DNA DamageDNA DamageCheckpointCheckpoint

ApoptosisApoptosisCheckpointCheckpoint

Spindle Spindle AssemblyAssemblyCheckpointCheckpoint

Length of TelomeresLength of Telomeres

Telomeres are Telomeres are structures at the ends structures at the ends of chromosomes that of chromosomes that shorten with each cell shorten with each cell division. After 50 division. After 50 divisions, the divisions, the shortened length of shortened length of telomeres causes telomeres causes mitosis to stop.mitosis to stop.

telomeres telomeres

Failure to Stop atFailure to Stop atCell Cycle CheckpointsCell Cycle Checkpoints

Mutation in a gene that Mutation in a gene that usually slows the cell usually slows the cell cyclecycle

Rate of cell division is Rate of cell division is accelerated.accelerated.

Failure to pause for Failure to pause for DNA repairDNA repair

Faulty DNA leads to Faulty DNA leads to unregulated cell growth.unregulated cell growth.

Loss of control over Loss of control over telomere lengthtelomere length

Cancer cells have Cancer cells have telomerase, an enzyme telomerase, an enzyme that elongates telomeres. that elongates telomeres. Cells continue to divide Cells continue to divide after 50 mitoses.after 50 mitoses.

Chemical Signals that Control the Cell CycleChemical Signals that Control the Cell Cycle

1.1. Cyclin and KinaseCyclin and Kinase--proteins that initiate mitosis proteins that initiate mitosis

-requires buildup of cyclin to pair with kinase -requires buildup of cyclin to pair with kinase

2.2. HormonesHormones--chemical signals from specialized glands chemical signals from specialized glands that stimulate mitosis that stimulate mitosis

3.3. Growth FactorsGrowth Factors-chemical factors produced locally that -chemical factors produced locally that stimulate mitosisstimulate mitosis

Apoptosis: Cell DeathApoptosis: Cell Death

Signal arrives at “death” receptor

on cell

White blood cells destroy cell

fragments

Caspase enzymes carry

out cell destruction

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. • The growth of a cancer cell is stopped by contact The growth of a cancer cell is stopped by contact

with another cell.with another cell.• Apoptosis is a process for destroying damaged Apoptosis is a process for destroying damaged

cells. cells. • Structures at the ends of chromosomes are Structures at the ends of chromosomes are

called centromeres.called centromeres.

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

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.

Oncogene Tumor Suppressor Gene

Genetic Mutations That Genetic Mutations That Can Cause CancerCan Cause Cancer

OncogenesOncogenes• Formed when proto-oncogenes that Formed when proto-oncogenes that

promote cell division are improperly promote cell division are improperly activated. activated. May lead to May lead to – increased expression of the gene in a increased expression of the gene in a

new locationnew location– production of fusion proteins with new production of fusion proteins with new

functionsfunctions

Ras Proto-OncogeneRas Proto-Oncogene

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 to stimulate cell division

Movement of a proto-oncogene on chromosome 8 Movement of a proto-oncogene on chromosome 8 to the vicinity of a highly active gene on to the vicinity of a highly active gene on chromosome 14 causes Burkitt’s lymphoma. chromosome 14 causes Burkitt’s lymphoma.

The Philadelphia Chromosome found in The Philadelphia Chromosome found in patients with Chronic Myeloid Leukemia causes patients with Chronic Myeloid Leukemia causes a fusion protein to be made from a combination a fusion protein to be made from a combination of genes on chromosomes 9 and 22. of genes on chromosomes 9 and 22.

Genetic Mutations That Can Cause CancerGenetic Mutations That Can Cause Cancer

Tumor Suppressor GenesTumor Suppressor Genes• Genes that inhibit cell division are Genes that inhibit cell division are

inactivated. inactivated. – Mutation in a gene that halts the cell cycle Mutation in a gene that halts the cell cycle

in G1 causes retinoblastoma.in G1 causes retinoblastoma.– Mutation in p53, a gene that promotes Mutation in p53, a gene that promotes

apoptosis if a cell has damaged DNA, leads apoptosis if a cell has damaged DNA, leads to a variety of cancers. to a variety of cancers.

– Mutation in BRCA1, involved in tumor Mutation in BRCA1, involved in tumor suppression and DNA repair, leads to suppression and DNA repair, leads to inherited breast cancer.inherited breast cancer.

In Normal Cells, the Rb Gene Product In Normal Cells, the Rb Gene Product

Controls the G1Controls the G1 S Transition S Transition Rb = product of

Retinoblastoma gene, inhibits action of E2F until

chemically modified

People prone to retinoblastoma have one mutated copy of the Rb People prone to retinoblastoma have one mutated copy of the Rb gene (Rb-) and one normal copy (Rbgene (Rb-) and one normal copy (Rb++). Conversion of the Rb). Conversion of the Rb++ copy copy

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 mediate the G1S transition

In Normal Cells, the p53 Gene Product In Normal Cells, the p53 Gene Product Acts at the G1Acts at the G1 S Checkpoint Preventing S 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.

In Normal Cells, the p53 Gene Product Stimulates In Normal Cells, the p53 Gene Product Stimulates Apoptosis If DNA Damage Cannot Be RepairedApoptosis If DNA Damage Cannot Be Repaired

p53 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.

Genetic Mutations That Can Cause CancerGenetic Mutations That Can Cause Cancer

DNA Repair Genes DNA Repair Genes • Genes that promote DNA repair are inactivated.Genes that promote DNA repair are inactivated.

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

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

Applying Your KnowledgeApplying Your Knowledge

Indicate whether each statement is Indicate whether each statement is TRUE or FALSE:TRUE or FALSE:

• Oncogenes are formed by mutations of genes Oncogenes are formed by mutations of genes that normally stimulate cell division. that normally stimulate cell division.

• Cancer-causing mutations in tumor suppressor Cancer-causing mutations in tumor suppressor genes inhibit cell divisiongenes inhibit cell division

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

Applying Your KnowledgeApplying Your Knowledge

Which description best represents theWhich description best represents the

• Cancer-causing Rb mutation? Cancer-causing Rb mutation?

• Cancer-causing p53 mutation? Cancer-causing p53 mutation?

• Cancer-causing RAS mutation?Cancer-causing RAS mutation?

• Cancer-causing BRCA1 mutation?Cancer-causing BRCA1 mutation?

Thumbs Up: OncogeneThumbs Up: OncogeneThumbs Down: Tumor Suppressor GeneThumbs Down: Tumor Suppressor Gene