Genetics of Cancer Genetic Mutations that Lead to Uncontrolled Cell Growth

How do we define cancer? Cancer is a group of disorders that causes cells to escape normal controls on cell division Cancer is a group of disorders that causes cells to escape normal controls on cell division - cancer cells divide more frequently -cancer cells divide an unlimited number of times -cancer cells divide an unlimited number of times -cancer cells are not inhibited by contact with other cells and can form tumors -cancer cells can invade other tissues, a process called metastasis

Non-cancerous cells form sheets. Cancer cells grow into tumors. Cancer cells can invade other tissues.

A series of mutations is responsible for the development of FAP colon cancer. Oncogene Tumor Suppressor Cancer is the result of a series of mutations in genes already existing within the cell. Environmental agents cause a significant number of these mutations.

Clonal Evolution of Tumor Cells Cells gain mutations that increase their ability to divide and metastasize Cells gain mutations that increase their ability to divide and metastasize

Types of Mutations Causing Cancer Dominant Oncogenic AllelesDominant Oncogenic Alleles –Gain of function mutations –Dominant allele codes for gene product that stimulates cell proliferation –Proto-oncogene undergoes mutation or comes under alternate control to become an oncogene (may involve viruses) –Increased cell division provides an opportunity to accumulate mutations in additional genes

Dominant Oncogenic Alleles

Types of Mutations Causing Cancer Recessive Tumor Suppressor AllelesRecessive Tumor Suppressor Alleles –Loss of function mutations –Recessive allele codes for gene product that fails to inhibit cell proliferation –Heterozygous individual is prone to cancer development when the single copy of dominant allele is mutated to a recessive allele

Recessive Tumor Suppressor Alleles

Applying Your Knowledge Indicate whether each statement is TRUE or FALSE Cancer cells escape the normal controls on cell division.Cancer cells escape the normal controls on cell division. Oncogenes are recessive mutations.Oncogenes are recessive mutations. The growth of a cancer cell is stopped by contact with another cell.The growth of a cancer cell is stopped by contact with another cell. Cancer-causing mutations in tumor suppressor alleles represent a loss of function.Cancer-causing mutations in tumor suppressor alleles represent a loss of function. TRUE: Thumbs Up FALSE: Thumbs Down

Control of the Cell Cycle Mechanisms for controlling progress through the cell cycle Mechanisms for controlling progress through the cell cycle Extracellular Signals Extracellular Signals Control the timing of cell division Control the timing of cell division Transitions Transitions Orderly progression from one stage of cell cycle to another Orderly progression from one stage of cell cycle to another Checkpoints Checkpoints Delay progression to next stage if cell must repair damage Delay progression to next stage if cell must repair damage

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

Extracellular Signals The normal RAS protein product is reversibly activated by a signal from a growth factor and stimulates cell proliferation only when active. The RAS oncogene is always activated, leading to uncontrolled growth.

Cell Cycle Transitions and Checkpoints G1 S G2 cytoplasm doubles chromosomes replicate assembly of components for division cytokinesis P M A T Mitosis G1  S Transition G2  M Checkpoint DNA Damage Checkpoint ApoptosisCheckpoint G2  M TransitionSpindleAssemblyCheckpoint G1  S Checkpoint S  G2 Transition

Proteins Controlling Cell Cycle Transitions G1  S and G2  M Transitions are controlled by CDK-cyclin complexesG1  S and G2  M Transitions are controlled by CDK-cyclin complexes –CDK = cyclin-dependent kinase Enzyme that activates or inactivates a target protein by phosphorylationEnzyme that activates or inactivates a target protein by phosphorylation –Cyclin Protein that accumulates at specific stages of cell cycle to associate with CDK and specify the target proteinsProtein that accumulates at specific stages of cell cycle to associate with CDK and specify the target proteins Cyclin levels are controlled by gene regulation and protein degradationCyclin levels are controlled by gene regulation and protein degradation

Phosphorylation of Rb Protein Mediates the G1  S Transition Rb = product of the retinoblastoma gene E2F = transcription factor

How Do Mutations in Rb Cause Retinal Cancer? In heterozygotes, conversion of the Rb + allele to Rb - by mutation leads to uncontrolled growth of retinal cells.

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

How Do Mutations in p53 Cause Cancer? In the absence of p53 function, cells enter S phase despite breaks in chromosomes. This can lead to chromosomal rearrangements.

How Do Mutations in p53 Cause Cancer? If DNA damage cannot be repaired, functional p53 protein triggers apoptosis (programmed cell death). Mutations in p53 allow defective cells to proliferate. p53 gives an internal signal for apoptosis

Defects in DNA Repair BRCA1 is a tumor suppressor involved in DNA repair. Faulty copies of BRCA1 cause inherited breast cancer.BRCA1 is a tumor suppressor involved in DNA repair. Faulty copies of BRCA1 cause inherited breast cancer. The disease Xeroderma Pigmentosum results from a defect in nucleotide excision repair.The disease Xeroderma Pigmentosum results from a defect in nucleotide excision repair.

Viral Origin of Some Cancers Retroviruses can cause cancer by mutating or rearranging host genes

Viral Origin of Some Cancers Retroviruses can cause cancer by changing the expression of host genes

Applying Your Knowledge Which 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 progress through phosphorylation of molecules?Component that influences cell cycle progress through phosphorylation of molecules? 1.Dominant Oncogenic Allele 2.Recessive Tumor Suppressor Allele 3.CDK-Cyclin Complex 4.Growth Factor