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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 cells divide more frequently -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. Cancer is the result of a series of mutations in genes already existing within the cell. Environmental agents cause a signficant number of these mutations. Oncogene Tumor Suppressor A series of mutations is responsible for the development of FAP colon cancer. Types of Mutations Causing Cancer • Dominant 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 opportunity to accumulate mutations in additional genes Types of Mutations Causing Cancer • Recessive Tumor Suppressor Alleles – Loss of function mutations – Recessive allele codes for gene product that fails to inhibit cell proliferation. Applying Your Knowledge TRUE: Thumbs Up FALSE: Thumbs Down Indicate whether each statement is TRUE or FALSE • Cancer cells escape the normal controls on cell division. • Oncogenes are recessive mutations. • 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. Control of the Cell Cycle Mechanisms for controlling progress through the cell cycle Extracellular Signals Control the timing of cell division Transitions Orderly progression from one stage of cell cycle to another Checkpoints Delay progression to next stage if cell must repair damage Extracellular Signals The normal RAS protein product is reversibly activated by a signal from a growth factor and stimulates cell proliferation when active. The RAS oncogene is always activated, leading to uncontrolled growth. Cell Cycle Transitions and Checkpoints G2M Transition Apoptosis Checkpoint G2M Checkpoint SG2 Transition P M G2 assembly of components for division S A T Mitosis cytokinesis G1 chromosomes replicate DNA Damage Checkpoint Spindle Assembly Checkpoint cytoplasm doubles G1S Transition G1S Checkpoint Proteins Controlling Cell Cycle Transitions • G1S and G2M Transitions are controlled by CDK-cyclin complexes – CDK = cyclin-dependent kinase • Enzyme 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 proteins • Cyclin 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 Rbby 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? p53 gives an internal signal for apoptosis If DNA damage cannot be repaired, functional p53 protein triggers apoptosis (programmed cell death). Mutations in p53 allow defective cells to proliferate. Defects in DNA Repair •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. Applying Your Knowledge 1. 2. 3. 4. Dominant Oncogenic Allele Recessive Tumor Suppressor Allele CDK-Cyclin Complex Growth Factor Which description best represents the • Cancer-causing allele for Rb protein? • Extracellular signal for cell division? • Cancer-causing RAS allele? • Component that influences cell cycle progress through phosphorylation of molecules?
