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MCDB 1041 Class 36: Genetics of Cancer Learning goals • Describe how cells become cancerous, and how cancer spreads • Explain how the kinds of mutations that usually lead to cancer affect the cell • Relate onset of cancer to the genes involved in the progression of the cell cycle • Explain where the cell cycle has checkpoints and what these checkpoints are testing for. • Predict the effects of losing one of the checkpoints. • Cancer is a group of diseases characterized by out of control cell division and ability to spread throughout the body • Cancer is caused by mutations in DNA, but is not necessarily inherited Why Do We Care About Cancer? – 2nd Leading cause of death in the US, behind heart disease • Around 500,000 Americans are expected to die this year from cancer – The total economic impact of cancer in the US is estimated to be 228 billion dollars http://www.pbs.org/pov/inthefamily/ video_classroom3.php#.UVscVhnagZ0 Cancer is a genetic disease • Cancer arises from the accumulation of genetic changes (mutations) • Most cancers have a minimum of 6-9 different genes mutated • We do not directly inherit cancer: we can only pass on susceptibility to cancer. • Many genes that are mutated in cancer code for proteins that are involved in regulating the cell cycle Cancer: Unregulated Cell Division Cell Division: One part of the cell cycle Cell Cycle: How cells normally reproduce to replace cells Cancer • Mis-regulating the cell cycle. – Cells divide when they aren’t supposed to. – Cells divide in a place they aren’t supposed to. • How does the cell normally coordinate this process? Handout Cell Cycle Overview On your sheet of paper, use these terms below to mark the arrows and make simple pictures of the cell at different stages to create your own cell cycle diagram. Chemotherapy Agents Indicate on your diagram where the three major types of chemotherapy agents would work: Inhibitors of DNA Duplication Inhibitors of Cell Division Inhibitors of Cell Growth What would happen if the cell cycle proceeded normally, except that cell division did not occur? A. The cell growth phases would become shorter. B. The separa6on of chromosomes couldn’t occur. C. The resul6ng cells would get smaller and smaller. D. Cells without nuclei would be formed. E. A large cell with mul6ple nuclei would result. There are three major points where the cell checks the progress of the cell cycle to insure that all is ready to proceed to the next step. Place these three “Checkpoints” on your diagram: Checkpoints 1 Cell Size Big Enough? 1. DNA undamaged before copying? 2. All Chromosomes Attached 2 to spindle and aligned? 3. 3 All Genetic Material Duplicated? Environment Favorable? Indicate the location of each cell cycle checkpoint III I 1. Cell Size Big Enough? DNA undamaged before copying? 2. All Chromosomes attached to spindle and aligned? 3. All Genetic Material Duplicated and undamaged? Environment Favorable? A. B. C. D. II= 3; III=2; IV= 1 II= 1; III= 2; IV=3 I= 1; II=3; IV= 2 II= 1; III=3, IV=2 DNA damage such as double strand breaks are detected at G1/S checkpoint by a protein called ATM. ATM activates another protein called p53 that halts the cell cycle at that checkpoint. If you were testing a new drug designed to activate the p53 protein, you could look for cells that were successfully arrested at this G1/S checkpoint by: A. determining if the amount of DNA is at half the level of a normal cell. B. counting chromosomes, arrested cells would be missing some. C. determining if the amount of DNA per cell always remains the same rather than doubling during S phase. D. determining if a spindle forms but never gets broken apart. What genes typically get mutated to lead to cancer? Types of cancer-causing genes Type of gene Normal function Tumor suppressor Suppresses cell division ProtoOncogene Promotes division Promotes division Repair genes Mutated function Fails to suppress division at abnormal levels, or in cells that shouldn’t divide Repair DNA mutations Fail to repair DNA mutations Types of proteins Growth factor inhibitors Growth factors Enzymes If you lose the function of a tumor suppressor gene, what do you think would happen? a. Decreased cell division b. Increased cell division c. No cell division Tumor suppressors normally put a stop to division: they make cells go into G0 rather than continuing into S phase Mutations in tumor suppressor are recessive Tumor&Suppressor&genes&at&the&cellular&level& Homozygous&&&&&&&& wild&type&(+/+)& Normal&cell&division& Heterozygous&(+/>)& *&& Normal&cell&division& Homozygous&& mutant&(>/>)& *&& *&& Excessive&cell&proliferaCon& Proto-oncogenes act dominantly at the cellular level • Genes that promote cell division when mutated, become “oncogenes” • Cancerous situations: • Expression of oncogene at the wrong time or in the wrong cell type • Mutation (dominant) causes protein to always “ON” What causes mutations? Most mutations are random, caused by “carcinogens”: Radiation UV light Some foods Chemicals In addition, a mutation can be inherited from a parent, resulting in a higher chance (predisposition) of getting cancer (as in the BRCA1 scenario).