Genetics of CancerLecture 34Age Specific Cancer Rates: Males and Females,Ireland, 1994-1999Properties of Cancer Cells• Loss of Contact inhibition• Anchorage independent growth• Can grow indefinitely• Can grow with low levels of serum growth factorsWhat do cancer cells look like?http://140.116.60.1/mdlai/Handout/cancer-medicine-2000/img009.GIFhttp://140.116.60.1/mdlai/Handout/cancer-medicine-2000/img009.GIFWhat do cancer cells look like?Where do they come from?Most of the mutations that contribute to cancer occur insomatic cells – but germ line mutations can also contributeegg spermzygoteendodermcolongrowth anddifferentiationmitoticdivisionsmitoticdivisions2 meioticdivisionsgametes (eggs or sperm)All tissuesMost of the mutations that contribute to cancer occur insomatic cells – but germ line mutations can also contributeegg spermzygoteendodermcolongrowth anddifferentiationmitoticdivisionsmitoticdivisions2 meioticdivisionsgametes (eggs or sperm)germ lineAll tissuesThe Genetic Basis of Cancer andTheodor Boveri 1862 - 1915• Established that chromosomescarry the hereditary information byshowing that aberrant segregationof chromosomes leads to certainphenotypes in sea urchin eggs.• Suggested that aberrantsegregation of human chromosomescould be responsible for a normal cellbecoming a tumor cell• Suggested that some chromosomespromoted cell growth and othersinhibit cell growthMarcella O’Grady Boveri (1863-1950) also contributedMajor complications in understandingthe genetic basis of cancer• Multiple mutations are necessary to produce a tumor cell• Different types of tumor have different genes mutated• Early initiating events occur rarely in complex tissuesand are therefore extremely difficult to detect• The key initiating event often leads to an increase inmutation rate thus tumor cells often bear many fortuitousmutationsOncogenesdominant gain-of-function mutationspromote cell transformationTumor suppressor genesrecessive, loss-of-function mutationspromote cell transformationMutator genesUsually recessive, loss-of-function mutationsthat increase spontaneous and environmentallyinduced mutation ratesAlterations in different kinds ofGenes cause CancerMost of the mutations that contribute to cancer occur insomatic cells – but germ line mutations can also contributeegg spermzygoteendodermcolongrowth anddifferentiationmitoticdivisionsmitoticdivisions2 meioticdivisionsgametes (eggs or sperm)germ lineAll tissuesCytoplasmicsignaltransductionproteinsNuclearproteinsGrowthFactorGenesSignal Transduction and Growth RegulationCytoplasmicsignaltransductionproteinsNuclearproteinsGrowthFactorGenesGreat Targets for Dominant Acting OncogenesSecreted Growthfactors, e.g. EGF,PDGFSpecific Receptorsfor Growth factorse.g., RET, EGFRG-proteins,kinases andtheir targetse.g., RAS, ABL,(RB)Transcriptionfactors, e.g.,MYC, JUN, FOSReceptor Tyrosine Kinases (RTKs)Receptor Tyrosine Kinases (RTKs)Receptor Tyrosine Kinases (RTKs)Zwick et al, (2002) TIMM 8:17-23Extracellular GrowthfactorEngages with anddimerizes specificreceptors on cell surfaceDimerized Receptoractivates cascade ofmolecular eventsMachinery for increasedcell proliferation ismobilizedReceptor Tyrosine Kinases (RTKs)KinasesTrans-criptionFactorsZwick et al, (2002) TIMM 8:17-23Constitutive Activation converts RTKsto Dominant Acting OncogenesGenetic alterations leading toConstitutive Activation of RTKs• Deletion of extracellular domain• Mutations that stimulate dimerizationwithout ligand binding• Mutations of the kinase domain•Overexpression of Ligand•Overexpression of ReceptorTwo ClassicExamplesHer2receptorEGFreceptorHer2 = Human Epidermalgrowth factor receptor 2EGFR = Epidermal growthfactor receptorEGF Receptors signal through the RAS G-proteinCytoplasmicsignaltransductionproteinsNuclearproteinsGrowthFactorGenesSignal Transduction and Growth RegulationSecreted Growthfactors, e.g. EGF,PDGFSpecific Receptorsfor Growth factorse.g., RET, EGFRG-proteins andkinases, e.g.,RAS, ABL, RBTranscriptionfactors, e.g.,MYC, JUN, FOSG-proteins,kinases andtheir targetse.g., RAS, ABL,RBcABL – A non-receptor, cytoplasmic tyrosinekinase that can be converted into anoncoprotein• cABL proto-oncogene productsignals to many of the samemolecules as the RTKs• Signals cell cycle progressionand cell proliferationThe Philadelphia Chromosome and ChronicMyeloid LeukemiaHuman Chromosome Spread – G-banding KaryotypeHuman Chromosome Spread – G-banding KaryotypeNormalThe Philadelphia Chromosome created by aTranslocation between Chrs 9 and 22Chronic Myeloid Leukemia mutant mutantABLBCRABLBCRABLBCRThe Philadelphia Chromosome and ChronicMyeloid LeukemiaThe Philadelphia Chromosome and ChronicMyeloid LeukemiaUncontrolled ABL Kinase Activityand Signal TransductionChronic Myeloid LeukemiaFusion ProteinCytoplasmicsignaltransductionproteinsNuclearproteinsGrowthFactorGenesSignal Transduction and Growth RegulationSecreted Growthfactors, e.g. EGF,PDGFSpecific Receptorsfor Growth factorse.g., RET, EGFRG-proteins andkinases, e.g.,RAS, ABL, RBTranscriptionfactors, e.g.,MYC, JUN, FOSG-proteins,kinases andtheir targetse.g., RAS, ABL,RBOncogenesdominant gain-of-function mutationspromote cell transformationTumor suppressor genesrecessive, loss-of-function mutationspromote cell transformationMutator genesUsually recessive, loss-of-function mutationsthat increase spontaneous and environmentallyinduced mutation ratesAlterations in different kinds ofGenes cause
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