Genetics of Cancer Lecture 35Alterations in different kinds of Genes cause CancerOncogenesdominant gain-of-function mutationspromote cell transformationTumor suppressor genes recessive, loss-of-function mutationspromote cell transformationMutator genes Usually recessive, loss-of-function mutations that increase spontaneous and environmentally induced mutation ratesWhat chromosomal events convert proto-oncogenes to dominantly acting oncogenes• Point mutations (e.g., RAS)• Partial deletion mutations (e.g., RTKs)•Chromosomal translocations that produce novel fusion proteins (e.g., Bcr-Abl)• Chromosomal translocation to juxtapose a strong promoter upstream and the proto-oncogene such that it is inappropriately expressed (e.g., cMyc, Bcl2)• Gene amplification resulting in overexpression(e.g., N-Myc)Point Mutation Non-DisjunctionChromosome loss& duplicationChromosomelossRecombinationDeletionInterchromosomalRecombinationGene ConversionTranslocationMutant Rbwt RbLOH - Loss of heterozygositySunlightPollutionOxidationFoodCigarette SmokeCourtesy of Professor Bevin P. Engelward. Used with permission.Excision RepairProteins Detect DamageEnzymes Excise DNA Segment with DamageDNA Polymerase Copies the Undamaged StrandDNA LigaseSeals the ends together Courtesy of Professor Bevin P. Engelward. Used with permission.Figure by MIT OCW.SunlightPollutionOxidationFoodCigarette SmokeCourtesy of Professor Bevin P. Engelward. Used with permission.Xeroderma Pigmentosum An Autosomal Recessive Disease2000-fold increased risk of skin cancerImages removed due to copyright reasons.Complementation in fused cells reveals 7 genes that cause Xeroderma Pigmentosum=DNA Excision Repair after UV Irradiationnucleuscytoplasm=No DNA Excision Repair after UV IrradiationWT XPA WT + XPAXPA XPAXPA XPBXPA + XPBXPA + XPAWT XPA WT + XPAXPA XPAXPA XPXPA + XPXPA + XPAAge at First Skin Cancer10090807060504030201000 10XP population Non-XP population20 30 40 50 60Age (years)Cumulative Cancer Incidence (%)70 80 90Figure by MIT OCW.There are Many Other Human Cancer Prone Syndromes Deficient in DNA RepairColonColon Ovary EndometrialSkinBreast Ovary LeukemiasIf DNA Repair pathway is defectiveImages removed due to copyright reasons.Hereditary Nonpolyposis Colon Cancer DNA Mismatch Repair DefectSyndrome inherited as Autosomal DominantImages removed due to copyright reasons.Please see Lodish, Harvey, et. al. Molecular Cell Biology.5th ed. New York : W.H. Freeman and Company, 2004.Hereditary Breast Cancer Susceptibility DNA Recombination Repair DefectSyndrome inherited as Autosomal DominantBRCA2 Family PedigreeImages removed due to copyright reasons.Please see Lodish, Harvey, et. al. Molecular Cell Biology.5th ed. New York : W.H. Freeman and Company, 2004.• DNA damage signals cell cycle check points• If the damage is too great to fix by repair a signal is sent for the cell to undergo suicideCells need time to repair DNA: DNA Damage induces Cell Cycle Checkpoints Extracellular growthcontrol signalsIntracellularquality controlchecks(DNA synthesis)SDaughter cellsM (Mitosis)G1G0G2Figure by MIT OCW.DNA damage is sensedSunlightPollutionOxidationFoodCigarette SmokeSunlightPollutionOxidationFoodCigarette SmokeSignal Transduction KINASES are activatedp53p53PPPG1, G2, & M arrestApoptosisIncreased DNA repairCigaratte SmokeCourtesy of Professor Bevin P. Engelward. Used with permission.Loss of p53 function occurs in more than 50% of human cancers!!•These cancer cells are genetically unstable because they are unable to do the following:• Stop the cell cycling to allow time for DNA repair• Carry out efficient DNA repair• Undergo apoptosisLi-Fraumeni Syndrome –Inheritance of one p53 null alleleImages removed due to copyright reasons.Please see Lodish, Harvey, et. al. Molecular Cell Biology.5th ed. New York : W.H. Freeman and Company, 2004.Most fully blown cancers require inactivation of tumor suppressor genes and activation of oncogenesInactivation of APC Tumor Suppressor genesActivation of K-RAS OncogeneInactivation of p53 Tumor Suppressor gene20 – 40 YearsTake the case of Colon CancerNormal E pitheliumE arly A denoma /Dysplastic CryptL ate A denoma CarcinomaMetastasisAPCK R AS TP53OtherChangesFigure by MIT OCW.Xeroderma Pigmentosum ~ 1/250,000 Image removed due to copyright reasons. Please see Wei et al., Clinical Chemistry, Vol. 41, No. 12,
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