Genetics of Cancer Lecture 35 Alterations in different kinds of Genes cause Cancer Oncogenes dominant gain-of-function mutations promote cell transformation Tumor suppressor genes recessive, loss-of-function mutations promote cell transformation Mutator genes Usually recessive, loss-of-function mutations that increase spontaneous and environmentally induced mutation rates What 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-Disjunction Chromosome loss & duplication Chromosome loss Recombination Deletion Interchromosomal Recombination Gene ConversionTranslocation Mutant Rb wt Rb LOH - Loss of heterozygosity Sunlight Pollution Oxidation Food Cigarette Smoke Courtesy of Professor Bevin P. Engelward. Used with permission. Excision Repair Proteins Detect Damage Enzymes Excise DNA Segment with Damage DNA Polymerase Copies the Undamaged Strand DNA Ligase Seals the ends together Courtesy of Professor Bevin P. Engelward. Used with permission. Figure by MIT OCW. Sunlight Pollution Oxidation Food Cigarette Smoke Courtesy of Professor Bevin P. Engelward. Used with permission. Xeroderma Pigmentosum An Autosomal Recessive Disease 2000-fold increased risk of skin cancer Images removed due to copyright reasons. Complementation in fused cells reveals 7 genes that cause Xeroderma Pigmentosum = DNA Excision Repair after UV Irradiation nucleus cytoplasm = No DNA Excision Repair after UV Irradiation WT XPA WT + XPA XPA XPA XPA XPB XPA + XPB XPA + XPA XP PA + XP Age at First Skin Cancer 100 90 80 70 60 50 40 30 20 10 0 0 10 XP population Non-XP population 20 30 40 50 60 Age (years) Cumulative Cancer Incidence (%) 70 80 90 Figure by MIT OCW. There are Many Other Human Cancer Prone Syndromes Deficient in DNA Repair Colon Colon Ovary Endometrial Skin Breast Ovary Leukemias If DNA Repair pathway is defective Images removed due to copyright reasons. Hereditary Nonpolyposis Colon Cancer DNA Mismatch Repair Defect Syndrome inherited as Autosomal Dominant Images 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 Defect Syndrome inherited as Autosomal Dominant BRCA2 Family Pedigree Images 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 suicide Cells need time to repair DNA: DNA Damage induces Cell Cycle Checkpoints Extracellular growth control signals Intracellular quality control checks (DNA synthesis) S Daughter cells M (Mitosis) G 1 G 0 G 2 Figure by MIT OCW. DNA damage is sensed Sunlight Pollution Oxidation Food Cigarette Smoke Signal Transduction KINASES are activated p53p53 PP P G1, G2, & M arrest Apoptosis Increased DNA repair Cigaratte Smoke Courtesy 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 apoptosis Li-Fraumeni Syndrome – Inheritance of one p53 null allele Images 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 oncogenes Inactivation of APC Tumor Suppressor genes Activation of K-RAS Oncogene Inactivation of p53 Tumor Suppressor gene 20 – 40 Years Take the case of Colon Cancer Normal E pithelium E arly A denoma / Dysplastic Crypt L ate A denoma Carcinoma Metastasis A PC K R A S T P53 Other Changes Figure 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, 1995.