Genetics of Cancer Lecture 35
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
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)
What chromosomal events convert protooncogenes 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 protooncogene such that it is inappropriately expressed (e.g., cMyc, Bcl2) • Gene amplification resulting in overexpression (e.g., N-Myc)
Point Mutation Non-Dis junction LOH Loss of heterozygosity Chromosome Chromosome loss loss duplication wt l Rb Mutant Rb Recombination Interchromosomal Deletion Translocation Gene Conversion Recombination
Point Mutation Non-Disjunction Chromosome loss & duplication Chromosome loss Recombination Deletion Interchromosomal Recombination Translocation Gene Conversion wt Rb Mutant Rb LOH - Loss of heterozygosity
Sunlight Oxidation Pollution Food Cigarette Smoke Courtesy of Professor Bevin P.Engelward.Used with permission
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
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
0 Deoxyribose-N C=0 0 CH3 H -N Deoxyribose-N C=0 H CH3 Two thymine residue UV irradiation 0 c一N Deoxyribose-N H C=0 CH3 ⊙ 0 -N Deoxyribose—N CC=0 H CH3 Thymine-thymine dimer residue Before After Figure by MIT OCW
Figure by MIT OCW
Sunlight Oxidation Pollution Food Cigarette Smoke Courtesy of Professor Bevin P.Engelward.Used with permission
Sunlight Pollution Oxidation Food Cigarette Smoke Courtesy of Professor Bevin P. Engelward. Used with permission
Images removed due to copyright reasons. Xeroderma Pigmentosum An Autosomal Recessive Disease 2000-fold increased risk of skin cancer
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 nucleus DNA Excision Repair after UV Irradiation No DNA Excision Repair after UV Irradiation cytoplasm ● ● ● WT XPA WT+XPA XPA XPA XPA+XPA ●● XPA XPB XPA+XPB
Complementation in fused cells reveals 7 genes that cause Xeroderma Pigmentosum nucleus = DNA Excision Repair after UV Irradiation cytoplasm = No DNA Excision Repair after UV Irradiation WT XPA WT + XPA XPA XPA XPA XPB XPA + XPB XPA + XPA WT XPA WT + XPA XPA XPA XPA XP XPA + XP XPA + XPA