Genetics of Cancer Lecture 34 Age Specific Cancer Rates Males and Females Ireland 1994 1999 Properties of Cancer Cells Loss of Contact inhibition Anchorage independent growth Can grow indefinitely Can grow with low levels of serum growth factors What do cancer cells look like http 140 116 60 1 mdlai Handout cancermedicine 2000 img009 GIF http 140 116 60 1 mdlai Handout cancermedicine 2000 img009 GIF What do cancer cells look like Most of the mutations that contribute to cancer occur in somatic cells but germ line mutations can also contribute egg sperm zygote mitotic divisions growth and differentiation 2 meiotic divisions All tissues Where do they come from Most of the mutations that contribute to cancer occur in somatic cells but germ line mutations can also contribute egg sperm zygote growth and differentiation germ line mitotic divisions mitotic divisions endoderm colon endoderm colon gametes eggs or sperm The Genetic Basis of Cancer and Theodor Boveri 1862 1915 Established that chromosomes carry the hereditary information by showing that aberrant segregation of chromosomes leads to certain phenotypes in sea urchin eggs Suggested that aberrant segregation of human chromosomes could be responsible for a normal cell becoming a tumor cell 2 meiotic divisions All tissues mitotic divisions gametes eggs or sperm Suggested that some chromosomes promoted cell growth and others Marcella O Grady Boveri 1863 1950 also contributed inhibit cell growth Major complications in understanding the 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 tissues and are therefore extremely difficult to detect 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 The key initiating event often leads to an increase in mutation rate thus tumor cells often bear many fortuitous mutations Mutator genes Usually recessive loss of function mutations that increase spontaneous and environmentally induced mutation rates Most of the mutations that contribute to cancer occur in somatic cells but germ line mutations can also contribute Signal Transduction and Growth Regulation egg sperm zygote growth and differentiation germ line mitotic divisions Cytoplasmic signal transduction proteins 2 meiotic divisions All tissues mitotic divisions endoderm colon gametes eggs or sperm Nuclear proteins Growth Factor Genes Great Targets for Dominant Acting Oncogenes Receptor Tyrosine Kinases RTKs Secreted Growth factors e g EGF PDGF Specific Receptors for Growth factors e g RET EGFR G proteins kinases and their targets e g RAS ABL RB Cytoplasmic signal transduction proteins Nuclear proteins Growth Factor Genes Transcription factors e g MYC JUN FOS Receptor Tyrosine Kinases RTKs Receptor Tyrosine Kinases RTKs Extracellular Growth factor Receptor Tyrosine Kinases RTKs Engages with and dimerizes specific receptors on cell surface Dimerized Receptor activates cascade of molecular events Zwick et al 2002 TIMM 8 17 23 Kinases Transcription Factors Machinery for increased cell proliferation is mobilized Constitutive Activation converts RTKs to Dominant Acting Oncogenes Genetic alterations leading to Constitutive Activation of RTKs Deletion of extracellular domain Mutations that stimulate dimerization without ligand binding Mutations of the kinase domain Overexpression of Ligand Overexpression of Receptor Zwick et al 2002 TIMM 8 17 23 Two Classic Examples EGF Receptors signal through the RAS G protein Her2 receptor EGF receptor Her2 Human Epidermal growth factor receptor 2 EGFR Epidermal growth factor receptor Signal Transduction and Growth Regulation Secreted Growth factors e g EGF PDGF cABL proto oncogene product signals to many of the same molecules as the RTKs Specific Receptors for Growth factors e g RET EGFR G proteins G proteins and kinases kinases e g and RAS their ABL targets RB e g RAS ABL RB Cytoplasmic signal transduction proteins Nuclear proteins Growth Factor Genes cABL A non receptor cytoplasmic tyrosine kinase that can be converted into an oncoprotein Transcription factors e g MYC JUN FOS Signals cell cycle progression and cell proliferation The Philadelphia Chromosome and Chronic Myeloid Leukemia Human Chromosome Spread G banding Karyotype Human Chromosome Spread G banding Karyotype The Philadelphia Chromosome created by a Translocation between Chrs 9 and 22 Chronic Myeloid Leukemia Normal mutant mutant The Philadelphia Chromosome and Chronic Myeloid Leukemia BCR ABL BCR ABL The Philadelphia Chromosome and Chronic Myeloid Leukemia ABL BCR Fusion Protein Signal Transduction and Growth Regulation Secreted Growth factors e g EGF PDGF Specific Receptors for Growth factors e g RET EGFR Uncontrolled ABL Kinase Activity and Signal Transduction Chronic Myeloid Leukemia G proteins G proteins and kinases kinases e g and RAS their ABL targets RB e g RAS ABL RB Cytoplasmic signal transduction proteins Nuclear proteins Growth Factor Genes Transcription factors e g MYC JUN FOS 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
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