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Genetics of Cancer Lecture 34
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dominant gain-of-function mutations promote cell transformation
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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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 mitotic divisions 2 meiotic divisions m itotic divisions endoderm colon gametes (eggs or sperm)
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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 2 meiotic divisions mitotic divisions endoderm colon gametes (eggs or sperm)
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Cytoplasmic signal transduction proteins
Signal Transduction and Growth Regulation Nuclear proteins Growth Factor Genes Cytoplasmic signal transduction proteins
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Secreted Growth factors, e.g. EGF, PDGF G-proteins, kinases and
Signal Transduction and Growth Regulation 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) Nuclear proteins Growth Factor Genes Cytoplasmic signal transduction proteins Transcription factors, e.g., MYC, JUN, FOS
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Receptor Tyrosine Kinases (RTKs)
Extracellular domain Exterior Cytoplasm Transmembrane domain Kinase active site Cytoplasmic domain Figure by MIT OCW.
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Receptor Tyrosine Kinases (RTKs)
Images removed due to copyright reasons.
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Extracellular Growth factor
Engages with and dimerizes specific receptors on cell surface Images removed due to copyright reasons. Please see Figure 1 in Zwick, E., J. Bange and A. Ullrich. "Receptor Tyrosine Kinases as Targets for Anticancer Drugs.“ Trends Mol Med. 8, no.1 (Jan 2002): Dimerized Receptor activates cascade of molecular events Machinery for increased cell proliferation is mobilized
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Receptor Tyrosine Kinases (RTKs)
Images removed due to copyright reasons. Kinases Trans- cription Factors
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Constitutive Activation converts RTKs to Dominant Acting Oncogenes
Images removed due to copyright reasons. Please see Figure 2 in Zwick, E., J. Bange and A. Ullrich. "Receptor Tyrosine Kinases as Targets for Anticancer Drugs." Trends Mol Med. 8, no. 1 (Jan 2002):17-23.
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Genetic alterations leading to Constitutive Activation of RTKs
• Deletion of extracellular domain • Mutations that stimulate dimerization without ligand binding • Mutations of Kinase domain • Overexpression of Ligand • Overexpression of Receptor
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Her2 receptor EGF receptor
Two Classic Examples Her2 receptor EGF receptor 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. Her2 = Human Epidermal growth factor receptor 2 EGFR = Epidermal growth factor receptor
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EGF Receptors signal through the RAS G-protein
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.
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Secreted Growth factors, e.g. EGF, PDGF G-proteins, kinases and
Signal Transduction and Growth Regulation 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) Nuclear proteins Growth Factor Genes Cytoplasmic signal transduction proteins Transcription factors, e.g., MYC, JUN, FOS
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signals to many of the same molecules as the RTKs
cABL – A non-receptor, cytoplasmic tyrosine kinase that can be converted into an oncoprotein • cABL proto-oncogene product signals to many of the same molecules as the RTKs • Signals cell cycle progression and cell proliferation
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The Philadelphia Chromosome and Chronic
Myeloid Leukemia Images removed due to copyright reasons.
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Human Chromosome Spread – G-banding Karyotype
Images removed due to copyright reasons.
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Human Chromosome Spread – G-banding Karyotype
Images removed due to copyright reasons.
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The Philadelphia Chromosome created by a
Translocation between Chrs 9 and 22 Chronic Myeloid Leukemia Images removed due to copyright reasons.
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The Philadelphia Chromosome and Chronic Myeloid Leukemia
Images removed due to copyright reasons.
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The Philadelphia Chromosome and Chronic Myeloid Leukemia
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.
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Fusion Protein 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. Uncontrolled ABL Kinase Activity and Signal Transduction Chronic Myeloid Leukemia
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Secreted Growth factors, e.g. EGF, PDGF G-proteins, kinases and
Signal Transduction and Growth Regulation 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) Nuclear proteins Growth Factor Genes Cytoplasmic signal transduction proteins Transcription factors, e.g., MYC, JUN, FOS
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cMYC drives cells from G1 to S
Burkitt’s Lymphoma: A chromosome translocation cMYC to be expressed inappropriately in B-cells IgH c-myc Figure by MIT OCW. cMYC drives cells from G1 to S
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Red – staining of chromosome 4
Another way that oncogenic transcription factors can be up-regulated: Gene Amplification Chromosome from a TUMOR 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. Blue – staining of all chromosomes Red – staining of chromosome 4 Green – staining of the N-MYC gene (N-MYC and cMYC share many similar proerties)
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Immunoglobulin heavy chain gene (lgH)
One more example – with an interesting twist A translocation between Chr 14 and Chr 18 to put the BCL2 gene under the strong IgH promoter lgH enhancer Breakpoint Chromosome 14 Immunoglobulin heavy chain gene (lgH) Not active in B lymphocytes Chromosome 18 bcl2 gene Breakpoint Active in B lymphocytes Rejoining of breakpoints Translocation 4;18 Figure by MIT OCW. The BCL2 protein PREVENTS programmed cell death, B cells live longer than normal leading to B-cell Lymphomas
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What chromosomal events convert proto- oncogenes to dominantly acting oncogenes
• Point mutations (e.g., RAS) • 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., Bcl2) • Gene amplification resulting in overexpression (e.g., N-Myc)
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Secreted Growth factors, e.g. EGF, PDGF G-proteins, kinases and
Signal Transduction and Growth Regulation 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 Nuclear proteins Growth Factor Genes Cytoplasmic signal transduction proteins Transcription factors, e.g., MYC, JUN, FOS
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RB – the Retinoblastoma Gene – was the first example of a Tumor Repressor Gene (aka a Recessive Oncogene) Images removed due to copyright reasons. Loss of Function Mutations in both RB genes lead to malignant tumors of the retina during the first few years of life
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RB prevents cells from leaving G1 to enter S-phase,
Daughter cells Extracellular growth control signals Intracellular quality control checks M (Mitosis) G2 RB prevents cells from leaving G1 to enter S-phase, until the appropriatetime G2 S (DNA synthesis) Figure by MIT OCW.
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Transcribes genes for replication and cell proliferation
Phosphorylation of RB at the appropriate time in G1 allows release of the E2F Transcription Factor P Cell cycle Kinase RB RB E2F Must lose function of both RB alleles in order to lose cell cycle control Transcribes genes for replication and cell proliferation E2F
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Single tumors Unilateral Later-onset
Two ways to get retinal tumors due to loss of RB function Germline mutation Normal gene Somatic mutation Somatic mutation Multiple tumors Bilateral Early-onset Single tumors Unilateral Later-onset Mendelian Sporadic Figure by MIT OCW.
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The Retinoblastoma disease behaves as an autosomal dominant mutation
• In order to lose cell cycle control MUST lose function of both alleles • But, for Mendelian inheritance of RB, children need only inherit only one non-functional allele • To explain this the “TWO HIT” hypthesis was proposed • During development of the retina a second mutation is almost certain to occur Germline mutation Somatic mutation Multiple tumors Bilateral Early-onset Figure by MIT OCW. • RB is one of the very few cancers that seems to require defects in only one gene (but in both alleles
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How is the second RB allele rendered non-functional?
Loss of Heterozygosity LOH This can happen is several ways wt Rb Mutant RB Heterozygous for RB mutation
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Point Mutation Non-Disjunction
Chromosome loss Chromosome loss & duplication Mutant Rb wt Rb Recombination Interchromosomal Recombination Deletion Translocation Gene Conversion
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Secreted Growth factors, e.g. EGF, PDGF G-proteins, kinases and
Signal Transduction and Growth Regulation 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 Nuclear proteins Growth Factor Genes Cytoplasmic signal transduction proteins Transcription factors, e.g., MYC, JUN, FOS
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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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