1. Genetics: From Genes to Genomes
PowerPoint to accompany
Genetics: From Genes to Genomes
Fourth Edition
Leland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M. Silver
Prepared by Mary A. Bedell
University of Georgia
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2. 17 Somatic Mutation and the Genetics of Cancer CHAPTER OUTLINE PART V
How Genes Are Regulated
CHAPTER
Somatic Mutation and the Genetics of Cancer
CHAPTER OUTLINE
17.1 Overview: Initiation of Division
17.2 Cancer: A Failure of Control over Cell Division
17.3 The Normal Control of Cell Division
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3. The relative percentages of new cancers in the United States that occur at different sites
Fig. 17.1
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4. Two unifying themes about cancer genetics
Cancer is a disease of genes
Multiple cancer phenotypes arise from mutations in genes that regulate cell growth and division
Environmental chemicals increase mutation rates and increase chances of cancer
Cancer has a different inheritance pattern than other genetic disorders
Inherited mutations can predispose to cancer, but the mutations causing cancer occur in somatic cells
Mutations accumulate in clonal descendants of a single cell
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5. Overview of the initiation of cell division
Two basic types of signals that tell cells whether to divide, metabolize, or die
Extracellular signals – act over long or short distances
Collectively known as hormones
Steroids, peptides, or proteins
Cell-bound signals – require direct contact between cells
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6. An example of an extracellular signal that acts over large distances
Thyroid-stimulating hormone (TSH) produced in pituitary gland Moves through blood to thyroid gland, which expresses thyroxine
Fig. 17.2a
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7. An example of an extracellular signal that is mediated by cell-to-cell contact
Fig. 17.2b
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8. Each signaling system has four components
Growth factors
Extracellular hormones or cell-bound signals that stimulate or inhibit cell proliferation
Receptors
Comprised of a signal-binding site outside the cell, a transmembrane segment, and an intracellular domain
Signal transducers
Located in cytoplasm
Transcription factors
Activate expression of specific genes to either promote or inhibit cell proliferation
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9. Hormones transmit signals into cells through receptors that span the cellular membrane
Fig. 17.3a
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10. Signaling systems can stimulate or inhibit growth
Signal transduction - activation or inhibition of intracellular targets after binding of growth factor to its receptor
Fig. 17.3b&c
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11. RAS is an intracellular signaling molecule
Fig. 17.3d
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12. Cancer phenotypes result from the accumulation of mutations
Mutations are in genes controlling proliferation as well as other processes
Result in a clone of cells that overgrows normal cells
Cancer phenotypes include:
Uncontrolled cell growth
Genomic and karyotypic instability
Potential for immortality
Ability to invade and disrupt local and distant tissues
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13. Phenotypic changes that produce uncontrolled cell growth
Most normal cells
Many cancer cells
Autocrine stimulation:
Cancer cells can make their own stimulatory signals
a.1
Most normal cells
Many cancer cells
Loss of contact inhibition:
Growth of cancer cells doesn't stop when the cells contact each other
a.2
Fig. 17.4
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14. Phenotypic changes that produce uncontrolled cell growth (cont)
Most normal cells
Many cancer cells
Loss of cell death:
Cancer cells are more resistant to programmed cell death (apoptosis)
a.3
Most normal cells
Many cancer cells
Loss of gap junctions:
Cancer cells lose channels for communicating with adjacent cells
a.4
Fig. 17.4
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15. Phenotypic changes that produce genomic and karyotypic instability
Defects in DNA replication machinery: Cancer cells have lost the ability to replicate their DNA accurately Increased mutation rates can occur because of defects in DNA replication machinery
b.1
Fig. 17.4
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16. Phenotypic changes that produce genomic and karyotypic instability (cont)
Increased rate of chromosomal aberrations: Cancer cells often have chromosome rearrangements (translocations, deletions, aneuploidy, etc) Some rearrangements appear regularly in specific tumor types
Fig. 17.4b.2
Fig. 17.4b.2
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17. Phenotypic changes that produce a potential for immortality
Loss of limitations on the number of cell divisions: Tumor cells can divide indefinitely in culture (below) and express telomerase (not shown)
Most normal cells
Many cancer cells
c.1
Immortality
c.2
Growth in soft agar
Fig. 17.4
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18. Phenotypic changes that enable a tumor to disrupt local tissue and invade distant tissues
Ability to metastasize: Tumor cells can invade the surrounding tissue and travel through the bloodstream
d.1
Angiogenesis:
Tumor cells can secrete substances that promote growth of blood vessels
d.2
Fig. 17.4
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19. Evidence from mouse models that cancer is caused by several mutations
Transgenic mice with dominant mutations in the myc gene and in the ras gene
Mice with recessive mutations in the p53 gene
(a)
(b)
Fig. 17.5a
Fig. 17.5
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20. Evidence that cancer cells are clonal descendants of a single somatic cell
Analysis of polymorphic enzymes encoded by the X chromosome in females Sample from normal tissues has mixture of both alleles Clones of normal cells has only one allele Sample from tumor has only one allele
Fig. 17.6
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21. The incidence of some common cancers varies between countries
Table 17.1
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22. The role of environmental mutagens in cancer
Concordance for the same type of cancer in first degree relatives (i.e. siblings) is low for most forms of cancer
The incidence of some cancers varies between countries (see Table 17.2)
When a population migrates to a new location, the cancer profile becomes like that of the indigenous population
Numerous environmental agents are mutagens and increase the likelihood of cancer
Some viruses, cigarette smoke
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23. Cancer development over time
Lung cancer death rates and incidence of cancer with age
Fig. 17.7
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24. Some families have a genetic predisposition to certain types of cancer
Example: retinoblastoma caused by mutations in RB gene Individuals who inherit one copy of the RB− allele are prone to cancer of the retina During proliferation of retinal cells, the RB+ allele is lost or mutated Tumors develop as a clone of RB−/RB− cells
Fig. 17.8
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25. Cancer is thought to arise by successive mutations in a clone of proliferating cells
Fig. 17.9
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26. Cancer-producing mutations are of two general types
Fig
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27. Oncogenes act dominantly and cause increased proliferation
Oncogenes are produced when mutations cause improper activation a gene
Two approaches to identifying oncogenes:
Tumor-causing viruses (Fig 17.11a)
Many tumor viruses in animals are retroviruses
Some DNA viruses carry oncogenes [e.g. Human papillomavirus (HPV)]
Tumor DNA (Fig b)
Transform normal mouse cells in culture with human tumor DNA
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28. Cancer-causing retroviruses carry a mutant or overexpressed copy of a cellular gene
After infection, retroviral genome integrates into host genome If the retrovirus integrates near a proto-oncogene, the proto- oncogene can be packaged with the viral genome
Fig a
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29. Retroviruses and their associated oncogenes
Table 17.2
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30. DNA from human tumor cells is able to transform normal mouse cells into tumor cells
Human gene that is oncogenic can be identified and cloned from transformed mouse cells
Fig b
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31. The RAS oncogene is the mutant form of the RAS proto-oncogene
Normal RAS is inactive until it becomes activated by binding of growth factors to their receptors Oncogenic forms of RAS are constitutively activated
Fig c
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32. Oncogenes are members of signal transduction systems
This table and the previous one were labeled as Table 17.2 in the pdf, but the next one is 17.4
Table 17.3
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33. Cancer can be caused by mutations that improperly inactivate tumor suppressor genes
Function of normal allele of tumor suppressor genes is to control cell proliferation
Mutant tumor suppressor alleles act recessively and cause increased cell proliferation
Tumor suppressor genes identified through genetic analysis of families with inherited predisposition to cancer
Inheritance of a mutant tumor suppressor allele
One normal allele sufficient for normal cell proliferation in heterozygotes
Wild-type allele in somatic cells of heterozygote can be lost or mutated  abnormal cell proliferation
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34. The retinoblastoma tumor-suppressor gene
Fig
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35. Mutant alleles of these tumor-suppressor genes decrease the accuracy of cell reproduction
Table 17.4
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36. The normal control of cell division
Four phases of the cell cycle: G1, S, G2, and M
Fig
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37. Experiments with yeast helped identify genes that control cell division
Two kinds of used: Saccharomyces cerevisiae (budding yeast) and Schizosaccharomyces pombe (fission yeast)
Usefulness of yeast for studies of the cell cycle
Both grow as haploids or diploids
Can identify recessive mutations in haploids
Can do complementation analysis in diploids
S. cerevisiae – size of buds serves as a marker of progress through the cell cycle
Daughter cells arise as small buds on mother cell at end of G1 and grow during mitosis
Stage of cell cycle can be determined by relative appearance of buds (see Fig 17.14)
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38. The isolation of temperature-sensitive mutants of yeast
Mutants grow normally at permissive temperature (22°) At restrictive temperature (36°), mutants lose gene function After replica plating, colonies that grow at 22° but not at 36° have temperature-sensitive mutation
Fig
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39. A temperature-sensitive cell-cycle mutant in S. cerevesiae
Cells grown at permissive temperature display buds of all sizes (asynchronous division)
Growth of the same cells at restrictive temperature – all have large buds
Fig a
Fig b
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40. Some important cell-cycle and DNA repair genes
Table 17.5
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41. CDKs interact with cyclins and control the cell cycle by phosphorylating other proteins
Cyclin-dependent kinases (CDKs) – family of kinases that regulate the transition from G1 to S and from G2 to M
Cyclin specifies the protein targets for CDK
Phosphorylation by CDKs can activate or inactive a protein
Fig a
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42. CDKs control the dissolution of the nuclear membrane at mitosis
Lamins – provide structural support to the nucleus
Form an insoluble matrix during most of the cell cycle
At mitosis, lamins are phosphorylated by CDKs and become soluble
Fig
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43. Mutant yeast permit the cloning of a human CDK gene
Human CDKs and cyclins can function in yeast and replace the corresponding yeast proteins
Fig
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44. CDKs mediate the transition from the G1 to the S phase of the cell cycle
Fig
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45. CDK activity in yeast is controlled by phosphorylation and dephosphorylation
Fig
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46. Cell-cycle checkpoints ensure genomic stability
Checkpoints monitor the genome and cell-cycle machinery before allowing progression to the next stage of cell cycle
G1-to-S checkpoint
DNA synthesis can be delayed to allow time for repair of DNA that was damaged during G1
The G2-to-M checkpoint
Mitosis can be delayed to allow time for repair of DNA that was damaged during G2
Spindle checkpoint
Monitors formation of mitotic spindle and engagement of all pairs of sister chromatids
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47. The G1-to-S checkpoint is activated by DNA damage
Fig a
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48. Disruption of the G1-to-S checkpoint in p53-deficient cells can lead to amplified DNA
Tumor cells often have homogenously staining regions (HSRs) or small, extrachromosomal pieces of DNA (double minutes)
Fig b
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49. Disruption of the G1-to-S checkpoint in p53-deficient cells can lead to many types of chromosome rearrangements
Fig c
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50. Checkpoints acting at the G2-to-M cell-cycle transition or during M phase
Fig
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51. The necessity of checkpoints
Checkpoints are not essential for cell division
Cells with defective checkpoints are viable and divide at normal rates
But, they are much more vulnerable to DNA damage than normal cells
Checkpoints help prevent transmission of three kinds of genomic instability (Fig 17.22)
Chromosome aberrations
Changes in ploidy
Aneuploidy
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52. Three classes of error lead to aneuploidy in tumor cells
Fig a
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53. Chromosome painting can be used to detect chromosome rearrangements
Chromosomes from normal cells
Chromosomes from tumor cells
Fig
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