genetics of cancer part 2. review two mutations must occur:
TRANSCRIPT
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Genetics of Cancer
Part 2
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Review
• Two mutations must occur:
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Review
• Two mutations must occur:
• Protooncogene stuck in the “on” position (gas pedal down), constantly stimulating cell division
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Review
• Two mutations must occur:
• Protooncogene stuck in the “on” position (gas pedal down), constantly stimulating cell division
• Tumor Suppressor Gene inactivated (brakes disconnected from accelerating car)
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What else must happen?
• External controls overcome
• Cells not limited by: Crowding Lack of attachment Lack of nutrients
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What else must happen?
• Telomerase must be present to create cellular immortality.
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What else must happen?
• Telomerase must be present to create cellular immortality.
• Most human cells divide 50-100 times before entering G0 permanently or committing cell suicide (apoptosis)
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Telomerase
• OK, but…how does a cell know it has divided 50-100 times???
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Telomerase
• OK, but…how does a cell know it has divided 50-100 times???
• Tips of chromosomes are capped with a sequence of bases (TTAGGG) repeated 1000’s of times.
• Each division removes 50-200 of these bases
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Telomerase, con’t
• TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG
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Shortening…
• TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG
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Shortening, until…
• TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG
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Shortening, until…
• TTAGGGTTAGGGTTAGGG
• It can’t divide any longer!
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Stem Cells
• Stem cells produce cells (sex cells, blood, hair) that need to be replaced regularly - must keep dividing!
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Stem Cells
• Stem cells produce cells (sex cells, blood, hair) that need to be replaced regularly - must keep dividing!
• Telomerase is an enzyme that rebuilds the telomeres (adds TTAGGG)
• If telomeres don’t get shorter, cells don’t get older
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Back to cancer cells…
• Cancer cells have a mutation that allows the production of telomerase.
• Leads to cells being immortal that should die out.
• Telomerase = gas tank!
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Metastasis must spread cancerous cells
• Cells spread via the circulatory or lymphatic system
• 99% of cancer cells die en route, but some lodge in capillaries or lymph nodes
• Cancer cells can break down material between cells to travel within tissues, leading to new colonies
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Cancer and inheritance
• Two-hit hypothesis: TSG’s are inherited in pairs (as are all genes) and both copies must be mutated since they function as recessive alleles
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Cancer and inheritance
• Inherited one mutant TSG? You’re prone to developing cancer early in life (middle age or earlier)
• Two good TSG’s? Cancer may come later in life, if at all.
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Cancer and inheritance
• Inheritance is only a small part of developing cancer (15% of the risk of colon cancer is due to inheritance, breast cancer 7%)
• Environmental factors often more important determinant
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p53
• “THE GUARDIAN OF THE GENOME”
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p53
• “THE GUARDIAN OF THE GENOME”
• Your primary TSG
• Mutated in 55% of all cancers
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p53
• Activated when DNA damage is bad
• 1st - Halts cell cycle
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p53
• Activated when DNA damage is bad
• 1st - Halts cell cycle
• 2nd - Starts DNA repair and restarts cell cycle if successful
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p53
• Activated when DNA damage is bad
• 1st - Halts cell cycle
• 2nd - Starts DNA repair and restarts cell cycle if successful
• 3rd - Causes apoptosis (cell suicide) if repair unsuccessful
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Review
• Gas pedal =
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Review
• Gas pedal = protooncogene
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Review
• Gas pedal = protooncogene
• Brake =
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Review
• Gas pedal = protooncogene
• Brake = tumor suppressor gene
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Review
• Gas pedal = protooncogene
• Brake = tumor suppressor gene
• Gas tank =
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Review
• Gas pedal = protooncogene
• Brake = tumor suppressor gene
• Gas tank = Telomerase (adds telomeres TTAGGG)
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Review
• Two-hit hypothesis?
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Review
• Two-hit hypothesis = BOTH copies of a TSG must be mutated
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Review
• Two-hit hypothesis = BOTH copies of a TSG must be mutated
• Guardian of the cell?
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Review
• Two-hit hypothesis = BOTH copies of a TSG must be mutated
• Guardian of the cell = p53
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Review
• Two-hit hypothesis = BOTH copies of a TSG must be mutated
• Guardian of the cell = p53
• Cell suicide?
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Review
• Two-hit hypothesis = BOTH copies of a TSG must be mutated
• Guardian of the cell = p53
• Cell suicide = apoptosis