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Genetics of Cancer. Part 2 - January 23, 2007. Review. Two mutations must occur:. Review. Two mutations must occur: Protooncogene stuck in the “on” position (gas pedal down), constantly stimulating cell division. Review. Two mutations must occur:

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Genetics of Cancer

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Genetics of cancer l.jpg

Genetics of Cancer

Part 2 - January 23, 2007


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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

    • (remember “angiogenesis”?)


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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 and both copies must be mutated


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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 (colon cancers are inherited 15% of the time, breast 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


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