Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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Genetics of Cancer Part 2 - January 23, 2007

Transcript of Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Page 1: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Genetics of Cancer

Part 2 - January 23, 2007

Page 2: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Two mutations must occur:

Page 3: 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

Page 4: 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

• Tumor Suppressor Gene inactivated (brakes disconnected from accelerating car)

Page 5: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

What else must happen?

• External controls overcome

• Cells not limited by: Crowding Lack of attachment Lack of nutrients

(remember “angiogenesis”?)

Page 6: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

What else must happen?

• Telomerase must be present to create cellular immortality.

Page 7: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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)

Page 8: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Telomerase

• OK, but…how does a cell know it has divided 50-100 times???

Page 9: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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

Page 10: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Telomerase, con’t

• TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG

Page 11: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Shortening…

• TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG

Page 12: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Shortening, until…

• TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG TTAGGGTTAGGGTTAGGGTTAGGG

Page 13: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Shortening, until…

• TTAGGGTTAGGGTTAGGG

• It can’t divide any longer!

Page 14: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Stem Cells

• Stem cells produce cells (sex cells, blood, hair) that need to be replaced regularly - must keep dividing!

Page 15: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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

Page 16: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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!

Page 17: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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

Page 18: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Cancer and inheritance

• Two-hit hypothesis: TSG’s are inherited in pairs and both copies must be mutated

Page 19: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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.

Page 20: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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

Page 21: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

p53

• “THE GUARDIAN OF THE GENOME”

Page 22: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

p53

• “THE GUARDIAN OF THE GENOME”

• Your primary TSG

• Mutated in 55% of all cancers

Page 23: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

p53

• Activated when DNA damage is bad

• 1st - Halts cell cycle

Page 24: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

p53

• Activated when DNA damage is bad

• 1st - Halts cell cycle

• 2nd - Starts DNA repair and restarts cell cycle if successful

Page 25: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

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

Page 26: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Gas pedal =

Page 27: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Gas pedal = protooncogene

Page 28: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Gas pedal = protooncogene

• Brake =

Page 29: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Gas pedal = protooncogene

• Brake = tumor suppressor gene

Page 30: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Gas pedal = protooncogene

• Brake = tumor suppressor gene

• Gas tank =

Page 31: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Gas pedal = protooncogene

• Brake = tumor suppressor gene

• Gas tank = Telomerase (adds telomeres TTAGGG)

Page 32: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Two-hit hypothesis?

Page 33: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Two-hit hypothesis = BOTH copies of a TSG must be mutated

Page 34: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Two-hit hypothesis = BOTH copies of a TSG must be mutated

• Guardian of the cell?

Page 35: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Two-hit hypothesis = BOTH copies of a TSG must be mutated

• Guardian of the cell = p53

Page 36: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Two-hit hypothesis = BOTH copies of a TSG must be mutated

• Guardian of the cell = p53

• Cell suicide?

Page 37: Genetics of Cancer Part 2 - January 23, 2007. Review Two mutations must occur:

Review

• Two-hit hypothesis = BOTH copies of a TSG must be mutated

• Guardian of the cell = p53

• Cell suicide = apoptosis


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