Genetics of Cancer

Chapter 18 problems: 1, 6, 12, 15, 16, 17, 18

Cancer is caused by mutant genes

• Mutations in regulatory genes lead to uncontrolled cell growth
• Understanding gene regulation is the key to understanding cancer

Clonal nature of cancer

• All cancers trace back to single cell
• Must accumulate multiple mutations, all in the same cell lineage

Three main checkpoints in the cell cycle

• G1/S
• Is cell the correct size?
• Is DNA damaged?
• G2/M
• Is DNA fully replicated?
• Is DNA damage repaired?
• M
• Have spindle fibers formed?
• Have they attached to chromosomes correctly?

Cell Cycle

• Normal cell cycle is controlled by signal transduction:
• Growth factors bind to surface receptors on the cell; transmembrane proteins relay signals into the cell.
• Two types of growth regulators:
• Growth factors stimulate cell division.
• Growth-inhibiting factors inhibit cell division.
• Healthy cells divide only when growth factor and growth-inhibiting factor balance favors cell division.

Oncogenes

• Lots of different oncogenes have been identified.
• All are involved in positive control of cell growth and division.
• Two classes:
• • Growth factors, regulatory genes involved in the control of cell multiplication.
  • Protein kinases, add phosphate groups to target proteins, important in signal transduction pathways.
• Proto-oncogenes: Normal form of the gene that is involved in positive regulation of the cell cycle

How to convert a proto-oncogenes into an oncogene?

Example: Ras Proto-oncogene

• Mutated in 30% of all cancers.
• A "molecular switch" in the signal transduction pathway leading from growth factors to gene expression controlling cell proliferation:
• • GF ® receptor ® ® Ras ® ® ® TF ® target genes ® growth.
• A single amino acid change in Ras protein can cause constant stimulation of the pathway, even in the absence of growth factors.

Tumor Suppressor Genes

• Normally inhibit cell growth; when mutated the inhibition is lost.
• Example: retinoblastoma
• • RB protein normally blocks a transcription factor, E2F
  • E2F required to enter the S phase
  • Inherited vs sporadic retinoblastoma
  • "Two-hit model": both copies must be mutated to cause cancer

another example: p53 Gene (tumor suppressor)

• Normal Function: also controls G1/S
• The ÒLast Gatekeeper"
• Involved in 50% of cancers
• Often not malignant despite other cancer-causing mutations until p53 is inactivated by mutation.
• Two possible responses to DNA damage:
• 1) Acts as a Transcription Factor to activate expression of p21, which inhibits CDK/G1 cyclin to halt the cell cycle; then activates DNA repair.
• 2) Triggers apoptosis (programmed cell death) if damage can't be repaied.

Oncogenes vs Tumor Suppressors

• Oncogenes are usually dominant mutations
• Tumor Suppressors are recessive
• Why?

Avoiding Cell death

• Telomerase must be functional in cancer cells so they can keep replicating

Mutator genes

• Cancer is caused by mutations, so factors that increase mutation rate will increase cancer rate.

What kinds of genes would increase mutation rate?

• Many environmental factors also cause DNA damage or mutations, that can lead to cancer