In-Depth Notes on Oncogenes and Cancer Biology

Oncogenes and Cancer Biology

Definition of Oncogenes

  • What is an oncogene?
    • A gene with a gain-of-function mutation.
    • Promotes uncontrolled cell growth.
    • Mutations are usually dominant:
    • Only one allele needs to be mutated.
    • Often affects genes regulating:
    • Cell proliferation.
    • Growth.
    • Survival.

Proto-oncogenes to Oncogenes Transformation

  • How can proto-oncogenes become oncogenes?
    • Point mutations.
    • Gene amplification.
    • Chromosomal translocations.
    • Insertional mutagenesis: e.g., via retroviruses.
    • Results in:
    • Overexpression.
    • Constitutive activation.

Proteins Encoded by Oncogenes

  • Common types of proteins:
    • Growth factors:
    • Examples: PDGF, EGF.
    • Growth factor receptors:
    • Example: EGFR.
    • Intracellular signal transducers:
    • Examples: RAS, BRAF, MAPK, ABL.
    • Transcription factors:
    • Examples: MYC, AP-1.

EGF Signaling Pathway Steps

  • Main steps:
    1. EGF binds to EGFR.
    2. Receptor dimerization occurs.
    3. Autophosphorylation of the receptor.
    4. Recruitment of GRB2 and SOS.
    5. SOS activates RAS by exchanging GDP for GTP.
    6. RAS activates RAF, which activates MEK, leading to MAPK activation.
    7. MAPK enters the nucleus and activates AP1 and MYC.
    8. This promotes the expression of Cyclin D1/D2, facilitating cell cycle entry.

Role of SOS in EGF Signaling

  • SOS (Son of Sevenless):
    • A guanine nucleotide exchange factor (GEF).
    • Binds to GRB2 via the SH3 domain.
    • Functions by replacing GDP with GTP on RAS, converting RAS into its active form.

Impact of MAPK on Cell Cycle

  • How does MAPK affect the cell cycle?
    • Enters the nucleus and phosphorylates transcription factors:
    • AP-1 (composed of Fos/Jun) activates Cyclin D1.
    • MYC activates Cyclin D2.
    • Promotes the G1/S phase transition of the cell cycle.

Cyclin-CDK Complexes

  • What are Cyclin-CDK complexes?
    • Cyclins: Phase-specific regulatory proteins.
    • CDKs (Cyclin-Dependent Kinases): Activated by cyclins.
    • The complex phosphorylates pRB which releases E2F.
    • E2F activates genes necessary for DNA synthesis and the S-phase of the cell cycle.
    • Action halted by proteolysis of cyclins.

RAS Oncogene and Mutation Frequency

  • Role of RAS as an oncogene:
    • Intracellular GTPase involved in the MAPK pathway.
    • Mutations lock RAS in a GTP-bound, active state and are found in significant percentages of various cancers:
    • 90% of pancreatic cancers.
    • 60% of papillary thyroid cancers.
    • 50% of colon cancers.
    • 30% of non-small cell lung cancers.
    • Present in 20-25% of all cancers.

Significance of EGFR in Cancer

  • Role of EGFR:
    • It is a receptor tyrosine kinase.
    • Overexpression or mutations lead to constant activation.
    • Found in numerous cancers:
    • 27-77% of colorectal cancers.
    • 30-50% of pancreatic cancers.
    • 40-80% of lung cancers.
    • 14-91% of non-small cell lung cancers (NSCLC).
    • 10% of NSCLC mutations.
    • 20% of glioblastoma mutations.

Importance of Understanding Oncogenes

  • Why is understanding oncogenes important?
    • Explains cancer development.
    • Aids in cancer prevention strategies.
    • Supports the design of targeted therapies.
    • Enables personalized treatment plans.

KRAS as a Predictive Biomarker

  • Why is KRAS important in colorectal cancer?
    • It encodes a GTPase downstream of EGFR and is mutated in 35-45% of colorectal cancers.
    • A mutation indicates poor response to anti-EGFR therapies and helps predict treatment outcomes.

Effects of Multiple Oncogene Activation

  • What happens with multiple oncogenes activated?
    • It leads to faster tumor development.
    • Example: Activation of MYC + RAS in mice results in aggressive cancer.
    • Reflects the multi-hit hypothesis in human cancer.

Contribution of Tumor Viruses to Oncogenesis

  • Differences in RNA and DNA tumor viruses:
    • RNA tumor viruses:
    • Integrate into the host genome.
    • Cause deregulation of proto-oncogenes.
    • DNA tumor viruses:
    • Interfere with the cell cycle and apoptosis.
    • Inactivate tumor suppressor genes.