In-Depth Notes on Cancer Genetics

Cancer Overview

  • Definition: A group of diseases characterized by abnormal cell growth with a potential to invade or spread to other body parts.
  • Cell Behavior:
    • Normal cells vs. cancer cells:
    • Cancer cells replicate uncontrollably.
    • Differentiated cells may revert to an embryonic state.
  • Tumor Growth: Tumors can grow their own blood vessels (angiogenesis) and invade surrounding tissues (local invasion).
  • Metastasis: Cancer cells may move to new body locations through the circulatory (blood vessels) or lymphatic systems.

Cancer Genetics

  • Genetic Nature: Cancer is primarily a genetic disorder involving mutations.
    • Not inherited in the traditional sense, but some inherited mutations can predispose individuals to cancer.
Mutation Types
  • Germ-line Mutations: Present throughout the organism, impacting all cells.
  • Somatic Mutations: Occur in specific cells and are not inherited; they are localized to patches.
Cell Cycle and Cancer
  • Cell Cycle Control: Cancer begins with a loss of control over the cell cycle, leading to unregulated cell proliferation.
  • Key Players:
    • Tumor-Suppressor Genes:
    • Function: Control cell cycle and repair DNA, e.g., RB and TP53.
    • Characteristics: Mutations inactivate these genes; they exhibit recessive behavior.
    • Oncogenes:
    • Function: Stimulate cell proliferation and are activated by mutations.
    • Characteristics: Mutant alleles act dominantly.

Mechanisms of Cell Cycle Regulation

  • Checkpoints: Ensure cell cycle progresses properly, monitoring:
    • Cell size, DNA integrity, chromosome segregation.
  • Cyclins and CDKs: Cyclins activate CDKs to push cell cycle progression, with checkpoint mechanisms determining progression based on cell health.
    • The G1-S checkpoint is crucial for checking DNA damage before DNA synthesis begins.
Role of Rb and p53
  • Rb Protein:
    • Function: A tumor-suppressor that prevents passage into S phase unless phosphorylated by CDK.
    • Mechanism: When phosphorylated, Rb releases E2F, allowing transcription of S-phase genes.
  • p53:
    • Function: Acts as a transcription factor that, when activated by phosphorylation, induces expression of p21.
    • p21 inhibits CDK complexes, preventing entry into S phase and allowing DNA repair or inducing apoptosis if damage is irreparable.

Cancer Development

  • Two-Hit Hypothesis: Retinoblastoma provides a classic example. It requires two mutations to develop:
    • Hereditary: All cells have one mutant allele; one acquires a second mutation.
    • Sporadic: A single cell acquires both mutations.
  • Mutations in TP53: Often lead to further mutations and cancer development in about 50% of cases.
Categories of Mutations
  • Driver Mutations: Essential for cancer initiation and progression; involve inactivation of tumor suppressors.
  • Passenger Mutations: Do not cause cancer but arise as a byproduct of the mutations involved in the malignant process.

Clinical Implications

  • BRCA1/BRCA2: Mutations in these genes are high-risk factors for breast cancer. They function in DNA repair, and mutations lead to increased cancer risk due to genomic instability.
  • Ras Oncogene: Mutated Ras leads to continuous cell proliferation, contributing to tumorigenesis even in the absence of growth factors.

Conclusion

  • Cancer as a Mutational Disease: The occurrence of cancer is tied to the cumulative effect of mutations within a cell's genome, leading to abnormal behaviors such as immortalization, unchecked growth, and the ability to metastasize.