Cancer Genetics

Unit Overview

  • Unit #4: Cancer Genetics

Basic Features of Cancer

  • Definition: Cancer is a group of diseases characterized by unregulated cell division.

  • Types of Tumors:

    • Benign Tumors: Non-cancerous, localized growths.

    • Malignant Tumors: Cancerous, can invade other tissues.

    • Metastasis: Process by which cancer cells leave the original site, invade other tissues, and form secondary tumors.

Multistep Model of Cancer

  • Overview:

    1. Mutations accumulate within a cell altering gene activity.

    2. Sufficient mutations lead to cell transformation into a tumor.

  • Supporting Evidence: Cancer incidence increases with age due to the accumulation of mutations.

Clonal Evolution of Tumors

  • Mechanism:

    • Mutations primarily occur in genes that control:

      • Proliferation

      • DNA Repair

      • Apoptosis (programmed cell death)

Gene Types and Their Roles

  • Proto-Oncogenes: Normal genes that promote cell growth. When mutated, they become oncogenes that drive excess growth.

  • Tumor Suppressor Genes: Typically inhibit cell division. Approximately half of these function in cell cycle control to prevent over-proliferation.

  • Examples: Mutations in these genes lead to uncontrolled cell division, contributing to cancer promotion.

Cell Cycle Checkpoints

  • Cdk and Cyclins: Regulate cell growth and activity:

    • Work in complexes that fluctuate levels during the cell cycle.

    • Phases include: G1, S, G2, M (Mitosis).

G1 Checkpoint Mechanism

  • Components: Cdk-Cyclin, Rb (Retinoblastoma protein), and E2F.

    • Function: Rb is phosphorylated by Cdk-Cyclin, releasing E2F to upregulate transcription of S phase genes.

  • Activation Influences: Growth hormones and signaling pathways such as EGF (Epidermal Growth Factor).

Ras and Cancer

  • Activation: Ras-GTP levels often elevated in many cancers.

    • Leads to increased proliferation and cell growth (e.g., myelogenous lymphoma, Philadelphia chromosome).

  • Translocation: Specific translocation between chromosomes 9 and 22 results in persistent tyrosine kinase activity.

p53 Tumor Suppressor Role

  • Function: Critical for regulating the cell cycle, DNA repair, and apoptosis initiation.

    • Over 50% of cancers show mutations or deletions in the p53 gene.

  • Pathways: Interactions with genes like p21 and cyclins are essential for halting cancerous growths.

Rb Gene Mutation Impact

  • A mutation producing a non-functional Rb protein prevents binding to E2F. This may lead to tumor formation due to unfettered transcription of target genes.

Importance of DNA Repair

  • Role: Deficits in DNA repair mechanisms often correlate with inherited cancer syndromes.

Epigenetic Modifications

  • Mechanism: Typically lead to decreased gene expression, notably through methylation of CpG islands in promoter regions.

  • Methylation Targets: Primarily adenine and cytosine residues.

Methylation and Cancer

  • Focusing on methylation of the MGMT promoter, which may influence DNA repair functions, contributing to cancer pathology.

Conclusion

  • Understanding cancer genetics requires familiarity with cellular mechanisms including the roles of specific genes and mutations that dysregulate traditional cellular processes.