Cancer Genetics

Unit #4: Cancer Genetics

Basic Features of Cancer

  • Cancer is defined as a group of diseases characterized by unregulated cell division and proliferation.

  • It often results from the dysregulation of signaling systems, which may be spontaneous or inherited, and is commonly associated with developmental genes.

Types of Tumors

  • Benign tumors: Remain local and do not invade other tissues.

  • Malignant tumors: Cells invade other tissues, leading to metastasis, where cancer cells leave the original tumor site and form secondary tumors in different body regions.

Multistep Model of Cancer

  • Mutations accumulate in a specific cell, altering gene activity over time.

  • When enough genes are altered, the cell transitions into a tumor.

  • There is a correlation between age and the incidence of cancer due to the accumulation of mutations.

Clonal Evolution of Tumors

  • Tumor evolution is driven by mutations occurring in genes that control cell proliferation, DNA repair mechanisms, and pro-apoptotic signals.

Key Genes in Cancer Development

Proto-oncogenes and Oncogenes

  • Proto-oncogenes: Normal genes that, when mutated, can lead to uncontrolled cell growth as oncogenes.

  • Mutations in proto-oncogenes may result in overactivity and increased production of their respective proteins.

Tumor Suppressor Genes

  • These genes help regulate the cell cycle and prevent over-proliferation.

  • Approximately half of all cancers exhibit mutations in tumor suppressor genes.

Cell Cycle Checkpoints

  • Cdk and Cyclins: Protein complexes that regulate growth activity throughout the cell cycle (G1, S, G2, M).

  • Growth factors can influence Cdk-cyclin activity, affecting pathways that promote proliferation.

G1/S Checkpoint Mechanism

  • Key components include Cdk-cyclin, Rb (Retinoblastoma protein), and E2F, which control the transition from G1 to S phase.

  • Rb is phosphorylated by the G1 Cdk-cyclin complex, releasing E2F, resulting in the upregulation of S phase gene transcription.

Implications for Cancer

  • High levels of Ras-GTP are observed in many cancers, leading to uncontrolled proliferation.

  • Examples:

    • Myelogenous lymphoma associated with the Philadelphia chromosome translocation (ABL1 and BCR genes).

Role of p53

  • The p53 gene is a critical tumor suppressor that activates DNA repair, arrests growth at the G1/S checkpoint, and can initiate apoptosis.

  • Mutations in p53 are found in over 50% of cancers, indicating its importance in cancer regulation.

DNA Repair Mechanisms

Importance of DNA Repair

  • Mutations in DNA repair genes are frequently linked to inherited cancers.

  • Effective DNA repair mechanisms are essential to prevent the accumulation of mutations.

Epigenetic Modifications

  • Lead to decreased gene expression and can play a significant role in cancer development.

  • DNA methylation often occurs in CpG islands within promoter regions and affects gene activity.

Methylation Process

  • Methylation Targets: Adenine and Cytosine residues are commonly modified.

  • Methylation patterns on genes, such as the MGMT promoter, can influence DNA repair capabilities and cancer risk.

Case Study: Rb Gene Mutation

  • A mutation in the Rb gene results in an inability to bind to E2F, often leading to uncontrolled cell proliferation and tumor formation.

Conclusion

  • Understanding cancer genetics involves integrating knowledge of cell cycle regulation, the role of specific genes, and the impact of epigenetic factors.