Cancer Genetics

Learning Objectives

• Cancer as a Genetic Disease

  • Cancer is a genetic disorder at the somatic cell level, caused mainly by mutations in somatic cells (only 5% linked to germ-line mutations).

• Genetic Defects in Cancer Cells

  • Cancer cells exhibit genetic defects affecting genomic stability, DNA repair mechanisms, and chromatin modifications, leading to tumorigenesis.

• Cell-Cycle Regulation

  • Alterations in cell-cycle regulation are notable in cancer cells, affecting their growth and division.

• Role of Proto-Oncogenes and Tumor-Suppressor Genes

  • Cancer is associated with mutations in proto-oncogenes (which promote cell growth) and tumor-suppressor genes (which regulate cell cycle).

• Metastasis

  • Cancer cells have the ability to metastasize, invading other tissues ultimately affecting overall health.

• Genetic Predisposition

  • Some cancers can be inherited, indicating a genetic predisposition.

• Contribution of Viruses

  • Certain viruses are known to contribute to cancer in both humans and animals.

• Environmental Factors

  • Various environmental agents can cause human cancers, including carcinogens.

Cancer: A Genetic Disease

• Genomic Alterations: Includes single-nucleotide substitutions, chromosomal rearrangements, amplifications, and deletions.
• Somatic Mutation: Cancer is caused primarily by mutations that occur in somatic cells rather than being inherited.
• Characteristics of Cancer Cells:
  • Unregulated Proliferation: Cancer cells demonstrate uncontrolled cell growth and division.
  • Metastasis: Cancer cells have the ability to spread to other tissues.

Tumor Types

• Benign Tumors: Formed by unregulated growth but do not invade other tissues; can usually be removed by surgery without serious harm.
• Malignant Tumors: Formed by cancer cells that have metastasized, causing severe health issues.

Clonal Origin of Cancer Cells

• All cancer cells within a tumor arise from a common ancestral cell that accumulated various mutations, showing that cancer is a clonal disease.

Types of Genetic Mutations

• Driver Mutations: Provide a growth advantage to cancer cells; relatively few in number (2 to 8 total).
• Passenger Mutations: Do not directly contribute to cancer phenotype and accumulate over time due to high DNA damage in cancer cells.

Cancer Stem Cell Hypothesis

• Proposes that most cells within a tumor are not proliferative. Instead, a subset of cancer stem cells drives tumor growth and has self-renewal capacity.

Carcinogenesis

• Cancer development is a multistep process necessitating multiple mutations that accumulate over time, primarily influenced by age and environmental factors.
• Carcinogens: Agents that induce mutations in proto-oncogenes or tumor-suppressor genes. Example: radiation leading to leukemia shows a delay between exposure and the onset of disease, indicative of the multistep process.

Tumorigenesis

• The formation of malignant tumors stems from genetic alterations that allow cells to escape normal regulatory mechanisms governing cell growth.

Key Genes in Cancer

• Tumor-Suppressor Genes:
  • Example: APC Gene - associated with colorectal cancer; inactivating mutations lead to polyp formation.
• Proto-Oncogenes:
  • Example: Ras - frequently mutated leading to abnormal cell signaling and increased proliferation.
• p53:
  • Most commonly mutated gene in cancers; plays a crucial role in the cell cycle and apoptosis regulation; inability to function in damaged cells allows proliferation.

Metastasis Process

• Involves cancer cells breaking down extracellular matrix components, potentially entering the lymphatic or blood circulatory system.
• Only a small fraction of cells can form secondary tumors; this process is regulated by numerous gene products.

Cancer Associated with Environmental Factors

• Carcinogens include natural and man-made agents such as tobacco smoke, UV radiation, certain viruses, and dietary components.
• Chronic exposure to some agents increases cancer risk significantly.