Cancer Mutation and Heterogeneity Overview

Mutation and Tumour Heterogeneity

• Mutations are random and occur in any cell at any time
• Mutations are most likely to occur during DNA replication
• Mutations are passed on only if the cell divides
• Stepwise mutations lead to heterogeneity between tumors and within a single tumor
• Heterogeneity has implications for cancer therapy

Tumor Co-option of Cellular Pathways

• Tumors co-opt existing cellular pathways
• Examples include disruption of:
  • VEGF affecting angiogenesis
  • P53 affecting apoptosis
  • MAPK signaling affecting tissue invasion, growth, and proliferation

Selective Pressures

• Tumors face selective pressures from the immune system, tumor suppressor genes, and the microenvironment.
• These pressures can lead to tumor evolution and resistance to therapies.

Feedback Loop

• Reduced tumor cell death leads to an increase in proliferation and DNA replication.
• Increased DNA replication results in a greater chance of mutations and instability.

Oncogenes and Tumor Suppressor Genes

• Oncogenes "push the accelerator" of cell growth, while tumor suppressor genes "release the brakes".

Oncogenes

• Proto-oncogenes are typically one of:
  • Cell division stimulators
  • Differentiation blockers
  • Apoptosis inhibitors
  • Components of signaling pathways
  • Growth factors.

Epigenetic Regulation of Gene Expression

• Epigenetic alterations do not involve changes in the DNA sequence but impact gene expression.
• DNA methylation:
  • Addition of a methyl group to cytosine at CpG islands.
  • Inhibits transcription by preventing promoter access.
  • Plays a role in silencing tissue-specific genes.
• Histone modifications:
  • Acetylation is associated with euchromatin (active transcription).
  • Deacetylation is associated with heterochromatin (inactive transcription).
• Histone acetyltransferases, HDACs, and other proteins regulate these modifications.
• Some cancer cells overexpress or aberrantly recruit HDACs leading to:
  • Hypoacetylation
  • Condensed chromatin structure
  • Reduced transcription
• HDAC inhibitors are cancer therapeutics that can increase transcription, leading to cell cycle arrest and apoptosis.

Regulation of Gene Expression

• Cancer cells reproduce without restraint and invade foreign tissue
• Most cancers originate from a single abnormal cell due to epigenetic or genetic changes.
• A single mutation is not enough to cause cancer.
• DNA repair mechanisms and redundancy prevent some mutations from causing damage.
• There are multiple stages of development from mildly aberrant cells to cancer.

Multiple Stages of Tumor Development

• Initiation
• Promotion
• Progression
• Invasion
• Metastasis

Gene Expression and Cancer

• Cancer is a disease of dysregulated gene expression that grants a survival advantage to the cell.
• Cancer growth relies on defective control of cell death and differentiation.

Gene Expression in Cancer Cells

• Alterations in gene expression occur at all levels, including:
  • Histone acetylation
  • Activation of transcription factors
  • Increased mRNA stability
  • Increased translational control
  • Protein modification

Loss of Cell Growth and Death Control

• Proto-oncogenes stimulate cell growth and division in normal cells but become oncogenes in cancer (gain of function mutation).
• Tumor suppressor genes inhibit cell division in response to DNA damage and allow repair to occur, but they lose function in cancer (loss-of-function).
• Changes in gene expression have different effects.

Epithelial-Mesenchymal Transition (EMT)

• The process by which epithelial cells lose polarity, cell-cell adhesion, and gain migratory and invasive properties.
• Involved in natural processes like tissue repair, but also important for metastasis in cancer.

Gene Expression Profiling in Cancer

• Gene expression profiling captures total gene activities across a genome enabling the definition of different subtypes of cancer.
• Applications:
  • Treatment selection by targeting specific deregulated pathways.
  • Predicting cancer prognosis.
  • Understanding mechanisms behind cancer development.