Lecture 1-Intro and Mutation Signatures-2

Principles of Cancer Genetics

The Genetic Basis of Cancer

Chapter 1 Overview

  • Introduction to cancer genetics and its implications for understanding cancer pathology.

Cancer Gene Theory

Basics of Cancer Gene Theory

  • The human body consists of approximately 200 cell types.

  • Pluripotent stem cells commit to specific lineages, continuing differentiation throughout life.

  • Different cancers originate from these diverse cell types.

  • Carcinomas arise from epithelial cells:

    • Squamous Cell Carcinoma: non-glandular epithelium.

    • Adenocarcinoma: glands.

  • Sarcomas come from mesenchymal connective tissues.

  • Melanomas originate from neuronal ectoderm (skin).

  • Retinoblastoma affects developing retinal cells in children under 6.

  • Neuroblastomas arise from peripheral neurons.

  • Glioblastomas originate from glial cells in the CNS.

  • Lymphomas and Leukemias develop from lymphoid and blood cells.

Correlation of Cancer Phenotype

  • Cancer phenotype is linked to the originating tissue.

  • Caused by specific gene mutations in stem cell progenitors.

  • Gene expression patterns and mutations are influenced by the original stem cell type.

  • Cancer is primarily genetic, caused by acquired mutations despite environmental factors.

Genetic Disease and Cancer

  • Most familiar genetic diseases are monogenic (single gene mutations, e.g., sickle cell anemia).

  • Some are polygenic, involving multiple genes leading to complexity in identifying mutations.

  • Cancer is predominantly polygenic, with multiple mutations accumulating over time, but is not strictly Mendelian.

  • Cancer predisposition may sometimes follow Mendelian inheritance, but typically additional mutations are needed for cancer development.

Cancer Gene Mutations

Mechanism of Mutations

  • DNA polymerase, though efficient, is not infallible, leading to mutations.

  • Most mutations occur in somatic cells, often unnoticed.

  • Mutations can occur in germ cells (sperm and egg), impacting future generations if they persist.

  • Cancer predisposition mutations often only manifest post-reproduction, allowing them to be passed on undetected.

Types of Mutations

  1. Somatic Mutations: Mutations in non-germ cells (i.e. body cells) that can lead to cancer if in key genes regulating cell division or death.

    • These mutations confer a growth advantage, allowing for expansion of mutated cell populations.

    • The accumulation of additional mutations in prolonged divisions can lead to invasive cancers.

  2. Specific Types of Mutations:

    • Chromosomal Translocations: Create fusion genes that can drive aberrant gene expression.

    • Large Deletions/Insertions: Disrupt reading frames, affecting Tumor Suppressor Genes (e.g., TP53, APC, RB).

    • Single Nucleotide Substitutions (SNVs): Affect genes, including oncogenes, leading to unregulated cell division (e.g., KRAS, BRAF, PIK3CA).

Mutation Processes and Environmental Influences

Causes of Mutations

  • Environmental factors exacerbate mutation accumulation:

    1. Time: Aging increases mutation likelihood due to accumulated cell divisions.

    2. Tobacco Smoke: Causes significant mutation rates, notably in lung cancers by introducing specific chemical modifications to DNA.

    3. UV Light: Causes pyrimidine dimers leading to skin cancer if unrepaired.

    4. Ionizing Radiation: Causes mutations at non-CpG sites.

    5. Aflatoxin B1: A potent carcinogen that induces mutations in TP53.

Mutation Signatures

  • Environmental agents lead to distinct mutational signatures that help identify the causes of cancer.

  • Analyzing mutation signatures can reveal history and risk factors for specific cancers and can aid in understanding cancer etiology.

Inflammation and Cancer

Role of Inflammation

  • Chronic inflammation is associated with many cancers due to its role in increasing DNA damage and promoting tissue turnover due to repair processes.

  • Inflammatory diseases often precede cancer, emphasizing the need to understand inflammation in cancer development.

Conclusion

  • Cancer arises from a series of mutations influenced by genetic predisposition, environmental factors, and cell division rates.

  • Understanding these factors is crucial in cancer prevention and treatment strategies.