Lecture 20

BM210 Cancer Genetics Lecture Notes

Lecture Objectives

  • By the end of this lecture, students should be able to:

    • Understand how cancer cells bypass normal proliferative controls and colonize other tissues.

    • Comprehend the mutational basis underlying cancer.

    • Understand the multiple hit theory of cancer development.

    • Recognize the recurrent properties of cancer cells.

    • Recognize changes in cancer-related pathways involving tumor promoters (e.g., Ras) and tumor suppressors (e.g., p53).

Cancer Incidence and Mortality (US 2021 Data)

  • Overview of cancer incidence and mortality rates as reported in the US for the year 2021.

Benign vs Malignant Tumors

  • Benign Tumors:

    • Defined as neoplastic cells that have not become invasive.

    • Tumors are considered benign if they can be removed or destroyed locally, leading to a complete cure.

  • Malignant Tumors:

    • Defined as tumors where cells have acquired the ability to invade surrounding tissues.

    • Invasiveness: Essential characteristic of cancer cells, enabling them to enter blood or lymphatic vessels and form metastases.

    • Metastases are secondary tumors; their presence often complicates treatment and contributes to patient mortality.

Tumor Development from a Single Abnormal Cell

  • Most tumors arise from a single abnormal cell, leading to a common genetic origin.

  • Typical growth pattern:

    • Tumor diameter is often plotted on a logarithmic scale.

    • Tumors may remain undetectable (palpable) for years.

    • Example: The doubling time for breast tumors is about 100 days, although some grow more rapidly.

Multiple Hit Theory of Cancer

  • Single Mutation Insufficiency:

    • The incidence of cancer is steeply age-dependent; if a single mutation triggered cancer, the rates would be constant across all ages.

    • Development of solid tumors often requires 5-8 independent 'hits' (mutations).

  • Assumption: Mutation rate remains constant, yet it often increases as cancer progresses.

Cancer Cell Development

  • Cancer cells gradually develop from increasingly aberrant cells through genetic changes and mutations.

Somatic Mutations in Cancer Cells

  • Tumor cells manifest somatic mutations, displaying shared detectable abnormalities in their DNA sequences compared to normal cells.

  • Example: Chronic Myelogenous Leukemia (CML):

    • Involves a translocation between chromosomes 9 and 22, creating the Philadelphia chromosome, which drives abnormal cell growth.

Tumor Progression

  • Tumor progression includes:

    • Successive rounds of inherited genetic changes followed by natural selection.

    • At each mutation step, new clones of cells emerge that enhance proliferation or reduce apoptosis.

    • The final step involves invasion through the basement membrane, leading to metastasis.

    • The process involves numerous genetic and epigenetic changes throughout.

Genetic Instability in Cancer Cells

  • Cancer cells exhibit genetic instability, accumulating genetic changes abnormally rapidly.

  • Differences exist among cancers and patients in the extent and molecular origins of instability.

  • Many cancers show chromosomal abnormalities (duplications, deletions, and translocations) visible during mitosis.

  • Epigenetic changes also contribute to cancer phenotypes.

Altered Growth Conditions in Cancer Cells

  • Cancer cells exhibit a 'transformed phenotype':

    • Abnormal shape, motility, and interactions with the substratum and other cells.

    • Transformed cells often divide without attachment to a surface, unlike normal cells.

    • In a confluent culture, normal cells stop dividing, whereas transformed cells continue to proliferate uncontrollably.

Altered Metabolism in Cancer Cells (Warburg Effect)

  • Normal Cells:

    • Utilize oxidative phosphorylation for ATP production when oxygen is available.

    • Under oxygen deprivation, they shift to glycolysis to generate ATP, producing lactate.

  • Tumor Cells:

    • Exhibit increased glycolysis rates, producing lactate regardless of available oxygen.

    • This metabolic shift supplies building blocks essential for rapid cell growth.

Tumorigenesis: Increased Division and Decreased Apoptosis

  • Tumorigenesis involves both:

    • Increased cell division.

    • Decreased apoptosis.

  • Homeostasis in normal tissues is maintained through the balance between these two processes.

Steps in Metastasis

  • Tumor cells can proliferate in hostile environments.

Cancer Critical Genes

  • Cancer-critical mutations can be classified into two categories:

    • Dominant mutations (oncogenes).

    • Recessive mutations (tumor suppressor genes).

Transformation of Genes into Oncogenes

  • V-Src Example:

    • Discovered through Rous sarcoma virus where the gene v-Src leads to cancerous cells.

    • Proto-oncogenes are normal genes (e.g., c-Src) that regulate cell division before mutations convert them into oncogenes.

Overactivation of Oncogenes

  • Oncogenes can become overactive through various mechanisms, including mutations in the Ras family proteins, which account for ~30% of all human cancers.

  • Case Study: Ras Mutations:

    • Ras family members undergo point mutations leading to hyperactivity; only one of the gene’s two copies needs to mutate.

EGF Receptor and Oncogenesis

  • Mutation causing persistent activity of the EGF receptor, even in the absence of its ligand, resulting in oncogenic signaling.

Tumor Suppressor Genes

  • Initial discovery linked to retinoblastoma, showcasing the role of the Rb gene in regulating the cell cycle. Loss of function or deletion of the Rb gene leads to unregulated cell division.

  • Hereditary vs. Nonhereditary Forms:

    • In hereditary retinoblastoma, one normal copy of the Rb gene is missing from birth; in the nonhereditary form, both copies are inactivated through random mutations.

Mechanisms of Tumor Suppressor Gene Inactivation

  • The loss of a good copy of tumor suppressor genes can occur through:

    • Point mutations, large deletions, chromosomal rearrangements, or epigenetic silencing.

P53 Pathway and Cancer

  • Role of p53:

    • Acts as a nuclear transcription factor promoting apoptosis and preventing malignant transformation.

    • Found in over 50% of human cancers with loss-of-function mutations.

    • Levels of p53 are usually low and rise in response to cellular stresses such as DNA damage and hypoxia.

    • p53 can cause cell cycle arrest, trigger apoptosis, or induce senescence in response to damage.

Mouse Models for Cancer Research

  • Use of transgenic and knockout mice to study oncogene and tumor suppressor gene functions.

  • Evidence shows that expression of an oncogene alone (e.g., Myc or Ras) does not guarantee cancer development, but increases cancer risk significantly, especially in combination.

Colorectal Cancer Development

  • Colorectal cancer typically arises from adenomatous polyps, which are benign tumors.

  • Removal of polyps significantly decreases cancer rates.

  • Progression to cancer involves invasion of surrounding tissues, leading to metastasis to lymph nodes and distant organs.

Mutation and Tumor Development Over Time

  • Correlation exists between the accumulation of mutations and the progression of cancer.

Summary of Cancer Genetics

  • Cancer-critical genes include oncogenes and tumor suppressor genes altered by genetic/epigenetic events.

  • Inactivation of key pathways (e.g., p53 and Rb) allows damaged cells to survive and proliferate, leading to cancer progression.

  • Tumors generally emerge from a combination of 10 driver mutations and numerous passenger mutations, contributing to heterogeneous cell populations within tumors.

  • The mechanism of cancer development reflects complexity and randomness, yet certain mutation combinations are common across cancers.

Future Directions

  • Investigate the genomes of cancer cells, replicate mutations in model organisms (e.g., flies), and personalize drug treatment based on individual mutations in cancer therapy.