Genes and Cancer Notes

Cancer Development and Progression

• Cancers originate from a single somatic cell that accumulates mutations over time, often decades.
• The process of cancer development is a slow progression.
• Example: Colon cancer development involves multiple mutations.
  • Normal colon epithelium progresses through stages due to mutations in specific genes.
  • Mutation in the APC gene (tumor suppressor) leads to abnormal, benign growth (adenoma or polyp).
  • A mutation in the RAS gene (proto-oncogene to oncogene conversion) results in uncontrolled cell division.
  • Deletion of a second tumor suppressor gene (DCC) leads to more aggressive growth.
  • Mutation/loss of function in p53 (a critical tumor suppressor) leads to rapid cancer proliferation.
• Benign tumors (adenomas) are encapsulated and can be removed.
• Malignant tumors (cancers) invade surrounding tissues, metastasize through blood vessels, and form new tumors.

Somatic Origin and Cancer Development

• Cancer is of somatic origin; it arises from a single cell with a genetic mutation and is not inherited.
• Cancer development involves:
  • Abnormal cell growth.
  • Mutation of tumor suppressor genes and conversion of proto-oncogenes to oncogenes.
• Cancer is defined as malignant when it:
  • Destroys surrounding tissues.
  • Metastasizes, forming new tumors in other body parts.

Colon and Rectal Cancer

• Colon and rectal cancer is the second leading cause of cancer-related deaths in the US.
• Many people develop abnormal colon growth, but early detection is key.
• Prevention and survival:
  • 90% of colon cancers are preventable, or have a 90% survival rate if detected early.
  • Colonoscopies are recommended every 5 years after age 45 or 50 to detect and remove polyps.
• Colonoscopy procedure:
  • Polyps (abnormal growths) are removed.
  • More frequent colonoscopies may be recommended based on growth aggressiveness.

Genetic Disorders and Cancer Susceptibility

• Ataxia-telangiectasia:
  • Involves a gene related to cell cycle control.
  • Mutations can lead to lymphoid cancers.
  • Affected individuals are hypersensitive to X-rays.
• Bloom's Syndrome:
  • Involves a DNA repair gene.
  • Improper DNA repair increases cancer risk.
  • Patients are sensitive to sunlight.
• Fanconi Anemia:
  • Involves problems with DNA repair.
  • Patients are very sensitive to X-rays.
• Xeroderma Pigmentosum:
  • Involves problems with DNA repair.
  • Patients are very sensitive to sunlight.

Tumor Cell Karyotype and Genomic Instability

• Tumor cells exhibit chromosomal abnormalities.
• Unlike normal cells (46 chromosomes), tumor cells show:
  • Duplication of chromosomes.
  • Translocations.
  • Triplets and quadruplets of chromosomes.
• These abnormalities contribute to genomic instability and uncontrolled cell cycle progression.

Chronic Myeloid Leukemia (CML) and Translocation

• CML is caused by a translocation between chromosomes 9 and 22.
• Philadelphia chromosome:
  • Chromosome 22 is smaller after translocation, known as the Philadelphia chromosome.
  • The translocation results in a gene that's usually turned off being activated, leading to uncontrolled cell cycle stimulation.
• BCR-ABL protein:
  • The hybrid protein resulting from the translocation is called BCR-ABL. It is a kinase.
  • It binds to ATP which activates a signal protein, stimulating the cell cycle, leading to CML.

GLEEVEC: A Targeted Therapy for CML

• Scientists developed a drug (GLEEVEC) that targets the BCR-ABL protein.
• Drug design:
  • Using 3D modeling, they identified the active site of the BCR-ABL kinase.
  • GLEEVEC was designed to fit directly into this active site, inhibiting the enzyme.
• Treatment:
  • CML patients taking GLEEVEC can be cured, but must continue the medication for life.

Cancers Caused by Translocations

• Various cancers, mainly leukemias, are caused by translocations.
• Examples:
  • CML (Chronic Myeloid Leukemia).
  • Monocytic leukemia.
  • B-cell leukemia.
  • Burkitt's lymphoma.
  • Myelogenous leukemia.
  • ALL (Acute Lymphocytic Leukemia).

Genomics and Cancer

• Cancer genome sequencing:
  • With advancements in genomics, cancer-causing mutations can be identified.
  • Cancers were traditionally classified by their origin (e.g., lung cancer).
• Genomic approach:
  • Identifies specific gene mutations that can cause various cancers, regardless of origin.
  • Allows for the development of better-targeted therapies.

Cancer Mutation Identification

• Genomic sequencing has identified many cancer mutations.
• Examples:
  • Breast cancer mutations.
  • Colon cancer mutations.
  • Many mutations occur in signal transduction genes, transcription regulation, and metabolism-related genes.

Epigenetics and Cancer

• Epigenetics involves modifications to DNA that don't alter the sequence itself.
• DNA methylation:
  • Methyl groups (CH3) attach to DNA, preventing RNA polymerase from binding.
  • This turns off gene transcription and translation.
• Hypermethylation:
  • Leads to various cancers by silencing tumor suppressor genes.
  • Examples: APC gene, AR gene, BRCA1/BRCA2 genes, DNA repair genes, cell cycle control genes.

Cancer Therapy: Traditional vs. Modern Approaches

• Traditional therapies:
  • Radiation and chemotherapy damage cancer cells, but also harm normal cells.
  • This leads to severe side effects.
• Modern therapies:
  • Immunotherapy and gene therapy are newer, targeted approaches.

Immunotherapy: Emily Whitehead's Case

• Emily Whitehead's Story:
  • She was cured of acute lymphoblastic leukemia (ALL) through immunotherapy after multiple failed chemotherapy rounds.
• The immunotherapy process involved:
  • Collecting T cells from the patient.
  • Genetically modifying the T cells with a virus vector in vitro.
  • The virus introduced a gene that allowed the T cells to bind to and kill cancer cells.
  • Modified T cells were reintroduced into the patient.
• The modified T cells allow the cytotoxic T cells to kill cancer cells, which they were unable to do previously due to the cancer cells putting a "break" on them.

Environmental and Behavioral Causes of Cancer

• Epidemiology:
  • Studies the factors controlling the presence or absence of a disease.
  • Large studies are needed to determine if a substance is carcinogenic.
• Biological Carcinogens:
  • Fragile sites: Can cause breakage and translocations.
  • Sex-influenced inheritance: BRCA1 and BRCA2 genes can lead to breast, ovarian, and prostate cancer.
  • Viruses: Epstein-Barr virus, HPV (human papillomavirus) can cause cervical cancer.
• Other Agents:
  • Radiation and chemicals can modify nucleotides.
• Lifestyle/Behavioral Choices:
  • Sun exposure (UV light) causes thymine dimers.
  • Smoking causes severe DNA damage.
• Internal Metagenic Changes:
  • Reactive oxygen species: Byproducts of cellular respiration that can damage DNA.

Correlation Between Smoking and Lung Cancer

• Study showing increased cigarette consumption in men from 1900s-1940s.
• A corresponding increase in lung cancer rates about 20 years later was observed.
• Cancer studies take a long time to yield observable results.

Physical and Chemical Carcinogens

• Physical Carcinogens:
  • UV light: Mutates p53, leading to sarcomas (cancers of bone, connective tissue, blood vessel lining, nerves, fats, and fibers).
• Chemical Carcinogens:
  • Benzene and benzopyrenes: Mutate p53 genes, leading to various cancers including lung cancer.
  • Toluene: Found in nail polish, adhesives, lacquers; strong carcinogen.
  • Xylene: Found in paints, paint thinners, gasoline; carcinogenic activity.
  • Cigarettes: Contain tar and nicotine, causing DNA damage.
  • Vinyl chloride: Can lead to liver cancers.
  • Flame Retardants: Found in carpets, fabrics, upholstery, and bedding; can be carcinogenic.

More Chemical Carcinogens and Food-Related Carcinogens

• Dioxin:
  • Serious carcinogen found in many pesticides.
  • Disrupts hormone action, reduces immunity, causes birth deformities.
• Chlorinated organic chemicals:
  • PCBs and plastics can leach into food.
  • Burning plastic produces serious carcinogens.
• Food-related carcinogens:
  • Heterocyclic aromatic amines: Produced when meat is barbecued or grilled at high temperatures.
  • These substances are absorbed, metabolized, and turned into mutagens in the digestive tract.
• Protective Foods:
  • Cruciferous vegetables (Brussels sprouts, broccoli, kale) contain glucosinolates and xenobiotic metabolic enzymes.
  • These prevent the production of mutagens and can metabolize heterocyclic aromatic amines into non-mutagenic forms.