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Genes and Cancer - Part 1 Notes

Cancer as a Disorder of Somatic Cells

  • Cancer is a disorder of somatic cells, which are all body cells except gametes (eggs and sperm).
  • Cancer involves malignant tumors that invade other tissues and can be fatal.
  • Malignant means "bad" in several languages.
  • Age is a primary risk factor for cancer, as mutations accumulate over time.
  • Heritable predispositions to cancer often show dominant inheritance patterns, where inheriting a mutated gene involved in cell cycle control can lead to cancer development.

Age and Cancer Risk

  • The risk of cancer increases with age, particularly after age 30-35.
  • Cancer death rates per 100,000 individuals are relatively flat until around age 30.
  • Significant increases in cancer risk are observed in older age groups (e.g., 45-54, 55-64).

Characteristics of Cancer

  • Uncontrolled Cell Growth:
  • Benign tumors are non-invasive, encapsulated, slow-growing, and do not spread. They can often be surgically removed.
  • Malignant tumors are cancerous, non-encapsulated, fast-growing, and can metastasize.
  • Metastasis:
  • Metastasis involves the spread of cancer cells from the primary tumor to other parts of the body via the circulatory or lymphatic systems.
  • Metastasis is a sign of advanced cancer and makes it harder to control.

Causes of Cancer

  • Mutations:
  • Cancer is caused by mutations, which can arise from:
  • Heritable predispositions:
  • Inherited mutations in genes involved in cell cycle control or DNA repair.
  • Spontaneous mutations:
  • Errors during DNA replication by DNA polymerase.
  • Environmental and behavioral factors:
  • Exposure to toxins and behaviors like smoking.
  • Inheritable vs. Sporadic Cancers:
  • Most cancers are sporadic, resulting from accumulated mutations over time.
  • Heritable cancers involve inherited mutated genes that predispose individuals to cancer.
  • Mutations accumulate in somatic cells, with each cell division potentially introducing new mutations.

Accumulation of Mutations

  • Normal cell divides, mutation occurs, daughter cells inherit mutation.
  • Second mutation occurs later, subsequent cells inherit both mutations.
  • Heritable predispositions mean inheriting one mutated gene involved in cell cycle control or repair.

Examples of Cancers with Heritable Predispositions

  • Early Onset Familiar Breast Cancer:
  • Mutations in BRCA1 and BRCA2 genes (DNA repair genes).
  • Hereditary Nonpolyposis Colorectal Cancer:
  • Inherited colon cancer requiring multiple mutations to manifest.
  • Retinoblastoma:
  • Cancer behind the eye due to a mutation in a tumor suppressor protein.

Cancer Cells vs. Healthy Cells

  • Cancer cells exhibit uncontrolled cell division and odd shapes.
  • Healthy tissues eliminate damaged cells through apoptosis (cellular suicide).
  • Apoptosis involves chemical signals that cause a damaged cell to change shape, die, and be engulfed by macrophages.
  • In cancer cells, this elimination process fails, leading to uncontrolled growth and mutated offspring cells.

Cell Behavior In Vitro

  • Normal cells require growth factors to divide in a tissue culture flask.
  • They grow and cover the bottom of the flask and stop in one layer.
  • Cancer cells divide regardless of the presence of growth factors.

Tumor Suppressor Genes

  • RB (mutated in 48% of cancers) and p53 (mutated in 50% of cancers) are tumor suppressor genes.
  • They suppress the cell cycle and tumorous growth.
  • They work inside the nucleus.

Proto-oncogenes

  • Proto-oncogenes promote the cell cycle.
  • Examples include RAS proteins (activated by mutations in 20-30% of cancers) and SOK kinase.
  • RAS protein is normally active and inactive as part of cellular growth.

Cell Cycle Regulation

  • Tumor suppressor proteins (RB, p53) regulate the cell cycle.
  • Checkpoints:
  • G1 checkpoint: determines if DNA should be duplicated; cells can exit into G0 phase if something is wrong.
  • G2 checkpoint: between G2 and mitotic phase; prevents cell division if something is wrong.
  • Mitotic checkpoint: ensures chromosomes are properly separated.
  • Tumor suppressors act like brakes, stopping the cell cycle.

Role of p53

  • p53 is a tumor suppressor activated by DNA damage, hypoxia, nutrient deprivation, oxidative stress, and oncogene expression.
  • It can induce cell cycle arrest or apoptosis.
  • p53 is involved in DNA repair, metabolism, and senescence.

Retinoblastoma (RB)

  • RB mutation can lead to malignant eye tumors. Predisposition exists if a child inherits a mutated RB protein.
  • Genetic checks can identify family history and probability of retinoblastoma.
  • Early detection allows for eyeball removal or tissue treatment to restore eyesight.
  • Hereditary vs. Sporadic Retinoblastoma:
  • Hereditary retinoblastoma involves inheriting one mutated RB gene.
  • Sporadic retinoblastoma requires two mutations over a longer time.
  • The RB gene is on chromosome 13 (Q arm) and is often caused by deletion.

RB Gene Function

  • RB protein inhibits transcription factor E2F from binding to DNA and facilitating transcription.
  • If RB is phosphorylated, it releases E2F, allowing transcription to proceed and initiating cell division.

Overview of Cell Growth Regulation

  • Growth factors (e.g., PDGF) bind to receptors on the cell surface.
  • This initiates a cascade of events involving RAS protein.
  • RAS activates kinases, which phosphorylate and activate other proteins.
  • In the nucleus, RB binds to E2F, inhibiting transcription.
  • RAS and kinase cascade lead to RB phosphorylation, releasing E2F and activating transcription.
    (Growth\,Factor + Receptor \rightarrow RAS \,Activation \rightarrow Kinase\,Cascade \rightarrow RB\,Phosphorylation \rightarrow E2F\,Activation \rightarrow Transcription)

Proto-oncogenes and Oncogenes

  • Proto-oncogenes (like RAS) are like gas pedals, promoting cell cycle.
  • Tumor suppressors are like brakes, inhibiting cell cycle.
  • Normal RAS can be turned on and off, but mutant RAS is often always on.
  • Normal growth is controlled via proto-oncogenes; RAS can be activated and inactivated.
  • Mutant RAS is constantly active, leading to uncontrolled growth.

Mutations in RAS Protein

  • Mutation at position 12 or 61 leads to mutant RAS protein remaining active.
  • Neither mutant protein can be turned off, resulting in uncontrolled cell growth.

Anchorage Dependence and Density-Dependent Inhibition

  • Anchorage dependence: cells must adhere to the bottom of the dish to grow.
  • Density-dependent inhibition: cells stop dividing when they sense neighboring cells.
  • Cancer cells ignore these rules and pile up on each other.

DNA Repair Genes

  • Factors causing DNA damage: radiation, aging, UV light, chemicals, DNA polymerase errors.
  • DNA repair enzymes fix errors and eliminate mutated base pairs.
  • If DNA repair mechanisms fail, mutations accumulate, leading to uncontrolled cell growth.

BRCA1 and BRCA2

  • BRCA1 and BRCA2 are DNA repair genes.
  • Mutations lead to breast and ovarian cancer.

Development of Breast Cancer

  • Initial abnormal growth in milk duct (benign tumor, encapsulated).
  • Cancer cells invade neighboring tissue (malignant).
  • Metastasis via circulatory or lymphatic system.