Genetics of Cancer

• CANCER

  A disease characterized by uncontrolled cell division.

  It is a genetic disease at the cellular level

  More than 100 kinds of human cancers are known
• ALTERATIONS – caused by mutations

  1.Sustainingproliferativesignaling

  2. Evading growth suppressors3. Resisting cell death

  4. Inducing angiogenesis

  5. Enabling replicative immortality

  6. Activating invasion and metastasis.
• Alterations are caused by mutations that affect growth factor receptors and signal transduction genes, cell cycle regulatory genes, DNA repair genes, or genes controlling apoptosis. Depending on whether the affected gene normally stimulates or inhibits proliferation, the mutated gene is called an oncogene or a tumor-suppressor gene.
• Cancers typically originate in dividing cells, such as precursor (progenitor) stem cells that give rise to differentiated tissues in the adult. Most cancers originate in somatic cells and not germ-line cells.
• CANCER CHARACTERISTICS

  1. Most cancers originate in a single cell

  • In this regard, a cancerous growth can be considered to be clonal.
• CANCER CHARACTERISTICS

  2. At the cellular and genetic levels, cancer is usually a multistep process

  • It begins with a precancerous genetic change (i.e., a benign growth)
  • Following additional genetic changes, it progresses to cancerous cell growth.
• CANCER CHARACTERISTICS

  3. Once a cellular growth has become malignant, the cells are invasive (i.e., they can invade healthy tissues)

  - They are also metastatic (i.e., they can migrate to other parts of the body.
• 5 to 10% of cancers are due to inherited predisposition
• --

  viruses.

  --

  90 to 95% are not

  • A small subset of these is the result of spontaneous mutations and
  • However, at least 80% of cancers are related to exposure to mutagens
  • These alter the structure and expression of genes
• • An environmental agent that causes cancer is termed a carcinogen
• METASTASIS

  Most malignant tumor cells eventually acquire the ability to metastasize. To do so they must degrade the basement membranes of connective tissue underlying epithelial cells and surrounding the endothelial cells of blood vessels. This can be accomplished by secretion of plasminogen activator, which activates the blood protease, plasmin. Malignant cells form structures called invadopodia which contain protein components needed for crossing basement membranes.
• Cancer stem cells


  Cells that originate cancers, possess the ability to continue to divide indefinitely
• Cancers are thought to typically originate in dividing cells, such as precursor (progenitor) stem cells that give rise to differentiated tissues in the adult
• Tumors do not contain a single type of transformed cell, although all are thought to come from a single original cell
• Cancer stem cells


  • Divide to produce a copy of themselves, and another cell of more limited replicative potential
• Many cancer therapies that shrink tumors kill the more differentiated cells, leaving the cancer stem cells alive and capable of seeding additional tumors
• The M checkpoint is monitored by proteins that can sense if a chromosome is not correctly attached to the spindle apparatus.
• Both the G1 and G2 checkpoints involve proteins that can sense DNA damage
• CONTROL OF CELL CYCLE

  • Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression to the next phase.
  • Function of many checkpoints is to assess DNA damage, which is detected by sensor mechanisms– function of checkpoint proteins.
• PROTEINS WITH A ROLE IN CANCER

  • Checkpoint proteins prevent division of cells that may have incurred DNA damage.
  • Provides a mechanism to stop accumulation of genetic abnormalities that could produce cancer DNA repair enzymes.
  • A second class of proteins involved with genome maintenance consists of
• GENETIC CHANGES LEADING TO CANCER

  • Some genes affect growth directly, others may enable metastasis which allows expansion to new locations, giving the cells a growth advantage
  • Estimated that 300 different genes may play a role in development of human cancer
  • Over 1% of our genes
  • Chromosome abnormalities are often associated with cancer

  Missing chromosomes may have carried tumor suppressor

  Duplicated chromosomes may overexpress proto-oncogenes.
• Genes commonly mutated in cancer

  Genes that control cell growth and proliferation
• Gain-of-function mutations


  • Increase the activity of proto-oncogenes such as:

  I. Growth-promoting signaling molecules

  II. Receptors

  III. Intracellular signal transduction pathways

  IV. Transcription factors
• Oncogenes


  Resulting mutated genes from gain-of-function mutations
• Loss-of-function mutations


  • In tumor-suppressor genes such as:

  V. Cell cycle control proteins

  VI. DNA repair proteins (caretaker genes)

  Anti-proliferative factor receptors such as the TGFß receptor
• Loss-of-function mutations in tumor-suppressor genes can cause cancer