Clinical Genetics Lecture 4
Cancer • Between 100-350 out of 100,000 people die of cancer each year. • One out of every two men and one out of every three women will develop cancer during their lifetime (American CancerSociety, 2008). • Caused by abnormal growth and proliferation of cells. • Genetic control system regulate the balance between cell birth and death in response to growth signals, growth-inhibiting signals and death signals. • Cell birth and death rates determine adult body size and rate of growth. • The short life of certain cells is short so cell proliferation occurs continuously as a constant tissue renewal.
Life of cells • RBCs– 120 days • WBCs- 13-20days • Taste receptor cells- 10 days • Intestinal epithelial cells – few days • Skin cells- 2-4 weeks • Muscle cells- 15 years • Nerve cells-life time • The cells in adult tissues only proliferate during healing process.
Carcinogens • Lifestyle factors (nutrition, tobacco use, physical activity, etc.) • Naturally occurring exposures (ultraviolet light, radon gas, infectious agents, etc.) • Medical treatments (chemotherapy, radiation, immune system-suppressing drugs, etc.) • Workplace exposures • Household exposures • Pollution • Carcinogens do not cause cancer in every case, all the time. Substances labeled as carcinogens may have different levels of cancer-causing potential. Some may cause cancer only after prolonged, high levels of exposure. And for any particular person, the risk of developing cancer depends on many factors, including how they are exposed to a carcinogen, the length and intensity of the exposure, and the person's genetic makeup.
International Agency for Research on Cancer • The International Agency for Research on Cancer (IARC) is part of the World Health Organization (WHO). • Its major goal is to identify causes of cancer. The most widely used system for classifying carcinogens comes from the IARC. In the past 30 years, the IARC has evaluated the cancer-causing potential of more than 900 likely candidates, placing them into one of the following groups: • Group 1: Carcinogenic to humans • Group 2A: Probably carcinogenic to humans • Group 2B: Possibly carcinogenic to humans • Group 3: Unclassifiable as to carcinogenicity in humans • Group 4: Probably not carcinogenic to humans • http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProductsScientificAdvisoryCommittee/UCM215717.pdf
Types of mutation • 1. Proto-oncogenes: promote normal cell growth. • Mutation in PO cause the gene to be excessively active in growth promotion. • 2. Tumor-supressor genes: restrain growth • Mutation in such genes inactivate them and allow inappropriate cell division. • 3. Caretaker genes: protect the integrity of the genome.
Proto-oncogenes (PO) • PO are a group of genes that cause normal cells to become cancerous when they are mutated. • Mutations in PO are typically dominant in nature, and the mutated version of a proto-oncogene is called an oncogene. • PO encode proteins that function to stimulate cell division, inhibit cell differentiation, and halt cell death. Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK. • All of these processes are important for normal human development and for the maintenance of tissues and organs. • Oncogenes, however, typically exhibit increased production of these proteins, thus leading to increased cell division, decreased cell differentiation, and inhibition of cell death; taken together, these phenotypes define cancer cells. • Thus, oncogenes are currently a major molecular target for anti-cancer drug design.
How Proto-Oncogenes Become Oncogenes • More than 40 different human PO are known. • Oncogenes arise as a result of mutations that increase the expression level or activity of a PO. Underlying genetic mechanisms associated with oncogene activation include the following: • Point mutations, deletions, or insertions that lead to a hyperactive gene product • Point mutations, deletions, or insertions in the promoter region of a PO that lead to increased transcription • Gene amplification events leading to extra chromosomal copies of a PO • Chromosomal translocation events that relocate a PO to a new chromosomal site that leads to higher expression
Point mutations • A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. The term point mutation also includes insertions or deletions of a single base pair.
Types of point mutation • Transition mutations occur when a pyrimidine base (i.e., T or C) substitutes for another pyrimidine base • Or when a purine base (i.e., A or G) substitutes for another purine base. • In contrast, transversion mutations occur when a purine base substitutes for a pyrimidine base, or vice versa; for example, when a TA or CG pair replaces the wild type AT pair.
At the level of translation, when RNA copied from DNA is converted into a string of amino acids during protein synthesis, point mutations often manifest as functional changes in the final protein product. • Thus, there exist functional groupings for point mutations. • These groupings are divided into: • Silent mutations result in a new codon (a triplet nucleotide sequence in RNA) that codes for the same amino acid as the wild type codon in that position. In some silent mutations the codon codes for a different amino acid that happens to have the same properties as the amino acid produced by the wild type codon. • Missense mutations involve substitutions that result in functionally different amino acids; these can lead to alteration or loss of protein function. • Nonsense mutations, which are a severe type of base substitution, result in a stop codon in a position where there was not one before, which causes the premature termination of protein synthesis and, more than likely, a complete loss of function in the finished protein.
Chromosomal Translocation • The exchange of genetic material between chromosomes. Some translocations cause cancer. And some translocations are targets for emerging, personalized therapies.
Role of PO • Many PO play an important role during embryogenesis, because they are often involved in stimulating cellgrowth and proliferation as an organism develops. • Some PO also negatively regulate cell differentiation. • PO activities are typically turned off once the developmental processes they regulate are completed. • However, if PO activity remains high, or if PO are inappropriately reactivated later in life, cancer may occur.
A number of PO code for cell surface receptors. • For growth and division, cells respond to outside signals through the binding of extracellular ligands (growth factors) to the extracellular region of the receptors. • Upon ligand binding, the receptor undergoes a confirmational change which in turn leads to activation of the intracellular domain and a chain of intracellular events that regulate cell growth, proliferation, or death. • Examples of PO receptors include EGFR, the receptor of the epidermal growth factor (EGF) that is involved in growth factor-mediated signaling, and KDR, the receptor of the vascular endothelial growth factor (VEGF) that is involved in angiogenesis.
Examples of PO • POcan also code for intracellular proteins that normally act downstream of cell surface receptor pathways to stimulate cell growth and division. • Examples of these downstream signaling proteins include HRAS and KRAS. • Additionally, some PO including cyclin D1 (CCND1) and cyclin E1 (CCNE1), normally act to push cells through distinct stages of the cell cycle when the cells receive the appropriate signals. • When these proto-oncogenes are expressed at higher than normal levels, or when their expression is inappropriately turned on, cancer can occur.
Oncogene activation • Oncogene activation can also arise through chromosomal translocation events. • The Philadelphia chromosome is the best-known example of an oncogenic chromosomal translocation. • In this case, one end of chromosome 9 is exchanged with one end of chromosome 22. • At the broken end of chromosome 22 lies the BCR gene, which fuses with a fragment of chromosome 9 that carries the ABL1 gene; this fused chromosome is called the Philadelphia chromosome. • When the chromosome ends fuse, the two genes also fuse with each other to become BCR-ABL (Heisterkamp et al., 1985). • The fused gene is expressed, and it encodes a protein that exhibits high protein tyrosine kinase activity, courtesy of the ABL1 half of the protein. The unregulated expression of this protein activates a repertoire of other proteins that are involved in cell cycle regulation and stimulation of cell division. • As a result, the Philadelphia chromosome is associated with chronic myelogenous leukemia (CML) and several other forms of leukemia.
Targeting Oncogene Addiction to Treat Cancer • Short report/review