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76 Cards in this Set
- Front
- Back
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What is the basis of cancer?
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Malignant transformation of normal cells due to non-lethal genetic changes
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What are 5 common causes of carcinogenesis?
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-Chemicals
-Radiation -Viruses -Inherited defects -Spontaneous defects |
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What does a tumor develop from?
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Clonal expansion of a SINGLE precursor cell that gets damaged.
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What are the 4 normal regulatory gene classes?
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1. Tumor suppressors
2. Protooncogenes 3. Apoptosis genes 4. DNA repair genes |
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What is the genetic inheritance of proto-oncogenes? Why?
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Dominant - they are the gas pedal and you only need one hit to have the disease.
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What is the genetic inheritance of tumor suppressor genes? Why?
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Recessive - because you need two hits to have the disease.
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What is the genetic inheritance of Apoptosis genes?
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Both dominant and/or recessive.
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What is the genetic inheritance of DNA repair genes?
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Recessive - need two hits.
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Do tumor suppressor genes always need two hits?
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No, there are exceptions to the rule.
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How many changes occur in cell physiology to determine a malignant phenotype?
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7
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What are the 7 changes in cell physiology that determine a malignant phenotype?
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SIEDUSA
-Self sufficiency in growth signals -Insensitivity to growth inhibition signals -Evasion of apoptosis -Defects in DNA repair -Unlimited replication potential -Sustained angiogenesis -Ability to invade and metastesize |
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What is self-sufficiency in growth signals usually a consequence of?
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Oncogene activation
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Once a genetic mutation has occurred, how do tumors PROGRESS?
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By the accumulation of genetic lesions
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What are the 3 features of carcinogenesis?
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-Excessive growth
-Local invasiveness -Ability to form distant metastases. |
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What is the normal counterpart of oncogenes?
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Proto-oncogenes
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What do proto-oncogenes regulate?
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Cell proliferation and differentiation
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What are 2 oncoproteins encoded by oncogenes?
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-Growth factors
-Growth factor receptors |
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What is the result of the fact that oncogenes encode for a cell to make its own growth factors and receptors?
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Autonomous growth
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How does overproduction of growth factors lead to cancer?
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By increasing the likelihood of spontaneous or induced mutations
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How does an increase in growth factor receptors lead to cancer?
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By the fact that the cell is continuously active and lacking in negative feedback.
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Give 2 examples of proto-oncogenes that cause cancer when mutated:
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1. RAS
2. EGFR and HER2/Neu |
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Which does targeted therapy exist for; RAS or EGFR/HER2/Neu?
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EGFR and Her2/Neu
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How is targeted therapy achieved for EGFR and Her2/Neu?
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By giving monoclonal antibodies to these overexpressed receptors.
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What is the EGFR gene overexpressed in?
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-Squamous cell carcinomas of lung
-Head/neck tumors |
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What is the Her2 receptor overexpressed in?
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Breast cancers
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What is the RAS gene protein involved in?
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Signal transduction in G-protein linked signalling
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What happens when a growth factor binds its receptor?
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RAS is converted from inactive to active by the exchange of a GTP of GDP
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What is the result of Active RAS?
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Activation of a MAP kinase pathway
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What is blocked in RAS mutations?
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The GTP-ase activating protein - RAS is stuck in its active form.
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What % of tumors have a RAS mutation?
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15-20%
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What category of regulatory genes are mutated causing insensitivity to growth inhibition?
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Tumor suppressor genes
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How many mutations are needed to result in disease via tumor suppressor genes?
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2
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What are the 3 common examples of tumor suppressor gene mutations?
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-Retinoblastoma gene
-p53 gene -APC gene |
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What is the hypothesis for how Retinoblastoma develops?
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the 2-hit hypothesis
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What are the 2 forms of Retinoblastoma?
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-Familial
-Sporadic |
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What occurs in the progression of familial retinoblastoma?
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1. A mutant gene is passed on from a parent to child
2. All of the child's somatic cells have one mutant allele 3. A retinal cell gets the 2nd hit and heterozygosity is lost |
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What occurs in the progression of sporadic retinoblastoma?
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2 hits to the DNA that cause mutations in the retinal cells.
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What increased risk is associated with familial, but not sporadic retinoblastoma?
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Osteosarcoma and other soft tissue sarcomas.
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So to review: what type of cancers is loss of heterozygosity seen in?
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Recessive
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What is the most common alteration in human tumors?
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p53
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What are the major functions of p53?
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-Cell cycle arrest in late G1
-Initiation of apoptosis in response to DNA damage |
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What is the silly name for p53?
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Guardian of the genome
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What happens when p53 is mutated?
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Failure to arrest the cell cycle, proliferation of mutations
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What are the therapeutic implications of a mutated p53?
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Radiation and chemotherapy won't work!
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Why don't radiation and chemotherapy work to treat cancers with p53 mutations?
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Because they rely on hypoxia to induce p53 activation which then repairs the DNA.
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What does APC stand for?
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Adenomatous Polyposis Coli gene
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What does a mutation in the APC gene cause?
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Familial polyposis coli
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What happens in the course of developing familial polyposis coli?
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-Infant is born with one mutant allele and gets multiple adenomatous polyps
-Infant undergoes a 2nd hit during lifetime and gets carcinoma |
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What pathway does the APC gene function in?
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The beta-Catenin pathway
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What is the function of the APC gene?
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Down-regulation of growth promoting signals in the WNT pathway.
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What results from an APC mutation?
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Unchecked proliferation.
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How is apoptosis evaded?
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By inactivating programmed cell death.
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What is an example of evasion of apoptosis?
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BCL-2 overexpression
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What disease is BCL-2 overexpression seen in?
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Bcell lymphomas
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What type of growth is seen in Bcell lymphoma?
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Indolent - because it's not due to explosive growth, but rather reduced death.
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What is the main result of DNA repair defects?
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Genomic instability
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What are 3 general categories of causes of DNA repair defects?
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-Environmental mutagens
-Spontaneous errors in DNA synthesis -Inborn genomic instability syndromes |
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Name 2 inborn genomic instability syndromes:
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-HNPCC
-Xeroderma pigmentosum |
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What is necessary for a DNA repair defect to cause genomic instability?
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A 2-hit loss of alleles
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What are the 3 main DNA repair systems?
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1. Mismatch repair
2. Nucleotide excision 3. Recombination repair |
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What disease is associated with defects in mismatch repair?
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HNPCC
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What happens when mismatch repair is not accomplished?
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Accumulation of errors and MICROSATELLITE INSTABILITY
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What are microsatellites?
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Tandem repeats of 1-6 nucleotides that are fixed for life in an individual.
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What is microsatellite instability?
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Contractions and expansions in microsatellites in tumor cells that are not normally found in cells.
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What % of all colon cancer is HNPCC?
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2-4%
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What % of sporadic colon cancers have microsatellite instability?
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15%
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What part of the colon are the cancers seen in HNPCC?
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Proximal
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What disease is associated with defects in nucleotide excision repair?
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Xeroderma pigmentosum
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How does Xeroderma Pigmentosum develop?
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1. UV light damages DNA
2. Pyramidine residues are crosslinked 3. DNA replication can't occur normally because NT excision repair is defective |
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What are patients with xeroderma pigmentosum at increased risk of?
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Skin cancer if exposed to UV light
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What is the cause of unlimited replication potential in cells?
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Telomere invincibility
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What are telomeres and what usually happens to them?
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Special structures at the ends of each chromosome; they shorten with each cell division.
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What happens once telomeres shorten beyond a certain point?
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Apoptosis is induced.
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What enzyme prevents telomere shortening?
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Telomerase
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How does cancer due to unlimited replication potential develop?
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If cells reactivate telomerase (it is inactive/absent in most somatic cells)
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How many tumors have reactivated telomerase that is detectable?
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>90%
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