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76 Cards in this Set

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