Term
Risk Factors for Prostate Cancer
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Definition
Age
Family History
Ethnicity
Dietary fat intake
Smoking
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Term
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Definition
Hallmarks:
Early age of onset
Bilateral
More aggressive phenotype
individuals share inherited susceptibility genes |
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Term
Susceptibility is inherited |
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Definition
-Susceptibility is inherited as a dominant trait
-Many affected in the family, but accounts for few cases (<10%) compared with sporadic cancers from the same tissue
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Term
Different genetic alterations may coincide with increasing progression of disease
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Definition
Colon:
-RAS Activation
-APC Loss
-HNPCC Mutation
-later loss of p53
Prostate:
-8p deletion
-PTEN loss
much later, loss of p53 and 8q amplification |
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Term
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Definition
Solid tumors:
•characterized by high number of random and non-random genomic deletions, amplifications and rearrangements
•Few have diagnostic single defect or diagnostic or causative translocations; PROSTATE IS AN EXCEPTION!
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•Heterogeneous temporally, spacially, genetically
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•Highly variable pattern of gene expression
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Term
Generation of clonal cancers
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Definition
If block occurs in differentiation, all progeny will be blocked at that stage
Proliferation (and decreased rate of death) of “early” stage cells are the cells of the hematopoeitic cancer
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Term
CML: Chronic Myeloid Leukemia
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Definition
• Ph. Chromosome
•BCR-ABL gene – “210” protein
• 6000 (US) develop CML each year
• risk increases after age 50
• 2x more prevalent in men compared to women
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• 3 phases: chronic, accelerated,
blast crisis
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Term
The Philadelphia chromosome
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Definition
-Diagnostic cytogenetic lesion in ~95% of Chronic Myelogenous Leukemia and 20% of ALL
Seen by eye (at microscope) in ~80% of CML cases by cytogenetics
The other 20% were almost all positive for translocation by molecular testing
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Term
Making use of the known molecular mechanism: Philadelphia positive CML refractory to conventional therapy |
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Definition
•A good, rationally designed therapy is specific for the defect involved; general metabolic poisons have low benefit relative to side effects
•Needs to differentiate between affected cells and normal cells
•New class of activated tyrosine kinase inhibitors recently developed
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Term
STI-571: A rational drug designed from understanding basic science
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Definition
STI-571 is marketed as Gleevec
Increased potency and efficiency of binding to activated receptor tyrosine kinase, specifically BCR-ABL, PDGF, and c-kit
Effective in treating CML and ALL with Ph+ chromosome
Effective in treating gastrointestinal stromal tumors (most are c-kit positive)
Appears to selectively induce differentiation and apoptosis of cells with the BCR-ABL (or c-kit) mutations; patients achieve a “cytogenetic remission”
Phase I trials for CML and ALL began in June 1998
Some complete remissions were achieved
Most effective against early disease
Affects progression, not survival long term
Trials to determine how to use Gleevec to affect survival are underway
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Term
Balanced translocations and solid tumors |
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Definition
Balanced translocations and gene fusions also occur in some solid tumors and are associated with progression and outcome
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Term
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Definition
•Cancer can be familial or sporadic
–List the differences in presentation between familial and sporadic tumors
•Tumors may preferentially metastasize to certain sites; probably genetically determined
•Tumors form because normal gene expression patterns are disrupted
–Gain or loss of function due to deletion, amplification, or mutation
•Tumors can be big or small, focal or not
•Solid tumors may have a gene fusion similar to hematopoeitic malignancies, but likely also have a plethora of other molecular changes
•The molecular mechanism can be used to develop therapeutics, diagnostics, predict recurrence
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