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17 Cards in this Set
- Front
- Back
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Cancer as a Disease |
Genetic Disease Heterogenous disease |
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Clonal Evolution Model |
Cancer is a micro-evolutionary process Positive selection of beneficial mutations leads to clonal expansion Monoclonal and polyclonal models |
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Self Seeding and Mutator Phenotype Models |
Self seeding: clones develop in distant sites and return to primary tumour, primary tumour is a sponge Mutator phenotype: mutation rate of cancer cells increases dramatically so constant production of new clones |
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Cancer Stem Cells Model |
Stem cells can be totipotent, pluripotent or oligopotent Most are oligopotent Cancer is heterogenous like an organ and proliferation may therefore be a feature of a sub-population of cancer stem cells Implies very different pattern of clonality and a different approach to treatment as the cancer stem cells would need to be targeted to prevent remission |
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These Models Are Not Mutually Exclusive |
Cancer evolution can be a picture of accumulation of mutations punctuated by dramatic events (chromothripis) Some cancers have fewer mutations than others : PIK3CA is most mutated gene in breast cancer as its mutated in 26% of samples |
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Chromothripsis |
Catastrophic model of genome change All happens at once Likely related to fate of micronuclei forming during aberrant segregation Chromosomes shatters during cell replication and reassemble in a certain order |
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Viewing Genes |
G banding Spectral karyotyping FISH |
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Detecting Heterogeneity: Morphology |
Histological staining methods are used to grade cancer cells Relates to prognosis Globally popular system for grading is Nottingham grading system |
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Nottingham Grading System |
Takes into account -Amount of gland formation -Nuclear features -Mitotic activity Each one of these features is scored 1-3 then added to give a grading score Grade 1 3-5 Grade 2 6-7 Grade 3 8-9 |
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The Philadelphia Chromosome |
First translocation implicated in human cancer T(9:22) (q24:q11) First detected by G-staining Creates BCR-ABL gene fusion Makes active tryosine kinase Tryosine kinases are photo-oncogenes |
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DNA Based Methods: Microarray |
Detect copy number changes at a gross level Also sensitive to smaller scale changes Compares normal cells to tumour cells Reveals deletions and copy number variations |
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DNA Based Methods: Whole-Genome Sequencing |
Multiple displacement amplification (MDA)= popular WGA method Not PCR, unspecific and amplifies many DNA targets Reaction is primed with random hexamers 30C reaction temp (no thermocycling) They polymerase makes 7-10kb amplicons |
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WGA and NGS: Implications |
We can sequence the genome of one or a few cells Since cancer is heterogenous this means we are better able to characterise individual clones |
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The Cancer Genome Atlas |
Began in 2006 National cancer institute and national human genome research institute Aims to systematically map genetic changes in different types of cancer |
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Driver and Passenger Mutations |
Driver mutations are positively selected during tumour development but due to high mutation rate some mutations go along for the ride = passenger mutations Cancer mutation prevalence (CaMP) is a mutation present more than expected by chance allowing for: -Background mutation rate -Nucleotide composition -Sample size |
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Driver Mutation Example |
Retinoblastoma gene (Rb) is unusual in that mutation in Rb is necessary and sufficient for development of retinoblastoma Two hit model explains hereditary and sporadic cases Involved in cell cycle control |
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p53: Guardian of the Genome |
p53- transcription factor Encoded by TP53 gene Central role in preventing inappropriate cell cycling Tumour cells with absent or non-functional p53 continue to replicate damaged DNA and don't undergo apoptosis |
