Lecture 10 : genetic instability Flashcards
What probably happened if a cancer arises at a young age ?
It is probably due to inheritance.
Cancer takes many years to develop and become clinically detectable.
What are the mutagenic events required to transform a mouse cell vs a human cell ?
mouse - 3 pathways : Ras, pRb and p53.
human - 5 pathways : Ras, pRb, p53, telomeres and PP2A.
Familial adenomatous polyposis (FAP) - kesako ?
- germ-line mutation in APC inherited.
- loss of heterozigosity frequent
- thousands of polyps in the colon
- become an adenocarcinoma with 20-40 years (long latency).
Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome - kesako ?
= Lynch syndrome
- germ-line disease
- benign lesions progress rapidly into aggressive invasive adenocarcinomas.
- affect the DNA repair system : mismatch repair enzymes (MMR)
What is a microsatellite ?
Simple sequence repeats of 6-7 bps
What is the particularity of microsatellite instability ?
Present in many cancer types and suggests defects in the repair of such mutations in the cancer cells.
MMR enzymes - 3 facts
-correct mis-matches introduced by DNA polymerases.
-decrease significantly the mutation rate.
-mutations in the MMR enzymes can be recognized by increased microsatellite instability.
the 2 most commonly mutated MMR enzymes
MSH2 and MLH1
15% of all colorectal cancers are due to …
microsatellite instability
How do most tumors acquire genetic instability ?
Through mechanisms that do not involve mutated or inactivated MMR enzymes but involve mutations in a large number of genes that control genomic integrity.
The problem with the Darwinian model
Does not take into account the effect of losing factors that prevent mutations.
Because of genetic instability, the rate of mutations exceeds the rate at which Darwinian selection positively selects fit clones.
-> rate of mutations highly accelerated.
Which type of cells is likely the origin of cancer ?
Stem cells, as they generate rapidly proliferating progenitors.
Because to become a tumor, they need a cell that expend and proliferate.
In which organ is there very little proliferation and thus rare tumor ?
The heart
What happens with mutations occurring in non-cancer stem cells ?
They are inconsequential to tumor progression
To kill a cancer, what should we do ?
Eliminate the cancer stem cells, otherwise the tumor regenerates.
Particularity of keratinocyte ?
protected from the UV light by melanin pigments, which are transferred from melanocytes to the keratinocytes.
Glutatione-S-transferases (GSTs) - facts
enzyme used by glutathione to neutralize toxic molecules.
some cancers downregulate GSTs via promoter methylation (90% of prostate cancer have low GST levels).
How works the exo-nuclease activity of the DNA polymerases ?
If a misincorporated nucleotide, the polymerase moves backward and degrades recently synthesized strand. It then moves forward again and undertakes once again to synthesize proper sequence.
What does the nucleotide excision repair (NER) ?
(+ link with p53?)
Correct pyrimidine dimers and DNA adducts.
Cleaves the DNA fragment (~24nt), and fills it again and it is closed by ligase.
p53 activates several genes involved in NER.
Pyrimidine dimers
induced by UV light.
10% CC dimers -> frequent in p53
stable mutations repaired by NER.
DNA adducts
Can be produced by mold which grows on corn stores of humid areas or benzopyrene contained in cigarette tar.
Induces G -> T transversion in p53 (found a lot in lung cancers)
What corrects the base excision repair (BER) ?
deamination.
Removes the chemically altered base, and his little helix distortion and inserts the correct nucleotide.
What is the most frequent mutations in tumors of visceral organs (67%)
The fact that when 5-methylcytosine becomes thymine, it is not recognized as an abnormal nucleotide.
What does and is alkylation ?
Used by chemotherapies.
It is a misread during DNA replication and can promote cancer.
Caused by environmental alkylating agents.
