Molecular Basis of Colon Cancer Flashcards
What percdentage of colorectal cancer patients have a FH?
~ 25%
What percentage of cases have a causitive mutation identified?
5-6%
What are the 2 familial syndromes that result in increased familial dysposition to colon cancer?
- Familial Adenomatous Polypoisis (FAP)
- Hereditary Nonpolypoisis colon cancer (HNPCC or Lynch syndrome)
How is Familial Adenomatous Polypoisis inherited?
Autosomal dominant
What are the features of FAmilial adenomatous polypoisis?
LArge number of polyps (100s or more) developing from adolescence onwards
- 90 % patients also have pigmented lesions in retina (CHRPE)
What is the gene defect associated with FAP?
- Adenomatous polyposis coli (APC)
- Usually creates shorter protein
- Chromosome 5 q21-22
- 2843 amino acids
- Mostly nonsense or frameshift mutations
How do you test for gene defect?
Direct sequencing
What greatly increases an individuals likelyhood to have colorectal cancer
If they have both copies of a APC mutation
What does APC do?
- Binds Beta-catenin
- Binds microtubules through EB1
What is Beta-catenin?
- APC binds to B-catenin in cytoplasm and mediate degradation keeping levels low
- Binds to transcription factors and stimulates transcription factors
- Involved in Wnt signalling
- Found in adherence junctions through other proteins attaches actin to adherence junction
- If Beta catenin is mutated complex is unstable making adherence junction not so tight, can lose polarity and aberrant cell migration -> cancer
What is Wnt signalling?
Wnt signal binds to receptor and inactivates APC which leads to stable B-catenin (not degraded) and an active TCF complex.
Transcription of Wnt-Responsive genes leadis to proliferation of gut stem cells
What does EB1 do?
- Binds and makes conncetions betweeen microtubules and chromosomes
- If EB1 and APC not bound properly chromosome is not attached properly to spindle at mitosis abborhent division -> chromosome instability -> cancer
How long does it take for a stem cell to reach the top of the crypt?
~ 5 days
Where is the Wnt pathway active?
Bottom section of crypt, inactive further up pathway
- When mutation proliferation can happen higher in crypt
What extra-intestinal problems can FAP cause?
- Masses of benign tumours
- Jaw cysts
- Sebaceous cysts
- Osteomata
- Pigmented lesions of the retina (CHRPE)
When are mutations in APC seen?
- FAP
- Sporadic tumours
- Mutations alone not suffiecient to cause cancer
How is Hereditary Nonpolyposis colorectal cancer (Lynch syndrome) inherited?
Autosomal dominant
What percentage of colon cancers are a result of Lynch syndrome?
~3%
What other cancers can be a result of Lynch syndrome?
- Endometrium
- Ovarian
- Small intestine
- Stomach
What are the 4 different genes potentially responsible for Lynch syndrome?
- MLH1 - 50%
- MSH2 - 40%
- MSH6 - 7-10%
- PMS1 - <5%
Usually a result of DNA mismatch
What do the genes which when mutated cause lynch syndrome do?
Mismatch repair genes, ring structure
What gene regions are more susceptible to errors?
- Repetitive regions (microsatelites)
- Called microsatelite instability
How are gene defects detected?
- Immohistochemical protein staining
- Allows you to apply an antibody to a specific histologcal section;
- If protein is present within the sample -> dark stain, +ve for protein,
- No dark stain = negative for protein
How can you compare FAP to HNPCC?
- Large number of polyps in FAp, low number in HNPCC
- Low mutation rate in FAP, high in HNPCC
- Penetrance ~100% for FAP, approx 80% for HNPCC
