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
What is the average age of onset of FAP and HNPCC?
~ 40
What can people do if they find they have FAP or HNPCC or a FH of the disease
- Offered regular screening from a young age
- Patients often elect to have their colon removed
How is screening done in Scotland for FAP and HNPCC?
- > 50 years screened every 2 years for occult blood, and if positive then colonoscopy
- If known FAP/HNPCC - biannual colonoscopy from 25 years
- High to moderate risk - colonoscopy every 5 years from age 50 - 75
What is meant by high to moderate risk of colon cancer?
- People with 3 or more affected relatives in a first degree kinship with each other (none less than 50 years old)
- Two affected relatives less than 60 years old in a first degree kinship with each other, or two affected relatives with a mean age less than 60 years old in a first degree kinship
What are patients with colon cancer screened for in Scotland?
Microsatelite instabilty testing to increase diagnosis of lynch syndrome
What protein is overexpressed in the majority of colorectal cancers?
EGFR
What are the other major risk factors for colon cancer other than genetics?
- Diet
- Overweight 25% increased
- Obese 50% increased risk
- Alcohol (40% increased risk if >5 units a day)
What study looks at cancer and nutrition links?
EPIC study
- European Prospective Investigation into Cancer and Nutrition
- > 500k ppl
- Recruited 93 - 99
- Follow for at least 10 years
What foods increase/reduce colon cancer risk?
- High fibre reduces risk
- Fish reduces
- Red and processed meat increases risk
Why are the results the way they are in relation to food?
- Less time in bowel
- Bile salts pass through more quickly
- Presence of anti-oxidants and folate in fruit and vegetables
- Cooking methods
What common drug is thought to prevent the risk of colon cancer?
Aspirin (low dose can decrease pre-cancerous lesions)
How can aspirin protect against colorectal cancer?
- Inhibit COX-2 (as it is an NSAID)
- COX-2 increased in early stages of colorectal cancer
- Increased prostaglandin synthesis
- Stimulates proliferation and angiogenesis
- Inhibits apoptosis
- could cause increased risk of CV problems (prostaglandins regulate BP)
What does EGFR do?
- Dimerises in response to EGF
- Tyrosin Kinase -> once dimerised sends signal down to nucleus to stimulate proliferation, metastasise, inhibit cell death
What does cetuximab do?
blocks EGFR - only used where wildtype Kras
