Molecular Basics of Colon Cancer Flashcards
Name two types of familial colorectal cancer
- Familial Adenomatous polyposis (FAP),
- Hereditary nonpolyposis colon cancer
- Both are autosomal dominant
What are some features of FAP
- Large number of polyps developing from adolescence onwards. Polyps are premalignant
What is the gene defect in Familial Adenomatous polyposis?
Defect in the Adenomatous polyposis coli (APC) gene. Mostly a nonsense or frameshift mutations, however a mutation of APC alone is not sufficient to cause cancer
Why do defects in APC predispose to cancer?
Normally APC binds to beta-catenin and microtubules. Beta-catenin riggers the transcription of genes that promote cell division and therefore APC prevents this. Defects in APC also therefore lead to chromosome instability.
Describe the role of beta-catenin and APC play in wnt signalling
When wnt is absent APC is active and it can therefore degrade beta-catenin and TCF is inactive. However in the presence of wnt, APC is inactive and therefore there is stable beta catenin and active TCF complex = cell division
Name some other features of FAP
Benign tumours, jaw cysts, sebaceous cysts and osteomata
What are the features of hereditary nonpolyposis colorectal cancer
- Causes high risk of colon tumours but there are low numbers of polyps.
What is the genetic mutations that occur with HNPCC?
Different genes have been identified but they all have the same function and that is Mismatch repair genes
What is the significance of repetitive regions of DNA?
They are more susceptible to errors (microsatelite instability) in that it is easier for DNA to slip and therefore the function of mismatch repair genes is essential.
How can you test for a defect?
immunohistochemical protein staining (HPNCC)
Direct sequencing (FAP)
What are the differences between FAP and HNPCC?
FAP - Large number of polups but a low mutation rate. High cancer risk due to high rumber of polyps penetrance close to 100%.
HNPCC - Low number of polyps but high mutation rate and therefore high cancer risk despite low number of polyps. Penetrance close to 80%.
K-RAS is involved in what? and how can this be targeted in treatment?
In the transition of a polyp to carcinoma. Using antibodies such as cetuximab we can block EGFR signalling which prevents the activation of KRAS. This therefore prevents proliferation, angiogenesis, metastasis and prevents inhibition apoptosis
Why does diet effect the risk of developing colon cancer
- The longer food spends in the bowels then secondary bile salts can be generated which are carcinogens. Fruit and veg however, provide anti-oxidants and folate which protects cells. Obesity and alcohol greatly increase risk of developing colon cancer
Why was aspirin and other NSAIDs seen as a potential preventitive measure?
They inhibit COX-2 which was seen to be increased in the early stages of colorectal cancer however there was in increased risk of CV problems
