7. Molecular Basis of Colon Cancer Flashcards
Define the inheritance patterns of:
- Familial Adenomatous Polyposis coli, FAP
2. Hereditary non-polyposis coli, HNPCC (Lynch syndrome)
- FAP = Autosomal dominant
2. HNPCC= Autosomal dominant
2 genetic tests for FAP and HNPCC?
FAP and HNPCC tests:
- Protein truncation
- Direct sequencing tumour support
To describe the molecular mechanisms underlying FAP
In FAP, mutated APC leads to:
- Distorted cytoskeletal network
- Loss of polarity
- Decreased cell-cell adhesion
- Aberrant cell migration
- -> Cancer initiation and progression
To identify additional risk factors for colon cancer
Diet:
- High fibre reduced risk
- High intake of red and processed meats increases risk
- Fish decreases risk
Obesity
Alcohol
How aspirin may protect against colon cancer. Risk?
Aspirin and other NSAIDs inhibit COX-2.
Mechanism of inhibition? COX-2 increased in early stages of colorectal cancer
–> increase prostaglandin synthesis
–> Stimulates proliferation and angiogenesis
–> Inhibits apopotsis
Risk? Less prostaglandins, less bp regulation, increase CV risk
What is beta- catenin?
Catenin beta-1, also known as β-catenin, is a protein that in humans is encoded by the CTNNB1 gene. β-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcription.
In cytoplasm B-catenin + APC –> B-catenin degradation
B-catenin – enter cell nucleus –> B-catenin + TCF –> Transcription and cell division
(TCF= T-cell factor)
Role of b-catenin and APC in wnt signalling and cell proliferation?
WITHOUT Ant SIGNAL 1. Inactive receptor 2. Inactive signalling protein 3. Active APC containing complex 4. Degradation of b-catenin 5. Inactive TCF complex Wnt-responsive genes OFF
With WNT SIGNAL 1. Wnt present and to receptor 2. Active receptor 3. Active signalling protein 4. Inactive APC containing complex 5. Stable b-catenin 6. Active TCF complex Transcription of Wnt- responsive genes leading to proliferation of gut stem cells
Why the colon?
Colon unusual organised means that there is a stem cell population in the centre of the colon, where the wnt pathway is active. Then areas of inactive pathway beyond it.
So areas of varying proliferation
Mutation in APC is also seen in ______ tumours
Mutations of ____ alone is not sufficient to cause cancer
Mutation of APC is also seen in sporadic tumours
Mutation of APC alone is not
sufficient to cause cancer
Which has higher risk of colon tumours, HNPCC or FAP?
Hereditary non-polyposis coli, HNPCC
Repetitive regions of DNA are more susceptible to…
Errors
Difference between FAP and HNPCC in number of polyps, mutation rate, risk of cancer, penetrance
FAP • Large number of Polyps • Low mutation rate • High cancer risk because of high number of polyps • 100% penetrance
HNPCC • Low number of polyps • High mutation rate • High cancer risk despite low number of polyps • 80% penetrance
What is the screening programme in Scotland for colon cancer?
> 50yrs screened every 2 years of occult blood and if positive then colonoscopy
If known FAP/HNPCC: bi annual colonoscopy from 25 years
If at high to moderate risk: Colonoscopy every 5 years from age 50-75
What is classed as “high to moderate risk” of colon cancer?
People with 3+ affected relatives in a first degree kinship with each other
Two affected relatives less than 60 years old in a first degree kinship with each other
What is the progression from polyp to carcinoma in HNPCC?
Intestinal epithelial lining – (APC signal)–> Adenoma (K-RAS –(p53, SMADs) –> Carcinoma
