Molecular Basis of Colon Cancer

Question 1

What are the 2 types of familial colorectal cancer?

Answer 1

• familial adenomatous polyposis (FAP)
• hereditary nonpolyposis colon cancer (HNPCC)
• autosomal dominant
• every generation affected
• both males and females affected

Question 2

What is the gene defect of familial adenomatous polyposis?

Answer 2

• defect in adenomatous polyposis coli (APC)

- mostly nonsense or frameshift mutations

Question 3

What are the genetic tests for familial colorectal cancer?

Answer 3

• FAP: direct genetic sequencing

- HNPCC: immunohistochemical protein staining

Question 4

Describe the 2 hit hypothesis for developing FAP

Answer 4

• humans can accumulate mutations by chance
• if normal individual has mutation in one APC gene, they will be okay because they have another to compensate
• if someone with an inherited defect in their APC gene develops a mutation in their other APC gene, they will go on to develop cancer

Question 5

Describe how defects in APC can affect the wnt signalling pathway

Answer 5

• when wnt is absent APC is active and can bind beta-catenin and degrade it and T cell factor is inactive
• when there is presence of wnt, APC is inactive meaning there is no degradation of beta catenin and therefore a positive T cell factor complex
• triggers the transcription of genes that promote cell division
• can lead to uncontrolled proliferation

Question 6

How can APC defects affect chromosome separation?

Answer 6

• APC is supposed to bind to EB1 to cause acceptable separation of chromosomes at the metaphase plate during cell division
• without the APC - EB1 complex forming (due to mutation) this means the chromosomes do not separate to opposite poles resulting in aneuploidy

Question 7

What are some features of FAP?

Answer 7

• benign tumours
• jaw cysts
• sebaceous cysts
• osteomata

Question 8

What are the genetic defects associated with HNPCC?

Answer 8

• mismatch repair genes

- different genes with the same function

Question 9

What is the risk of repetitive regions of DNA?

Answer 9

• more susceptible to errors
• easier for DNA to slip
• makes function of mismatch repair genes essential

Question 10

Contrast FAP and HNPCC

Answer 10

FAP:

• large number of polyps
• low mutation rate
• high cancer risk due to high number of polyps
• penetrance almost 100%

HNPCC;

• low number of polyps
• high mutation rate
• high cancer risk due to high mutation rate
• penetrance close to 80%

Question 11

Describe how K-RAS is involved in cancer progression

Answer 11

• involved in the transition of a polyp to a carcinoma
• can be targeted by using antibodies such as cetuximab
• blocks EGFR signalling which prevents activation of KRAS
• prevents proliferation, angiogenesis, metastasis and prevents inhibition of apoptosis

Question 12

What are the additional risks of colon cancer?

Answer 12

• diet
• obesity
• alcohol

Question 13

What are potential preventative measures against colon cancer?

Answer 13

• aspirin and other NSAIDs
• they inhibit COX-2 which was seen to be increased in early stages of colorectal cancer
• however risk of CV problems