Molecular Basis Of Colon Cancer

Question 1

Familial Adenomatous Polyposis - mode of inheritance?

Answer 1

Autosomal dominance - high levels of penetrance (97%)

Question 2

Features of familial adenomatous polyposis

Answer 2

• lots of polyps (100s) developing from adolescence onwards

- 90% patients also have pigmented lesions in retina (congenital hypertrophy of the retinal pigment epithelium)

Question 3

What is the gene defect of familial adenomatous polyposis?

Answer 3

-adenomatous polyposis coli gene on chromosome 5. Consists of 2843 amino acids. Mostly nonsense or frameshift mutations. Codons 1061 and 1309 are most frequently mutated.

Question 4

What are the methods to test for a gene defect?

Answer 4

• direct sequencing - sequences the DNA from tumour and from a control and detects a change in copy (FAP)
• microsatellite instability (MIN) - compares between tumour and non-tumour, checks repetitive regions for mismatch repair as they are more susceptible to errors as it can lose count so tends to delete or expand region. (HNPCC).
• immunohistochemical protein stain - tests for presence of normal genes using staining. (HNPCC).

Question 5

Why does a mutation in the adenomatous polyposis coli gene predispose cancer?

Answer 5

The adenomatous polyposis coli gene is a tumour suppressor gene. Cancer does not arise until both copies of the gene are mutated. APC usually binds beta-catenin (signal transductor protein which promotes cell division when bound with T-cell factor, ALSO helps to bind cytoskeleton and adherens which does not happen when mutated as no tight ordering of cells amd decreased cell-cell adhesion meaning increased abnormal cell division and migration as they do not know cell orientation), and microtubules (mutant APC might not bind EBI protein or chromosome well, chromosome wont know where to go and end up in wrong daughter cell).

Question 6

Why does mutation of the APC gene cause cancer in the colon?

Answer 6

Colon undergoes unique constant cycle of proliferation as cells only last ~5 days. Cells divide at the bottom of crypt where the stem cells are and as more cells are created they push up. If mutated they are not going to migrate or orientate well.

Delayed maturation and increase in immature cells, changes in proliferation and orientation = colon cancer

Question 7

What other symptoms occur outside of the intestines with FAP?

Answer 7

Masses of benign tumours, jaw cysts, sabacepus cysts, osteomata and congenital hyperteophy of retinal pigment epithelium.

Question 8

What is the mode of inheritance of Hereditay Non-Polyposis Colorectal Cancer (Lynch Syndrome)?

Answer 8

Autosomal dominant - causes approx. 3% of all colon cancer.

Question 9

What are the features of Hereditary Non-Polyposis Colorectal Cancer?

Answer 9

High risk of colon tumours, low number of polyps and can underlie other tumour types e.g. endometrial, ovarian, small intestine and stomach.

Question 10

What gene defects cause Hereditary Non-Polyposis Colorectal Cancer?

Answer 10

MLH1 (50%), MSH2 (40%), MSH6 (7-10%), & PMS2 (<5%). All genes effected work in DNA mismatch repair. Mutations are more likely sequence variants than frameshifts.

Question 11

What can patients elect to do to combat risk of cancer?

Answer 11

Elect to have colon removed.

Question 12

What is the screening program for colorectal cancer like in Scotland?

Answer 12

• Under 50 years old - screened for occult blood in faeces sample and if + then colonoscopy.
• If known FAP/HNPCC - biannual colonoscopy from 25 years old.
• High to moderate risk - colonoscopy every 5 years from 50-75years - categorised as this if people with three or more affected relatives in a first degree kinship (50% genetic info) with each other or two affected relatives less than or have a mean age of 60yo in first degree kinship with each other.

Question 13

Polyp to Carcinoma Sequence

Answer 13

Intestinal epithelial lining
\/ - APC
Adenoma < K-Ras
\/ - p53 or SMADs
Carcinoma

Question 14

Epidermal Growth Factor Receptor (EGFR) Signalling in colorectal cancer?

Answer 14

Overexpressed in large number of colorectal tumours. It is an oncogene so it is activated by increased expression or activating mutations. When active, it dimerises, activates proliferation, inhibits apoptosis, drives angiogenesis and metastasis.

Question 15

Cetuximab

Answer 15

Can be used to block wildtype K-Ras. No point if further down pathway is already activated.

Question 16

Risk factors other than genetics?

Answer 16

• Diet - high fibre and fish decrease risk of colorectal cancer. Fibre encourages faster movement of food through bowel which equals less time to react. Presence of anti-oxidants and folate - Oily fish, fruit and veg increase nucleotides and getting rid of things which damage DNA. Bile salts are generated by eating saturated fat, but too much or unsaturated fat can create secondary bile salts which can be carcinogenic. Red and processed meat increase risk of colorectal cancer. High temperatures can also be bad as asparigine and some sugars can be made into acryllamide which is a carcinogen.
• obesity - 50% increase risk in men
• alcohol - 40% increase in risk if over 5 units per day consumed.

Question 17

Why could aspirin be a preventative measure?

Answer 17

Inhibits Cyclo-oxygenase 2 (COX-2) which is increased in the early stages of colorectal cancer. COX-2 increases prostaglandin synthesis, stimulates proliferation and angiogenesis, and inhibits apoptosis.