Molecular Basis of Colon Cancer

Question 1

what are the two types of hereditary colorectal cancer

Answer 1

• Familial Adenomatous Polyposis (FAP)

* Hereditary nonpolyposis colon cancer (HNPCC or Lynch syndrome)

Question 2

Familial Adenomatous Polyposis pattern of inheritance

Answer 2

autosomal dominant

Question 3

features of Familial Adenomatous Polyposis

Answer 3

• large number of polyps developing from adolescence

- pigmented lesions in retina (CHRPE)

Question 4

Whats the gene defect for Familial Adenomatous Polyposis

Answer 4

• adenomatous polyposis coli (APC)
• Chromosome 5 q21-22
• mostly nonsense or frameshift mutations

Question 5

How to test for gene defect for Familial Adenomatous Polyposis

Answer 5

• Direct sequencing

Question 6

Why do defects in APC predispose to cancer?

Answer 6

• if first hit is a germline mutation, second somatic mutation more likely to enable cancer

Question 7

What does APC do?

Answer 7

• Binds Beta-catenin

* Binds microtubules

Question 8

beta-catenin

Answer 8

• APC Binds to beta-catenin in the cytoplasm
• binding to APC mediates the degeneration of beta-catenin, keeping overall beta-catenin levels low
• binding to TCF triggers the transcription of genes that promote cell division
• If not bound to APC and degraded, beta-catenin accumulates and can enter the nucleus and bind to T-cell factor (TCF)

Question 9

Extra-Intestinal involvement with for Familial Adenomatous Polyposis

Answer 9

• Masses of benign tumours
• Jaw cysts
• Sebaceouscysts
• Osteomata
• pigmented lesions of the retina (CHRPE)

Question 10

sporadic tumours

Answer 10

Mutation of APC is also seen in sporadic tumours
Mutation of APC alone is not
sufficient to cause cancer

Question 11

Hereditary Nonpolyposis colorectal cancer (Lynch syndrome)

Answer 11

• Autosomal Dominant

Question 12

features of Hereditary Nonpolyposis colorectal cancer

Answer 12

• High risk of colon tumours
• Can be underlying cause of other tumour types eg endometrium, ovarian, small intestine, stomach
• Low numbers of polyps

Question 13

gene defect in Nonpolyposis colorectal cancer

Answer 13

MLH1
MSH2
PMS2
MSH6

Question 14

Microsatelite instability (MIN)

Answer 14

Repetitive regions are more susceptible to errors

Question 15

• FAP

Answer 15

• Large number of Polyps
• Low mutation rate
• High cancer risk because of high number of polyps

Question 16

• HNPCC

Answer 16

• Low number of polyps
• High mutation rate
• High cancer risk despite low number of polyps

Question 17

High to moderate risk

Answer 17

• people with three 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

Question 18

Polyp to carcinoma sequence

Answer 18

INTESTINAL EPITHELIAL LINING  
> APC
ADENOMA = K-RAS
>p53 SMADs
CARCINOMA

Question 19

Diet - why is it important

Answer 19

• Time in bowel
• Bile salts generated
• Presence of anti-oxidants and folate • Cooking methods

Question 20

Preventative Measures

Answer 20

• Aspirin and other NSAID’s inhibit COX-2
• Cyclo-oxygenase 2 (Cox-2) increased in early stages of colorectal cancer
• Increased prostaglandin synthesis
• Stimulates proliferation and angiogenesis
• Inhibits apoptosis
• Potential therapeutic target?