Rod Dunbar 4

Question 1

Why might NZ have an unusually high rate of colorectal cancer?

Answer 1

This could be dietry due to a high red meat, low fibre and low Mediterranean food or due to genetic interactions with diet such as CYP polymorphisms which change the detoxification pathways for meat

Question 2

What is the treatment for colorectal cancer?

Answer 2

Prevention through early detection and surgery with conoscopies and polypectomys being effective
Chemotherapy can be used with classical chemotherapy as well as targeted agents like antiEGFR and its pathway or anti-angiogenic agents

Question 3

What are the causes of Colorectal cancer?

Answer 3

There may be a genetic predisposition, food as a carcinogen or due to chronic inflammation

Question 4

What are the risk factors for colorectal cancer?

Answer 4

Age
Family history of colorectal cancer
Presence of polyps of inflammatory bowel disease
High fat/ low fibre diet
Potentially physical inactivity or exposure to certain chemicals

Question 5

What is the importance of the increase of colorectal cancer incidence with age?

Answer 5

Incidence increases almost exponentially showing that colon cancer must be due to a time dependent accumulation of mutations

Question 6

What is being recognized about the subtypes of colorectal cancer?

Answer 6

They were initially based on different clinical features such as different sites, appearance of behaviour to treatment
However this has evolved into a molecular classification system

Question 7

What are the mechanistic classifications of colorectal cancer?

Answer 7

Chromosome instability (CIN+)
FAP is a familial version with loss of APC as an initiator
Microsatellite instability (MIN+/MSI+)
Such as HNPCC as a familial type where mismatch repair is lost
CpG island methylator phenotype (CIMP)
Global DNA hypomethylation

Question 8

What is the cell biology of colorectal cancer?

Answer 8

The adenomatous polyp was recognized early as being linked to colorectal cancer though this is only one subset of colorectal cancer with other morphologically distinct subsets such as serrated rather than tubular polyps

Question 9

What is the molecular biology of colorectal cancer?

Answer 9

Thinking largely follows the Vogelstein model where there is a series of stepwise mutations beginning with loss of the APC gene proceeding to DNA hypermethylation, kRas mutation, loss or mutation of DCC TS and finally loss of TP53

Question 10

What is the main CRC subgroup?

Answer 10

CIN, which is initiated by loss of APC

This is most commonly seen in familial adenomatous polyposis

Question 11

What is familial adenomatous polyposis?

Answer 11

An autosomal dominant condition which begins with benign polyps at age 10-15
By the 20s and 30s the colon becomes carpeted with hundreds and thousands of polyps and CRC occurring by about 50 years (as opposed to 65 years for sporadic cancer)
There is an effective treatment requires annual colonoscopic examination to detect early cancers

Question 12

What gene is responsible for Familial Adenomatous Polyposis?

Answer 12

When found on 5q21 ( an area of common loss of heterozygosity) it was called APC (Adenomatous Polyposis Coli) which was the same gene mutated in sporadic cancer
This gene is a classical tumour suppressor gene where inactivation of both alleles required

Question 13

What is the function of the APC gene?

Answer 13

It is a negative regulator of beta-catenin binding to beta-catenin into a complex with GSK3Beta which phosphorylates it targeting it for proteasomal degradation
Therefore loss of APC allows beta-catenin to accumulate in the nucleus to inducing c-myc and cyclin D1 transcription
This is also associated with stem-cell like properties such as division without differentiation
APC can also modulate actin filament and microtubule organisation causing cells to disregard their normal orientation and to disregulate the function of the mitotic spindle causing chromosome instability

Question 14

What is the role of the Mitogen-Activated Protein Kinase pathway in colorectal cancer and how does this demonstrate the Hannah-weinburg framework?

Answer 14

Mutation of this pathway is the second step in the Vogelstein model to colorectal cancer development
The most common mutation here is one in k-ras present in roughly 50% of tumours however this pathway can be mutated at any point to the same effect including in braf

Question 15

How does p53 play a role in colorectal cancer?

Answer 15

This is a tumour suppressor gene which is unusual as it exhibits a dominant negative effect and is thought to be a relatively late event in the progression to colorectal cancer

Question 16

What is hereditary non polyposis colon cancer?

Answer 16

The second important form of hereditary colon cancer which is autosomal dominant, and causes 2-4% of all CRC with it occurring at 45 years old (earlier than in FAP) and there is not an increased frequency of polyps and serrated rather than tubular polyps form. It also has a highly specific site (right side of proximal colon) and is associated with many other cancer types in the same patients

Question 17

What is the gene responsible for hereditary nonpolyposis colon cancer?

Answer 17

MSH2 which was mapped to 2p22 and is involved in mismatch repair this causes failed mismatched repair in the patients leading to microsatellite instability

Question 18

What is the result of failed mismatch repair?

Answer 18

There is an increase in point mutations with an increased frequency of insertions and deletions
There are replication errors and an increase in microsatellite instability
Overall this results in a mutator phenotype where there are increased mutations throughout the genome affecting oncogenes and tumour suppressor genes

Question 19

What are the molecular changes that differ between CIN+ (FAP) Colorectal cancer and MSI+ colorectal cancer?

Answer 19

There are different diagnostic criteria
Different clinical outcomes with prognosis better for MSI patients
Different treatment options for instance braf mutations are more common in MSI