Colorectal Cancer

Question 1

What is CRC graded between?

Answer 1

Grade I - well differentiate

Grade IV - poorly differentiated

Question 2

What is the adenocarcinoma sequence in CRC?

Answer 2

Hyper-proliferation
Small to large adenomatous polyps
Severe dysplasia (pre-cancerous polyp)
Adenocarcinoma
Cancer invading basement membrane
Metastasis

Question 3

What is dysplasia?

Answer 3

The enlargement of an organ/tissue by proliferation of cells of an abnormal type. Can be a developmental disorder or an early stage in the development of cancer

Question 4

What is APC?

Answer 4

Adenomatous polyposis coli

• a tumour suppressor gene
• negative regulator of the WNT/β-catenin signalling pathway

Question 5

Why is APC a classical Knudson tumour suppressor gene?

Answer 5

Wires two hits, two alleles to be lost

Question 6

What is responsible for familial adenomatous polyposis?

Answer 6

Germline mutations in APC

Question 7

How does a mutation to APC affect cell proliferation?

Answer 7

There is a mutation in the region that contains β-catenin binding sites so that it can no longer bind and be degraded. Wnt signalling is not switched off

Get a rise in free β-catenin, leading to nuclear translocation, gene expression and proliferation

Question 8

What is chromosome instability?

Answer 8

The continuous loss and gain of whole and/or parts of chromosomes

Question 9

What’s a factor that can cause CRC to have intratumour heterogeneity

Answer 9

Chromosomal instability - creates a genetically diverse pool of tumour cells upon which selection can act.

Question 10

What is the mechanism for chromosome instability?

Answer 10

Have high levels of mutant p53, however this is permissible, not causative
Loss of chromosome 18 induces chromosomal instability through placating stress A can be caused by pre-mitotic and mitotic defects causing bridges and breakages.

Question 11

Give the genomic features, initiating events, location and lesion of origin of CRC subtype-1

Answer 11

Genomic feature - chromosome instability
Initiating event - APC loss with/without KRas and p53 mutations
Predominantly in the left colon
Begins as adenomatous polyps

Question 12

What is bevacizumab?

Answer 12

A chemo drug used for sporadic CRC

It is a monoclonal antibody that binds and inhibits VEGF, hindering tumour angiogenesis

Question 13

What are the different types of CRC?

Answer 13

Sporadic CRC

Inherited CRC syndromes (5%) - caused by germline mutations in key genes, typically dominant

Familial CRC (20-30%) - hereditary genetic factors increase risk of disease in younger ages

Question 14

What is the MAPK pathway?

Answer 14

A pathway from the cell membrane to the nucleus

Causes cell proliferation

Question 15

How can the MAPK pathway become faulty?

Answer 15

A mutation to the BRAF oncogene, a kinase protein found in the MAPK pathway
Can constitutively activate the pathway, causing proliferation and survival

Question 16

What is the effect of DNA methylation?

Answer 16

It silences genes

Question 17

What is CIMP?

Answer 17

The addition of methyl groups to cytosine

Question 18

What does CIMP result in?

Answer 18

Compact heterochromatic DNA which is inaccessible to transcription factors, inhibiting transcription

Question 19

What are CpG islands?

Answer 19

Regions with lots of CG bases

Question 20

How can CpG islands lead to cancer?

Answer 20

They can be methylated, leading to loss of expression of tumour suppressor genes such as p53, p16, p21 and APC

Question 21

What are microsatellites?

Answer 21

Areas of DNA where there are repeating sequences of base pairs

Question 22

What are microsatellites prone to?

Answer 22

DNA replication errors such as insertion or deletion.

Question 23

What are errors in microsatellite replication normally repaired by?

Answer 23

Mismatch repair proteins

A defect in these proteins can increase the mutational rate in microsatellite regions.

Question 24

What can microsatellite instability (MSI) lead to?

Answer 24

Loss of tumour suppressor genes
Increased genomic instability
Resistance to cell death

Question 25

What are some features of CRC sub-type 2? (Genomic, initiating events, location, lesion of origin)

Answer 25

Genomic features: microsatellite instability, CIMP Initiating events: BRAF mutation (BRAFV600E) Location: predominantly right Lesion of origin: serrated adenomas

Question 26

Therapy for CRC type 2? What can reduce its efficacy?

Answer 26

Bevacizumab | A BRAF mutation

Question 27

How do cetuximab and panitumumab work?

Answer 27

They antagonise EGF by binding to EGFR CRC relies on active EGFR signalling for proliferation Known as EGFR blockade therapy

Question 28

Why can cetuximab and panitumumab become ineffective?

Answer 28

If KRas or BRAF mutate - the pathway can work without signals coming from the EGFR

Question 29

What are Ras?

Answer 29

A family of proto-oncogenes | GTP/GDP binding proteins which activate MAPK and PI3K

Question 30

What happens in mutant KRas?

Answer 30

It is constitutively activated and bound to GTP because mutations normally affect the GTP binding site.

Question 31

Features of CRC subtype 3? (Initiating events, location, lesion of origin)

Answer 31

Initiating events: Kras or BRAF mutations Location: even distribution Lesion of origin: serrated adenoma

Question 32

Why does subtype 3 have a poor prognosis?

Answer 32

High risk of recurrence due to metastasis This is due to enrichment of pro-metastatic and stem cell related genes Poorly differentiated

Question 33

Prognosis for different stages of CRC?

Answer 33

Stage I-II: surgery normally curative | Stage III: surgery followed by adjuvant chemotherapy

Question 34

What is the cell of origin in CRC?

Answer 34

Intestinal crypt-1 which contains CBCCs

Question 35

How is colorectal cancer staged?

Answer 35

``` Duke's A - invasion but not through the bowel wall B - invasion through the bowel wall C - involvement of lymph nodes D - distant metastases ```