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Flashcards in Colorectal Cancer Deck (35)
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1
Q

What is CRC graded between?

A

Grade I - well differentiate

Grade IV - poorly differentiated

2
Q

What is the adenocarcinoma sequence in CRC?

A
Hyper-proliferation
Small to large adenomatous polyps
Severe dysplasia (pre-cancerous polyp)
Adenocarcinoma
Cancer invading basement membrane
Metastasis
3
Q

What is dysplasia?

A

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

4
Q

What is APC?

A

Adenomatous polyposis coli

  • a tumour suppressor gene
  • negative regulator of the WNT/β-catenin signalling pathway
5
Q

Why is APC a classical Knudson tumour suppressor gene?

A

Wires two hits, two alleles to be lost

6
Q

What is responsible for familial adenomatous polyposis?

A

Germline mutations in APC

7
Q

How does a mutation to APC affect cell proliferation?

A

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

8
Q

What is chromosome instability?

A

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

9
Q

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

A

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

10
Q

What is the mechanism for chromosome instability?

A

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.

11
Q

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

A

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

12
Q

What is bevacizumab?

A

A chemo drug used for sporadic CRC

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

13
Q

What are the different types of CRC?

A

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

14
Q

What is the MAPK pathway?

A

A pathway from the cell membrane to the nucleus

Causes cell proliferation

15
Q

How can the MAPK pathway become faulty?

A

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

16
Q

What is the effect of DNA methylation?

A

It silences genes

17
Q

What is CIMP?

A

The addition of methyl groups to cytosine

18
Q

What does CIMP result in?

A

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

19
Q

What are CpG islands?

A

Regions with lots of CG bases

20
Q

How can CpG islands lead to cancer?

A

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

21
Q

What are microsatellites?

A

Areas of DNA where there are repeating sequences of base pairs

22
Q

What are microsatellites prone to?

A

DNA replication errors such as insertion or deletion.

23
Q

What are errors in microsatellite replication normally repaired by?

A

Mismatch repair proteins

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

24
Q

What can microsatellite instability (MSI) lead to?

A

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

25
Q

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

A

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

26
Q

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

A

Bevacizumab

A BRAF mutation

27
Q

How do cetuximab and panitumumab work?

A

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

28
Q

Why can cetuximab and panitumumab become ineffective?

A

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

29
Q

What are Ras?

A

A family of proto-oncogenes

GTP/GDP binding proteins which activate MAPK and PI3K

30
Q

What happens in mutant KRas?

A

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

31
Q

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

A

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

32
Q

Why does subtype 3 have a poor prognosis?

A

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

33
Q

Prognosis for different stages of CRC?

A

Stage I-II: surgery normally curative

Stage III: surgery followed by adjuvant chemotherapy

34
Q

What is the cell of origin in CRC?

A

Intestinal crypt-1 which contains CBCCs

35
Q

How is colorectal cancer staged?

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