Colorectal Cancer Flashcards
What is CRC graded between?
Grade I - well differentiate
Grade IV - poorly differentiated
What is the adenocarcinoma sequence in CRC?
Hyper-proliferation Small to large adenomatous polyps Severe dysplasia (pre-cancerous polyp) Adenocarcinoma Cancer invading basement membrane Metastasis
What is dysplasia?
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
What is APC?
Adenomatous polyposis coli
- a tumour suppressor gene
- negative regulator of the WNT/β-catenin signalling pathway
Why is APC a classical Knudson tumour suppressor gene?
Wires two hits, two alleles to be lost
What is responsible for familial adenomatous polyposis?
Germline mutations in APC
How does a mutation to APC affect cell proliferation?
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
What is chromosome instability?
The continuous loss and gain of whole and/or parts of chromosomes
What’s a factor that can cause CRC to have intratumour heterogeneity
Chromosomal instability - creates a genetically diverse pool of tumour cells upon which selection can act.
What is the mechanism for chromosome instability?
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.
Give the genomic features, initiating events, location and lesion of origin of CRC subtype-1
Genomic feature - chromosome instability
Initiating event - APC loss with/without KRas and p53 mutations
Predominantly in the left colon
Begins as adenomatous polyps
What is bevacizumab?
A chemo drug used for sporadic CRC
It is a monoclonal antibody that binds and inhibits VEGF, hindering tumour angiogenesis
What are the different types of CRC?
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
What is the MAPK pathway?
A pathway from the cell membrane to the nucleus
Causes cell proliferation
How can the MAPK pathway become faulty?
A mutation to the BRAF oncogene, a kinase protein found in the MAPK pathway
Can constitutively activate the pathway, causing proliferation and survival
What is the effect of DNA methylation?
It silences genes
What is CIMP?
The addition of methyl groups to cytosine
What does CIMP result in?
Compact heterochromatic DNA which is inaccessible to transcription factors, inhibiting transcription
What are CpG islands?
Regions with lots of CG bases
How can CpG islands lead to cancer?
They can be methylated, leading to loss of expression of tumour suppressor genes such as p53, p16, p21 and APC
What are microsatellites?
Areas of DNA where there are repeating sequences of base pairs
What are microsatellites prone to?
DNA replication errors such as insertion or deletion.
What are errors in microsatellite replication normally repaired by?
Mismatch repair proteins
A defect in these proteins can increase the mutational rate in microsatellite regions.
What can microsatellite instability (MSI) lead to?
Loss of tumour suppressor genes
Increased genomic instability
Resistance to cell death
What are some features of CRC sub-type 2? (Genomic, initiating events, location, lesion of origin)
Genomic features: microsatellite instability, CIMP
Initiating events: BRAF mutation (BRAFV600E)
Location: predominantly right
Lesion of origin: serrated adenomas
Therapy for CRC type 2? What can reduce its efficacy?
Bevacizumab
A BRAF mutation
How do cetuximab and panitumumab work?
They antagonise EGF by binding to EGFR
CRC relies on active EGFR signalling for proliferation
Known as EGFR blockade therapy
Why can cetuximab and panitumumab become ineffective?
If KRas or BRAF mutate - the pathway can work without signals coming from the EGFR
What are Ras?
A family of proto-oncogenes
GTP/GDP binding proteins which activate MAPK and PI3K
What happens in mutant KRas?
It is constitutively activated and bound to GTP because mutations normally affect the GTP binding site.
Features of CRC subtype 3? (Initiating events, location, lesion of origin)
Initiating events: Kras or BRAF mutations
Location: even distribution
Lesion of origin: serrated adenoma
Why does subtype 3 have a poor prognosis?
High risk of recurrence due to metastasis
This is due to enrichment of pro-metastatic and stem cell related genes
Poorly differentiated
Prognosis for different stages of CRC?
Stage I-II: surgery normally curative
Stage III: surgery followed by adjuvant chemotherapy
What is the cell of origin in CRC?
Intestinal crypt-1 which contains CBCCs
How is colorectal cancer staged?
Duke's A - invasion but not through the bowel wall B - invasion through the bowel wall C - involvement of lymph nodes D - distant metastases
