colorectal cancer Flashcards
How many cases of colorectal cancer are diagnosed in a year?
1,000,000
Why are the incidence rates higher in developed countries? How do mortality rates vary?
Incidence rates are generally higher in developed countries, e.g. North America, UK. However, generally the mortality rates in these areas aren’t particularly high. This is probably due to the treatments available, presence of screening programmes, stage at diagnosis, healthcare systems, etc. Incidence rates vary depending on environmental factors, e.g. typical diets, smoking.
What are the risk factors for colorectal cancer?
- Ageing
- High fat, low fibre diet
- IBD
- Sedentary lifestyle
- Personal history of colorectal cancer
- Family history of colorectal cancer
However, the main risk is associated with replicative errors, e.g. ageing.
What percentage of colorectal cancer cases are considered ‘sporadic’?
65% of all colorectal cancers are thought to be sporadic, therefore 35% of cases are via inheritance.
What areas of the body does colorectal cancer refer to?
- Cecum
- Ascending Colon
- Transverse Colon
- Descending Colon
- Sigmoid Colon
- Rectum
What is the multi-step carcinogenesis model involved in the acquisition of mutations promoting adeno-carcinoma sequence?
Colorectal cancers can be characterised by a clear progression from normal epithelium to a polyp, to a small adenoma, to overt adenocarcinoma, and finally to a disseminated carcinoma. From the normal epithelium, there is usually loss of APC, loss of proof-reading ability, and methylation, triggering hyper-proliferative epithelium. Here, further methylation may cause early adenoma formation. Activation of KRas and subsequently BRaf promotes intermediate adenoma formation. Deletion of 18q is involved in progression to late adenoma. Loss of TP53, as well as loss of microsatellite stability may cause formation into a carcinoma. Here, other alterations are responsible for the promotion of invasion and metastases, ultimately causing a higher stage cancer with worse prognosis.
For a cell to become metastatic, what are the 6 features it must acquire?
- Must become independent of external growth stimulus
- Must become insensitive to external anti-growth signals.
- Must become capable of tissue invasion and metastasis.
- Must become capable of indefinite replication.
- Must become capable of a sustained blood supply (angiogenesis).
- Must become capable of avoiding cell death (apoptosis).
What is Familial Adenomatous Polyposis Coli (FAP)
FAP is an inherited condition resulting in overproduction of tissue, causing polyp formation. This occurs due to a loss of APC function.
How is APC gene function related to colorectal cancer, in particular FAP.
APC gene encodes a protein which homodimerises and interacts with proteins to block cell cycle progression and act as a tumour suppressor. In normal cells APC binds to axin, beta-catenin, gamma-catenin, and GSK-3beta to form a large complex. The beta-catenin is then phosphorylated and degraded. If the beta-catenin is not phosphorylated then it can bind to transcription factors and initiate transcription.
In FAP, a defective APC gene is inherited preventing the tumour suppressor function of APC protein. This ultimately means transcription of proto-oncogenes can be initiated, leading to cancer formation via increased levels of beta-catenin binding to transcription factors.
How does a family history of colorectal cancer influence your lifetime risk of colorectal cancer?
Having a first degree relative with history of colorectal cancer, increases your personal lifetime risk by 2%-6%.
Importantly, having a HNPCC mutation increases your personal lifetime risk of having colorectal cancer by up to 80%.
What is HNPCC?
Hereditary Non Polyposis Colon Cancer is a hereditary form of cancer also known as Lynch Syndrome, often associated with high levels of micro-satellite instability.
Describe how different methylation status can influence tumour formation.
In our DNA, we have cystidines. These can become methylated by DNA methyltransferases (DNMT). This methylation affects the transcription of genes. If a normal cell becomes hypermethylated, the transcription machinery is not accessible, therefore there is reduced transcription. In cancer this may occur in tumour suppressor genes such as P16INK4A, APC, BRCA1, retinoblastoma protein.
The opposite of this is hypomethylation. This allows increased accessibility therefore transcription is increased. This can occur in cancer, promoting tumour proliferation and evasion of apoptosis, e.g. hypomethylation of Ras proto-oncogene can cause cell survival, apoptosis evasion, etc.
What mutations are typically present in colorectal cancer?
In colorectal cancer, it is typical to see KRas mutations, APC loss, TP53 mutation and 18q deletion. These have further knock on effect downstream.
What is the activation pathway of K-Ras in colorectal cancer?
K-Ras belongs to the superfamily that transduces signals from activated cell surface receptors. K-Ras is inactive when bound to GDP and active when bound to GTP. K-Ras has intrinsic GTPase activity, acting as a molecular switch to degrade signal and switch off activity.
When a growth factor is received, the tyrosine kinase cascade is initiated. GRB protein is recruited, activating SOS. SOS interacts with Ras-GDP, stimulating Ras to switch to its active form - Ras-GTP. Ras-GTP recruits Raf kinase to the membrane where MAPK activation occurs. This results in a kinase cascade.
In colorectal cancer cells, Ras is often mutated, therefore intrinsic GTPase activity may be destroyed, causing permanent activation. This leads to proliferation and transcription of oncogenes, promoting tumour cell survival, anti-apoptotic mechanisms and migration.
Describe how K-Ras and SOS interact.
Ras-GDP is bound via the phosphate binding loop. When SOS interacts with the P-loop, switch 1 and switch 2 loop, the interaction with GDP is lost as the P loop is distorted. There is then a temporary Ras-SOS complex (however the SOS is not bound via the P-loop). GTP can then enter the Ras binding site, causing SOS to dissociate and Ras-GTP to become active.
