case 4 - bowel cancer part 2 Flashcards
what is the form of bowel cancer that normally develops
adenocarcinoma
what are the rare family diseases
FAP
HNPCC
what is the epidemiology of bowel cancer
3rd most common cancer and the second most common cause of UK cancer deaths
56% of presentations are those in >70 year olds
Most are found in the rectum
Least likely is the descending colon
why is red meat a risk factor for bowel cancer
high levels of N-nitros compounds which are carcinogenic
what family history poses a risk for bowel cancer
neoplastic adenomatous polyps
colorectal cancer
what are the left sided bowel cancer presentations and what is it a disorder with
disorder with storage
bleeding/mucus
Altered bowel habit
Tenesmus (continual feeling of needing to evacuate the bowel)
Abdominal mass
Perforation
Haemorrhage
what are the features of right sided bowel cancer and what is it a disorder with
disorder with absorption
weight loss
Reduced haemoglobin
Abdominal pain
what is the blood test used for bowel cancer and what are the results
Full blood count (indicate low serum levels (microcytic anaemia))
Serum proteins
Calcium - check for metastatic hypercalcemia
what is the liver function test and what does it show
Bilirubin - colorectal cancer liver metastasis causes severe hyperbilirubinaemia
Alkaline phosphatase (ALP) - ALP levels elevated with liver metastasis of colorectal cancer
what is the kidney function test
creatine - creatine levels elevated with kidney metastasis of CRC
what is the barium enema test
test used to identify problems in the colon, such as polyps, inflammation, narrowing of the colon, tumours etc
what is the liquid and what does it do that is used in the barium enema test
A thick liquid (containing barium) is placed in the lower gut via the rectum
This coats the mucosal lining of the colon, thus highlighting the colon in an X-ray
Characteristic findings are indicative of pathology
what kind of sign does colon cancer leave
an applecore sign
what does chemotherapy reduce
duke’s C mortality by about 25%
what is Fluorouracil
a pyrimidine analog that is an antineoplastic antimetabolite
what does an antimetabolite do
prevents purine/pyrimadine from incorporating into the DNA during the S phase, stopping normal development and division
what does fluorouracil do
Fluorouracil blocks the enzyme which converts the cytosine nucleotide into the deoxy derivative
Fluorouracil inhibits the incorporation of the thymidine nucleotide into the DNA strand
what is the mechanism of action of fluorouracil
is converted in cells to 5-fluoro-2’5’ monophosphate (5-FdUMP) and 5-fluurouradine-5’-triphosphate (FUTP), its metabolites
5-dUMP incorporates into the DNA of fast growing cells in the body
Here, it interferes with DNA synthesis by blocking thymidylate synthesis
Normally, thymidylate synthetase converts uracil into thymidylate
Blocking this enzyme inhibits the synthesis of thymidylate
This means that thymidine can no longer be incorporated into DNA
what does the incorporaton of FdUMP into DNA do
inhibits DNA synthesis function
what does the incorporation of FdUMP do to RNA
interferes with RNA processing and function
what can tumour cell resistance mechanisms include
decreased activation of 5FU, increased thymidylate synthase activity and reduced drug sensitivity of this enzyme
what is folinic acid usually administered as
calcium or sodium folinate
what is it an adjuvant to
it is an adjuvant used in cancer chemotherapy involving the drug methotrexate
how is folinic acid administered
as a pill or into the vein
what are the indications for folinic acid
used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists, and to treat megaloblastic anaemias due to folic acid deficiency
also used in combination with 5-FU to prolong survival In the palliative treatment of patients with advanced colorectal cancer. It enhances the effect of 5FU by inhibiting thymidylate synthase
what is the mechanism of action of folinic acid
as leucovorin is a derivative of folic acid, it can be used to increase levels of folic acid under conditions favouring folic acid inhibition
Leucovorin enhances the action of fluorouracil by stabilising the bond of the active metabolite (5-dUMP) to the enzyme thymidylate sythetase
This is because 5-FU doesn’t stay long in the system and so folinic acid allows 5-FU to bind to this enzyme
describe the TMN staging of colon cancer
T =
tumour
Goes from Tis-T4b
(Go into this in more detail)
N =
node
Goes from N0-N2
M =
Metastasis
Goes from M0-M1
what is Duke’s staging for colorectal cancer
This provides a 5 year prognosis
duke’s A = 90% chance of survival
Dukes B = 66% chance of survival
Dukes C = 33% chance of survival
Dukes D = <5% chance of survivals
what is grade I of cancer
tumour cells resemble normal and aren’t growing rapidly
what is grade II of cancer
tumour cells dont look normal and are growing faster than normal cells
what is grade III of cancer
tumour cells look abnormal and are proliferating rapidly
cells that resemble tissue are more likely to be what
well differentiated
cells that resemble stem cells tend to be waht
poorly differentiated
what is the pathology of colon cancer
the mucosal lining of the colon contain crypts
These are the sites of mutations in colon cancer
If the mutation occurs in the differentiated villi / epithelial cells, then the development of the tissue isn’t so harmful
If the mutation occurs In the crypts then the development of the tissue is very harmful (polyps)
what is FAP
this is the inherited disease of the colon which predisposes the individual to developing colorectal cancer
in this condition, hundreds of polyps line the luminal surface of the colon
this condition has a low but predictable frequency of development into colorectal cancer
what is APC
APC forms part of the Wnt signalling pathwat, forms part of the intracellular protein complex
APC gene is a TSG
what does APC encode for
a protein consisting of 2800 amino acids which binds to b catenin, thus causing down regulation of it by initiating its proteloytic degradation
this stops the cell from over proliferation
what happens if there is a mutation in APC
Prevents the degradation of B-catenin and so results in excessive proliferation of the cell
Makes the genome unstable by affecting the spindling during mitosis
Stimulates the migration of malignant stem cells out of the crypts (polyps)
deregulation of APC/B-catenin is an obligate and early step in CRC
what is HNPCC
an inherited disease of the colon that causes 2-3% of all colorectal cancers
what is HNPCC also known as
lynch syndrome
what is the features of the polyps in HNPCC
very few polyps form, but the progression of development into colorectal cancer is faster - 2-3 years
what is the mismatch repair genes
they have a higher mutation rate than other genes
if mismatch genes are mutated then any errors in newly made DNA strands cant be repaired
what is MLH1 gene
is a mismatch repair gene, associated with micro satellite stability. a mutation of this can lead to microsatellite instability and HNPCC
how do the MLH1 mutations cause cancer
the cells are constantly making mistakes when making new DNA strands that aren’t being repaired
This means the mutation rate in these patients increases significantly
This means that they can acquire more mutations more easily in specific regions of the genome such as in oncogenes and TSGs
An elevated mutation rate doesn’t cause cancer; mutations in specific areas of the genome give us cancer I.e in oncogenes/TSGs
what normally happens when TGF beta binds to its receptor
causes a signalling cascade to occur via Smad intracellular proteins
what does this cause
This causes:
Activation of CKis - thus inhibiting proliferation
Inhibition of MYC - a pro-proliferative molecule - thus inhibiting proliferation
mutations can occur in the Smad 4 pathway, thus leading to an increase in proliferation
mismatch repair gene mutation explanation
TGF-beta is a growth inhibitory factor
Mismatch repair mutations cause deletion of AA bases
This causes a truncation of the TGF-beta receptor gene, meaning that it is no longer synthesised
As a result, the cell now becomes unresponsive to anti-proliferative signals
TGF-beta receptor gene mutation occurs in 90% of colorectal cancers with a mismatch repair gene
what is the inflammation pathway
thereforewithout the TGF-beta pathway, the colon become sensitised to inflammation and so can develop colorectal cancer
In response to the inflammatory response, the NF-kbeta pathway is upregulated, leading to increased gene expression
Proliferation
Anti apoptosis
what does chronic inflammation in this manner cause
ulcerative colitis, which increases the risk of developing colorectal cancer
what is angiogensis
damage to the vasculature leads to an increase in vascular endothelial growth factor -VEGF
this results in angiogenesis
what can angiogenesis be treated with
be treated by VEGF inhibitiors e.g avastin
