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92 Cards in this Set
- Front
- Back
What is the function of the colon? |
1.Reabsorbs water and electrolytes from chyme to form feces - proximal colon 2. Temporary storage of fecal matter - distal colon |
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What movements aid the colon? |
Mixing and propulsive |
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What happens when a gene is methylated? |
Less gene expression, transcription factors cannot bind to transcribe the gene. |
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What happens when a gene is acetylated? |
Increased access to the gene means increased transcription --> more expression |
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What is HDAC? |
Histone De-acetylase removes acetyl groups on histones therefore decreases access for transcription factors --> decreases gene expression |
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What % of colon cancers have a mutation in the APC gene? |
80 |
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What is the APC gene? |
Tumour suppressor gene - normally encodes proteins which transcription factors can adhere to. |
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What % colon cancers have a mutation in KRAS? |
50 - 60% |
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What is the function of the KRAS gene? |
Controls cellular division |
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What happens if KRAS is mutated? What do we call this? |
KRAS proto-oncogene Increased cell proliferation |
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What is a mismatch repair gene? |
Normally repairs mutations |
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What is p53 an example of? |
Tumour suppressor gene |
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What happens is there is a mutation with p53? |
Increased resistance of cancer cells to apoptosis |
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What are the 3 main types of genes that contribute to carcinoma-development? |
Proto-oncogenes Mutation in tumour suppressor genes Mutation in repair enzymes |
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What is metaplasia? |
Change in nature of tissue. |
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What is dysplasia? |
Displacement of tissue due to abnormal proliferation of cells. |
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What is anaplasia? |
Loss of intracellular structural differentiation |
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Describe the stages of cancer. |
Metaplasia -> Dysplasia -> Anaplasia |
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Describe interphase. |
G1- normal cell functions + cell growth + duplication of organelles G0 - Stationary phase - nothing happening S - DNA replication G2 - chromosomes condense in preparation for mitosis |
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What are the 5 phases of mitosis? |
Prophase - chromosomes condense, centrioles separate, nucleus disintegrates Metaphase - chromatids move to equator Anaphases - chromatids pulled apart Telephase - chromosomes uncoil, 2 nuclei formed Cytokinesis - cytoplasmic division |
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What are cyclins? |
Cyclins activate Cyclin Dependent Kinases - enzymes that control progression through cell cycle - patrol checkpoints - ensure time for DNA repair - cause apoptosis of faulty cells |
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What is cyclin B? |
Protein found in abundance in late G2. Activates cyclin dependent kinase (CDK1) which causes mitosis |
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What is RAS? |
Normally RAS is bound to GDP and inactive. Once bound to GTP --> active Once active, RAS initiates signalling cascades which cause: 1. inhibition of apoptosis 2. cell growth 3. protein synthesis |
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What is RAS? |
Oncogene - mutation causes it to remain active --> increases cell growth and proliferation |
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What happens when Wnt is absent? |
When Wnt is absent, GSK 3B is active and can phosphorylate Beta catenin which causes it to be degraded --> no cell growth. Beta catenin is a oncogene which normally promotes cell proliferation. |
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What happens when Wnt is present? |
When Wnt is present, it switches off GSK 3B so Beta catenin is not phosphorylated hence is active. In active form it promotes cell proliferation. |
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What does a mutation that causes Beta catenin to remain unphosphorylated mean? |
Beta catenin becomes a proto-oncogene as it promotes cell proliferation indefinitely. |
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What happens when RAS and WNT activate cyclin D1? |
Cyclin D1 now activates CDK4 which phosphorylates Rb. This means Rb can no longer bind to and inhibit E2F from entering the nucleus. E2F enters the nucleus and increases gene expression of cyclin E which activates CDK2 which activates S phase (DNA replication) |
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What is Rb? |
Rb is a tumour suppressor gene. |
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How many copies of Rb must be mutated in order to affect E2F? |
If both copies of Rb are mutated, E2F is always liberated and continuously enters S phase without checkpoint control. |
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What normally stops S phase is something goes wrong? |
p53 |
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What is p53? |
A transcription factor which is normally degraded. |
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What happens when p53 is activated? |
Stops cell cycle - inhibits CDKs DNA repair Block of angiogenesis Apoptosis |
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What is the extrinsic pathway for apoptosis? |
TNF alpha or Fas binds to receptor which activates DISC (death inducing signalling complex) to bind and activate caspases which induce a proteolytic cascade. |
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What is the intrinsic pathway for apoptosis? |
Cell recognises internal damage. BAX binds to receptor on mitochondria. Upon binding, BAX changes shape. Proteins (cytochrome C) in intramembranous space of mitochondria leak into cytoplasm. Cytochrome C activates caspases. |
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What genes are normally the cause of familial cancer? |
Tumour suppressor genes |
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What are most sporadic cancers the result of? |
Exposure to carcinogenic agents and un-repaired DNA replication errors. Activation of cancer genes. |
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Why are cancer genomes instable? |
Chromosomal instability - result of numerical and structural abnormalities Microsatellite instability - result of impaired DNA mismatch repair |
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What is telomerase? |
Enzyme that prevents shortening of telomere therefore prevents senescence. Normally it is switched off. It is on in cancer. |
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What makes a cancer cell malignant? |
1. independence to external growth signals 2. insensitive to external anti-growth signals 3. able to avoid apoptosis 4. able to divide indefinitely 5. angiogenesis 6. tissue invasion and metastasis |
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What are the 2 main types of cancer genes? |
Proto-oncogenes Tumour suppressor genes |
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Describe the characteristics of a proto-oncogene. |
Gain of function Dominant |
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Describe the characteristics of a tumour suppressor gene. |
Loss of function Recessive |
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What is a proto-oncogene? |
Normal gene that promotes cell division, survival and growth. Mutates into oncogene -> promotes cancer |
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How can proto-oncogenes be activated? |
1. point mutation 2. gene amplification 3. chromosomal translocation 4. viral stimulation |
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What is a oncogene? |
Gene that promotes cancer. Mutation in 1 allele leads to gain of protein function. |
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What do oncogenes usually code for? |
1. growth factors 2. cell surface receptors 3. signal transduction system components 4. nuclear proteins, transcription factors 5. cyclins |
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What are tumour suppressor genes? |
Recessive, cause loss in protein function. Natural defense against malignancy |
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How are tumour suppressor genes inactivated? |
1. mutations 2. chromosomal abnormalities 3. methylation of promoters 4. interaction with viral proteins |
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What are the functions of tumour suppressor genes? |
1. inhibit progression through cell cycle 2. promote apoptosis 3. inhibit cell growth 4. DNA repair 5. cell adhesion to prevent metastasis |
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What cells cannot metastasize? |
Glial cells |
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What are the most severe and rare familial colorectal cancers? |
FAP (Familial Adenomatous Polyposis) HNCC (Hereditary nonpolyposis colorectal cancer) |
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What % colorectal cancer is 70+ yrs? |
56 |
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Where is colorectal cancer most common? |
Rectum |
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What are the main risk factors for colorectal cancer? |
Diet high in red meat + Nitros compounds e.g. in cured meats Smoking Heaving drinking 50+yrs Obesity + inactivity FH |
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Common presenting findings? |
Bleeding Altered bowel habits Abdominal mass Perforation Hemorrhage Abdo pain Weight loss Anaemia |
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What tests do we do? |
Bloods- microcytic anaemia, hypercalcemia - spread to bones) LFT - hyperbilirubinemia, raised ALP KFT - raised creatinine Sigmoidoscopy/ colonoscopy/ barium enema |
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What is sigmoidoscopy? |
endoscope reaches top of descending colon |
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What is colonoscopy? |
endoscope reaches entire length of colon to ileocecal valve |
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What is a barium enema? |
identifies polyps, colitis, narrowing of colon due to tumour Barium coats the mucosal lining - shows up on x-ray |
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By how much can surgery increase survival? |
50% |
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What technique is commonly used? |
Laproscopy |
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When is a right hemicolectomy performed? |
For cecal, ascending or proximal transverse colon |
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When is a left hemicolectomy performed? |
For tumours in the distal transverse colon or descending colon |
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When is an anterior resection performed? |
For low sigmoid or high rectal tumours |
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When is a abdomin-perineal resection performed? |
For low rectum, involves removal of rectum and colostomy insertion |
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When is hartmann's procedure performed? |
For emergency bowel obstruction or palliation |
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Why is radiotherapy use pre-operatively? |
To reduce recurrence and increase 5 year survival. |
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What is used for chemotherapy? |
Fluoro-uracil - inhibits incorporation of thymidine into DNA by inhibiting thymidylate synthetase It is converted into FdUMP and FUTP FdUMP - inhibits DNA synthesis FUTP interferes with RNA processing + function |
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What is folinic acid? |
Adjuvant used in cancer chemotherapy where the drug used is methotrexate. It counteracts it's toxicity and ensures it is eliminated. Can also be used with 5-fluoro-uracil as it also inhibits thymidylate synthase |
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What is the survival rate over next 5 years with Duke's A? |
90% |
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What is the survival rate over next 5 years with Duke's B? |
66% |
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What is the survival rate over next 5 years with Duke's C? |
33% |
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What is the survival rate over next 5 years with Duke's D? |
5% |
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Why is a mutation in crypts of the colon harmful? |
Crypts contain stem cells which when mutated form polyps.
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What is familial adenomatous polyposis (FAP)? |
Inherited disease of the colon which predisposes to development of colorectal cancer. Characterised by hundreds of polyps lining the luminal surface of the colon. |
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What is APC? |
Tumour suppressor gene which binds to B-catenin and stimulates degradation of it. This stops the cell overproliferating. |
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What does a mutation in APC cause? |
1. Prevents degradation of B-catenin --> excessive proliferation. 2. Makes genome unstable by affecting spindling during mitosis. 3. Stimulates migration of malignant stem cells out of crypts --> polyps |
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In what % sporadic CRC is APC mutated? |
80-90% |
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In what % sporadic CRC is B-catenin mutated? |
10-20% |
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What % CRC does HNCC account for? |
2-3% |
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What else is hereditary non-polyposis colon cancer known as? |
Lynch syndrome |
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What is worrying about HNCC? |
Predisposes you to other cancers (not just CRC) Development of CRC is fast |
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What happens if mismatch repair genes are mutated? |
DNA cannot be repaired -> more mutations. |
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Give an example of a mismatch repair gene. |
MLH1 |
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What is TGF-B? |
Growth inhibitory factor |
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What happens if it is mutated? |
Cell becomes unresponsive to anti-proliferative signals e.g. from TGF-B |
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What % CRC is caused by mismatch repair gene defect in TGF-B? |
90% |
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What happens to the colon if TGF-B pathway is disrupted? |
Colon becomes inflamed -> increased chance of CRC development |
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What is activated in response to inflammation? |
NF-kB pathway is upregulated -> increased gene expression causing: 1. proliferation via cyclin D1 2. anti-apoptosis 3. Synthesis of pro-inflammatory prostaglandins via COX2 |
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What can chronic inflammation cause? |
Ulcerative colitis -> increased risk of CRC |
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What does damage to vasculature cause an increase in? What does this stimulate? |
Vascular endothelial growth factor Angiogenesis |