Colon Cancer

Front 1

What is the function of the colon?

Back 1

1.Reabsorbs water and electrolytes from chyme to form feces - proximal colon

2. Temporary storage of fecal matter - distal colon

Front 2

What movements aid the colon?

Back 2

Mixing and propulsive

Front 3

What happens when a gene is methylated?

Back 3

Less gene expression, transcription factors cannot bind to transcribe the gene.

Front 4

What happens when a gene is acetylated?

Back 4

Increased access to the gene means increased transcription --> more expression

Front 5

What is HDAC?

Back 5

Histone De-acetylase removes acetyl groups on histones therefore decreases access for transcription factors --> decreases gene expression

Front 6

What % of colon cancers have a mutation in the APC gene?

Back 6

80

Front 7

What is the APC gene?

Back 7

Tumour suppressor gene - normally encodes proteins which transcription factors can adhere to.

Front 8

What % colon cancers have a mutation in KRAS?

Back 8

50 - 60%

Front 9

What is the function of the KRAS gene?

Back 9

Controls cellular division

Front 10

What happens if KRAS is mutated?

What do we call this?

Back 10

KRAS proto-oncogene

Increased cell proliferation

Front 11

What is a mismatch repair gene?

Back 11

Normally repairs mutations

Front 12

What is p53 an example of?

Back 12

Tumour suppressor gene

Front 13

What happens is there is a mutation with p53?

Back 13

Increased resistance of cancer cells to apoptosis

Front 14

What are the 3 main types of genes that contribute to carcinoma-development?

Back 14

Proto-oncogenes

Mutation in tumour suppressor genes

Mutation in repair enzymes

Front 15

What is metaplasia?

Back 15

Change in nature of tissue.

Front 16

What is dysplasia?

Back 16

Displacement of tissue due to abnormal proliferation of cells.

Front 17

What is anaplasia?

Back 17

Loss of intracellular structural differentiation

Front 18

Describe the stages of cancer.

Back 18

Metaplasia -> Dysplasia -> Anaplasia

Front 19

Describe interphase.

Back 19

G1- normal cell functions + cell growth + duplication of organelles

G0 - Stationary phase - nothing happening

S - DNA replication

G2 - chromosomes condense in preparation for mitosis

Front 20

What are the 5 phases of mitosis?

Back 20

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

Front 21

What are cyclins?

Back 21

Cyclins activate Cyclin Dependent Kinases - enzymes that control progression through cell cycle - patrol checkpoints

- ensure time for DNA repair

- cause apoptosis of faulty cells

Front 22

What is cyclin B?

Back 22

Protein found in abundance in late G2.

Activates cyclin dependent kinase (CDK1) which causes mitosis

Front 23

What is RAS?

Back 23

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

Front 24

What is RAS?

Back 24

Oncogene - mutation causes it to remain active --> increases cell growth and proliferation

Front 25

What happens when Wnt is absent?

Back 25

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.

Front 26

What happens when Wnt is present?

Back 26

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.

Front 27

What does a mutation that causes Beta catenin to remain unphosphorylated mean?

Back 27

Beta catenin becomes a proto-oncogene as it promotes cell proliferation indefinitely.

Front 28

What happens when RAS and WNT activate cyclin D1?

Back 28

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)

Front 29

What is Rb?

Back 29

Rb is a tumour suppressor gene.

Front 30

How many copies of Rb must be mutated in order to affect E2F?

Back 30

If both copies of Rb are mutated, E2F is always liberated and continuously enters S phase without checkpoint control.

Front 31

What normally stops S phase is something goes wrong?

Back 31

p53

Front 32

What is p53?

Back 32

A transcription factor which is normally degraded.

Front 33

What happens when p53 is activated?

Back 33

Stops cell cycle - inhibits CDKs

DNA repair

Block of angiogenesis

Apoptosis

Front 34

What is the extrinsic pathway for apoptosis?

Back 34

TNF alpha or Fas binds to receptor which activates DISC (death inducing signalling complex) to bind and activate caspases which induce a proteolytic cascade.

Front 35

What is the intrinsic pathway for apoptosis?

Back 35

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.

Front 36

What genes are normally the cause of familial cancer?

Back 36

Tumour suppressor genes

Front 37

What are most sporadic cancers the result of?

Back 37

Exposure to carcinogenic agents and un-repaired DNA replication errors.

Activation of cancer genes.

Front 38

Why are cancer genomes instable?

Back 38

Chromosomal instability - result of numerical and structural abnormalities

Microsatellite instability - result of impaired DNA mismatch repair

Front 39

What is telomerase?

Back 39

Enzyme that prevents shortening of telomere therefore prevents senescence.

Normally it is switched off. It is on in cancer.

Front 40

What makes a cancer cell malignant?

Back 40

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

Front 41

What are the 2 main types of cancer genes?

Back 41

Proto-oncogenes

Tumour suppressor genes

Front 42

Describe the characteristics of a proto-oncogene.

Back 42

Gain of function

Dominant

Front 43

Describe the characteristics of a tumour suppressor gene.

Back 43

Loss of function

Recessive

Front 44

What is a proto-oncogene?

Back 44

Normal gene that promotes cell division, survival and growth.

Mutates into oncogene -> promotes cancer

Front 45

How can proto-oncogenes be activated?

Back 45

1. point mutation

2. gene amplification

3. chromosomal translocation

4. viral stimulation

Front 46

What is a oncogene?

Back 46

Gene that promotes cancer.

Mutation in 1 allele leads to gain of protein function.

Front 47

What do oncogenes usually code for?

Back 47

1. growth factors

2. cell surface receptors

3. signal transduction system components

4. nuclear proteins, transcription factors

5. cyclins

Front 48

What are tumour suppressor genes?

Back 48

Recessive, cause loss in protein function.

Natural defense against malignancy

Front 49

How are tumour suppressor genes inactivated?

Back 49

1. mutations

2. chromosomal abnormalities

3. methylation of promoters

4. interaction with viral proteins

Front 50

What are the functions of tumour suppressor genes?

Back 50

1. inhibit progression through cell cycle

2. promote apoptosis

3. inhibit cell growth

4. DNA repair

5. cell adhesion to prevent metastasis

Front 51

What cells cannot metastasize?

Back 51

Glial cells

Front 52

What are the most severe and rare familial colorectal cancers?

Back 52

FAP (Familial Adenomatous Polyposis)

HNCC (Hereditary nonpolyposis colorectal cancer)

Front 53

What % colorectal cancer is 70+ yrs?

Back 53

56

Front 54

Where is colorectal cancer most common?

Back 54

Rectum

Front 55

What are the main risk factors for colorectal cancer?

Back 55

Diet high in red meat + Nitros compounds e.g. in cured meats

Smoking

Heaving drinking

50+yrs

Obesity + inactivity

FH

Front 56

Common presenting findings?

Back 56

Bleeding

Altered bowel habits

Abdominal mass

Perforation

Hemorrhage

Abdo pain

Weight loss

Anaemia

Front 57

What tests do we do?

Back 57

Bloods- microcytic anaemia, hypercalcemia - spread to bones)

LFT - hyperbilirubinemia, raised ALP

KFT - raised creatinine

Sigmoidoscopy/ colonoscopy/ barium enema

Front 58

What is sigmoidoscopy?

Back 58

endoscope reaches top of descending colon

Front 59

What is colonoscopy?

Back 59

endoscope reaches entire length of colon to ileocecal valve

Front 60

What is a barium enema?

Back 60

identifies polyps, colitis, narrowing of colon due to tumour

Barium coats the mucosal lining - shows up on x-ray

Front 61

By how much can surgery increase survival?

Back 61

50%

Front 62

What technique is commonly used?

Back 62

Laproscopy

Front 63

When is a right hemicolectomy performed?

Back 63

For cecal, ascending or proximal transverse colon

Front 64

When is a left hemicolectomy performed?

Back 64

For tumours in the distal transverse colon or descending colon

Front 65

When is an anterior resection performed?

Back 65

For low sigmoid or high rectal tumours

Front 66

When is a abdomin-perineal resection performed?

Back 66

For low rectum, involves removal of rectum and colostomy insertion

Front 67

When is hartmann's procedure performed?

Back 67

For emergency bowel obstruction or palliation

Front 68

Why is radiotherapy use pre-operatively?

Back 68

To reduce recurrence and increase 5 year survival.

Front 69

What is used for chemotherapy?

Back 69

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

Front 70

What is folinic acid?

Back 70

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

Front 71

What is the survival rate over next 5 years with Duke's A?

Back 71

90%

Front 72

What is the survival rate over next 5 years with Duke's B?

Back 72

66%

Front 73

What is the survival rate over next 5 years with Duke's C?

Back 73

33%

Front 74

What is the survival rate over next 5 years with Duke's D?

Back 74

5%

Front 75

Why is a mutation in crypts of the colon harmful?

Back 75

Crypts contain stem cells which when mutated form polyps.

Front 76

What is familial adenomatous polyposis (FAP)?

Back 76

Inherited disease of the colon which predisposes to development of colorectal cancer.

Characterised by hundreds of polyps lining the luminal surface of the colon.

Front 77

What is APC?

Back 77

Tumour suppressor gene which binds to B-catenin and stimulates degradation of it. This stops the cell overproliferating.

Front 78

What does a mutation in APC cause?

Back 78

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

Front 79

In what % sporadic CRC is APC mutated?

Back 79

80-90%

Front 80

In what % sporadic CRC is B-catenin mutated?

Back 80

10-20%

Front 81

What % CRC does HNCC account for?

Back 81

2-3%

Front 82

What else is hereditary non-polyposis colon cancer known as?

Back 82

Lynch syndrome

Front 83

What is worrying about HNCC?

Back 83

Predisposes you to other cancers (not just CRC)

Development of CRC is fast

Front 84

What happens if mismatch repair genes are mutated?

Back 84

DNA cannot be repaired -> more mutations.

Front 85

Give an example of a mismatch repair gene.

Back 85

MLH1

Front 86

What is TGF-B?

Back 86

Growth inhibitory factor

Front 87

What happens if it is mutated?

Back 87

Cell becomes unresponsive to anti-proliferative signals e.g. from TGF-B

Front 88

What % CRC is caused by mismatch repair gene defect in TGF-B?

Back 88

90%

Front 89

What happens to the colon if TGF-B pathway is disrupted?

Back 89

Colon becomes inflamed -> increased chance of CRC development

Front 90

What is activated in response to inflammation?

Back 90

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

Front 91

What can chronic inflammation cause?

Back 91

Ulcerative colitis -> increased risk of CRC

Front 92

What does damage to vasculature cause an increase in?

What does this stimulate?

Back 92

Vascular endothelial growth factor

Angiogenesis