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Sem 4, case 4 (bowel cancer) > bowel cancer (mini learning) > Flashcards

bowel cancer (mini learning) Flashcards

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1
Q

Do the majority of colon cancers have familial history or occur sporadically ?

A

Sporadically
usually no familial history of colon cancer

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2
Q

What are 2 examples of colon cancers with a familial link ?

A
  • FAP (familial adenomatous polyposis)
  • HNPCC (hereditary non-polyposis colon cancer)
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3
Q

What does FAP stand for (name of a colon cancer) ?

A

Familial Adenomatous Polyposis

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4
Q

What % of colon cancers are accounted for by FAP ?

A

1%

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5
Q

What happens in FAP ?

A

hundreds of polyps form, lining the lumen of the colon

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6
Q

What does HNPCC stand for ? (type of colon cancer)

A

Hereditary Non-Polyposis Colon Cancer

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7
Q

What % of colon cancers are accounted for by HNPCC ?

A

2-3%

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8
Q

What is another name for HNPCC ?

A

Lynch syndrome
because it predisposes people to tiger cancers

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9
Q

What are the main cancers that HNPCC predisposes people to ?

A
  • ovarian
  • small intestine
  • urinary tract
  • skin
  • brain
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10
Q

How does HNPCC manifest ?

A

a few polyps form in colon lumen (not many) but progression is fast

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11
Q

How quickly can HNPCC develop into a full blown tumour?

A

2-3 years

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12
Q

How quickly can FAP develop into a full blown tumour?

A

8-10 years

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13
Q

Are FAP and HNPCC common or rare forms of colon cancer ?

A

Rare

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14
Q

What are the 6 main features/abilities of a cancer cell ?

A
  • avoid apoptosis
  • self-sufficiency in growth signals
  • insensitive to anti-growth signals
  • can invade tissues
  • limitless replication potential
  • sustained angiogenesis
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15
Q

What happens to metabolism in cancer cells ?

A

it is deregulated

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16
Q

How do cancer cells differ to normal body cells with respect to the immune system ?

A
  • Avoid immune detection/destruction
  • promote inflammation
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17
Q

Are cancer cells genetically stable or unstable ?

A

very unstable

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18
Q

How many chromosomes are there in the human genome ?

A

46 chromosomes
23 pairs

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19
Q

How many pairs of autosomes are there in the human genome ?

A

22 pairs

+ 1 pair of sex chromosomes

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20
Q

What are the 4 phases of the cell cycle ?

A
  • G1 = growth/gap phase 1
  • S phase = synthesis phase
  • G2 = growth/gap phase 2
  • M = mitosis
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21
Q

When does chromosome duplication occur in the cell cycle ?

A

During S phase

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22
Q

What is one arm of a chromosome called ?

A

a chromatid

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23
Q

How do cells become tissues ?

A
  • genome in cells used in protein synthesis (transcription and translation)
  • proteins drive cell function via metabolism/biogenesis pathways
  • cells work together to form tissues
  • tissues undergo proliferation
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24
Q

How does 1 mutated/cancer cell infiltrate a tissue ?

A

via clonal expansion

the mutated cell proliferates faster than the other ‘normal’ cells

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25
Q

Describe the process of forming a heterogenous cancer via clonal expansion …

A
  1. one cell has an initial mutation
  2. that mutated cell divides faster than the rest = multiple mutated cells (M1)
  3. another mutation occurs in one of the M1 cells
  4. this cell proliferates faster = cells with 2 mutations (M2)
  5. this keeps occurring until there are loads of cells with multiple, different mutations = a cancer
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26
Q

What are the 2 protein types that drive/regulate the cell cycle?

A
  • CDK (1, 2, 4, 6)
  • Cyclins (A, B, D, E)
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27
Q

In cancer, are oncogenes activated or inactivated ?

A

oncogenes = activated ”on”cogene

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28
Q

In cancer, are tumour suppressor genes activated or inactivated ?

A

TSGs = suppressed

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29
Q

Do both copies of an oncogene need to contain a mutation in order to cause cancer ?

A

No just 1 copy has to be mutated to cause a cancer

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30
Q

Do both copies of a tumour suppressor gene need to contain a mutation in order to cause cancer ?

A

both copies must contain a mutation to cause cancer

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31
Q

What are the 2 types of retinoblastoma ?

A
  • familial
  • sporadic
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32
Q

How does presentation of retinoblastoma differ between familial and sporadic types ?

A

FAMILIAL = both eyes, predisposes person to other/future cancers

SPORADIC = one eye, not associated with onset of other/future cancers

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33
Q

What are 2 important oncogenes relating to colon cancer ?

A
  • β-catenin
  • KRAS
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34
Q

What are 2 important tumour suppressor genes relating to colon cancer ?

A
  • APC
  • p53
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35
Q

What is the basic/general signalling pathway leading to gene expression ?

A
  • ligands
  • bind to receptors on cell surface
  • initiate an intracellular signalling cascade
  • converge on transcription factors
  • alters gene expression and cell function
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36
Q

What molecule activates the oncogene RAS ?

A

GTP

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37
Q

What is the interaction between RAS and GTP ?

A
  • RAS bound to GTP = active state of RAS
  • GTP is hydrolysed to GDP
  • RAS bound to GDP = inactive state of RAS

To re-activate:
- GDP is released and replaced by new GTP

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38
Q

What does activated RAS do ?

A

stimulates downstream pathways resulting in multiple regulatory processes for cell division

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39
Q

What regulatory effects does the oncogene RAS have on cell division ?

A
  • inhibits apoptosis / allows cell cycle progression
  • stimulates protein synthesis
  • stimulates cell proliferation
  • initiates chromatin remodelling
  • enables transcription
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40
Q

What effect do oncogene mutations have on RAS ?

A

locks RAS in the active form, allowing for unregulated protein synthesis and avoidance of apoptosis

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41
Q

In about what % of all cancers is a RAS a mutation found ?

A

20-30%

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42
Q

In about what % of colon cancers is a RAS a mutation found ?

A

45-50%

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43
Q

When bound to a receptor, what effect does the Wnt signal have on a cell ?

A

promotes proliferation

44
Q

Are levels of β-catenin high or low in a cell where a Wnt signal has not yet bound ?

A

unbound = low levels of β-catenin

due to degradation

45
Q

Are levels of β-catenin high or low in a cell where a Wnt signal has bound ?

A

bound = high levels of β-catenin

46
Q

In the context of colon cancer, what is β-catenin ?

A

an oncogene

47
Q

In the context of colon cancer, what is APC ?

A

a tumour suppressor gene

48
Q

Name which CDK molecules drives which part of the cell cycle ?

A
  • CDK 4/6 = G1 (up to the R point)
  • CDK 2 = from R point into S phase
  • CDK 2 = S phase
  • CDK 1 = S phase into G2
  • CDK 1 = G2 into M + all of M

CDK 1 = CDC 2, another name for same thing

49
Q

What happens to levels of CDKs throughout the cell cycle ?

A

the stay relatively constant

50
Q

What happens to levels of cyclins throughout the cell cycle ?

A

They each vary depending on when they’re needed

they regulate each other

51
Q

What regulates CDK molecules ?

A

CKIs = cyclin dependant kinase inhibitors

52
Q

Name one CKI that blocks action of multiple CDKs in the cell cycle …

A

p21

53
Q

Which cyclin enters the cell into the cell cycle ?

A

Cyclin D

54
Q

What is the order of cyclins that move a cell through the cell cycle ?

A
  • D
  • E
  • A
  • A
  • B
55
Q

Which CDK molecules are associated with cyclin D in the cell cycle ?

A

CDK 4
CDK 6

56
Q

Which CDK molecule is associated with cyclin E in the cell cycle ?

A

CDK 2

57
Q

Which CDK molecules are associated with cyclin A in the cell cycle ?

A

CDK 2
CDK 1 (CDC 2)

58
Q

Which CDK molecule is associated with cyclin B in the cell cycle ?

A

CDK 1

(a.k.a CDC 2)

59
Q

In roughly what % of colon cancers is p53 mutated?

A

50%

60
Q

In what % of ovarian cancers is p53 mutated ?

A

pretty much 100%

61
Q

Are levels of p53 normally high or low in cells ?

A

normally low due to degradation

62
Q

What is p53 regulated by ?

A
  • kinases
  • ubiquitin
  • ligases
63
Q

What is p53 ?

A

a transcription factor that suppresses tumor growth

64
Q

What activates p53 ?

A

stress

  • ionising radiation
  • UV radiation
  • hypoxia
  • oncogene signalling
  • blockage in transcription
65
Q

What is known as the ‘guardian of the genome’ ?

A

p53

66
Q

What does p53 do once activated ?

A

modulates genes effecting multiple downstream pathways …

- pause cell cycle
- DNA repair
- block angiogenesis
- cause apoptosis

67
Q

Which gene is a big target of p53 ?

A

p21

= a CKI that blocks multiple CDKs in the cell cycle

68
Q

How does p53’s interaction with p21 help with cell repair?

A
  • p53 stimulates p21 production
  • more p21 = more inhibition of CDK
  • inhibition of CDK = paused cell cycle
  • gives the cell time to repair the damage
69
Q

How does p53 induce apoptosis ?

A

stimulates expression of genes that induce cell death

(Noxa and Puma)

70
Q

Roughly what % of all UK cancer cases are colon cancer ?

A

13%

71
Q

Roughly what % of all UK cancer deaths are colon cancer ?

A

10%

72
Q

Roughly what % of colon cancer patients survive 10+ years since diagnosis ?

A

57%

73
Q

Are there villi in the large intestine ?

A

No

74
Q

Are there villi in the small intestine ?

A

yes

75
Q

What is APC ?

A

the tumour suppressor gene that causes most colon cancers when it is mutated

found on chromosome 5q21
discovered when studying the cause of FAP colon cancer

76
Q

How do Wnt, APC and β-catenin interact ?

A

Wnt unbound to receptor:
- APC complex in cell remains intact
- causes degradation of β-catenin

Wnt bound to receptor:
- APC complex is distrusted
- β-catenin remains stable
= drives proliferation by up regulating cyclin D

77
Q

Which cells in the intestinal crypt secrete the Wnt signals ?

A

Surrounding stromal cells at the base of the crypt

78
Q

Where in the intestinal crypt do normal epithelial cells proliferate ?

A

at the base of the crypt near the stromal cells as they release the Wnt

they migrate up from here

79
Q

Where in the intestinal crypt do epithelial cells proliferate if they have the APC mutation ?

A

anywhere along the crypt as they don’t rely on Wnt signals for proliferation

80
Q

Roughly what % of colon cancers have an APC mutation ?

A

80-90%

81
Q

What is the other most common mutation in colon cancers, besides APC mutations ?

A

β-catenin

10-20% of colon cancers

82
Q

Roughly what % of colon cancers have a β-catenin mutation ?

A

10-20%

83
Q

What does a β-catenin mutation cause ?

A

the β-catenin doesn’t get degraded like it would normally, so the cell is in constant proliferation mode

84
Q

Are crypts deeper in the small or large intestine ?

A

large intestine

85
Q

Where are paneth cells found ?

A

Base of the crypts in the small intestine

86
Q

What do Paneth cells do ?

A

secrete defensins

87
Q

What structures form the mid gut ?

A
  • caecum
  • ascending colon
  • first 2/3 of transverse colon
88
Q

What structures form the hind gut ?

A
  • last 1/3 transverse colon
  • descending colon
  • sigmoid colon
  • rectum
89
Q

Which genes are found to be mutated in Lynch syndrome (HNPCC) ?

A

MSH2
MLH1

90
Q

What is the normal function of the genes MHL1 and MSH2 ?

A

code for proteins that repair faulty DNA

(block progression from normal cell to tumour cell = effectively tumour suppressor genes)

91
Q

How does a mutation of MSH2/MLH1 cause progression into cancer ?

A

Losing their function gives rise to more frequent mutations/faults within cells during replication, which accelerates mutations fo other oncogenes/TSGs

92
Q

What are micro satellites ?

A

regions of repeated DNA that change in length (show instability) when mismatch repair is not working properly

93
Q

What is mismatch repair ?

A

a process of recognising and repairing DNA mutations during cell replication

MSH2, MLH1 code for the proteins that do this

94
Q

Which genes are involved in mismatch repair ?

A

MSH2
MLH1

code for the proteins that do this

95
Q

What is micro satellite instability testing ?

A

looks at the length of certain DNA microsatellites from the tumor sample to see if they have gotten longer or shorter as a measure of instability

96
Q

When did PCR amplification come about ?

A

1983

97
Q

When was the first human genome sequenced ?

A

2003

98
Q

What are the 3 subtypes of colon cancer ?

A
  1. POLE ultra-mutated
  2. MSI - hypermutated (mismatch repair defects = micro satellite instability)
  3. non-hypermutated (don’t have mismatch repair defects = micro satellite stable)
99
Q

What % of colon cancers are
a) POLE ultra-mutated
b) MSI - hypermutated ?
c) non-hypermutated ?

A

POLE ultra-mutated = <1%
MSI - hypermutated = 9%
non-hypermutated = 90%

100
Q

Which type of colon cancer (hypermutated/non-hypermutated) is more likely to benefit from immune checkpoint therapies ? Why ?

A

hypermutated

101
Q

How do immune checkpoint therapies work ?

A

block PD-1 receptors/PD-L1 antigens so Tcells retain the ability to attack cancer cells

Normally:
Hypermutated tumour expresses unusual antigens on its surface that interact with T-cells. This would allow Tcells to attack that cell.

In cancer:
Hypermutated tumour also expresses PD-L1 antigens. These interact with PD-1 receptors on Tcells that suppresses its ability to attack the tumour cell.

102
Q

What are the main ‘take homes’ to know about colon cancer ?

A
  • 3 subtypes (ultra/hyper/non-hypermutated)
  • Wnt pathway mutations are obligate target for developing colon cancer via APC/β-catenin
  • RAS/p53 are later, common targets
  • MSI tumours respond to immune checkpoint therapies
103
Q

What is a liquid biopsy ?

A

A blood test looking for circulating tumour cells/markers/DNA/RNA

104
Q

What are some pros of a liquid biopsy vs a regular biopsy ?

A
  • less invasive
  • cheaper
  • allows for early detection of
  • allows for early detection of predictive biomarkers
105
Q

Why is it helpful to use liquid biopsies to detect predictive bio markers ?

A

this can allow us to understand what therapies would work best to tackle the tumour, as we can see what it will respond well/badly to

106
Q

What are organoids + how could they be used to help tackle cancers ?

A

organoids = samples of tumour grown in petri-dishes that grow to form a mini version of the tumour in a lab

useful because drugs can be tested on the mini tumours to find what’s effective against that specific tumour/patient

Sem 4, case 4 (bowel cancer) (2 decks)

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