bowel cancer (mini learning) Flashcards
(106 cards)
1
Q
Do the majority of colon cancers have familial history or occur sporadically ?
A
Sporadically
usually no familial history of colon cancer
2
Q
What are 2 examples of colon cancers with a familial link ?
A
- FAP (familial adenomatous polyposis)
- HNPCC (hereditary non-polyposis colon cancer)
3
Q
What does FAP stand for (name of a colon cancer) ?
A
Familial Adenomatous Polyposis
4
Q
What % of colon cancers are accounted for by FAP ?
A
1%
5
Q
What happens in FAP ?
A
hundreds of polyps form, lining the lumen of the colon
6
Q
What does HNPCC stand for ? (type of colon cancer)
A
Hereditary Non-Polyposis Colon Cancer
7
Q
What % of colon cancers are accounted for by HNPCC ?
A
2-3%
8
Q
What is another name for HNPCC ?
A
Lynch syndrome
because it predisposes people to tiger cancers
9
Q
What are the main cancers that HNPCC predisposes people to ?
A
- ovarian
- small intestine
- urinary tract
- skin
- brain
10
Q
How does HNPCC manifest ?
A
a few polyps form in colon lumen (not many) but progression is fast
11
Q
How quickly can HNPCC develop into a full blown tumour?
A
2-3 years
12
Q
How quickly can FAP develop into a full blown tumour?
A
8-10 years
13
Q
Are FAP and HNPCC common or rare forms of colon cancer ?
A
Rare
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
15
Q
What happens to metabolism in cancer cells ?
A
it is deregulated
16
Q
How do cancer cells differ to normal body cells with respect to the immune system ?
A
- Avoid immune detection/destruction
- promote inflammation
17
Q
Are cancer cells genetically stable or unstable ?
A
very unstable
18
Q
How many chromosomes are there in the human genome ?
A
46 chromosomes
23 pairs
19
Q
How many pairs of autosomes are there in the human genome ?
A
22 pairs
+ 1 pair of sex chromosomes
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
21
Q
When does chromosome duplication occur in the cell cycle ?
A
During S phase
22
Q
What is one arm of a chromosome called ?
A
a chromatid
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
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
25
Describe the process of forming a heterogenous cancer via clonal expansion …
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
26
What are the 2 protein types that drive/regulate the cell cycle?
- CDK (1, 2, 4, 6)
- Cyclins (A, B, D, E)
27
In cancer, are oncogenes activated or inactivated ?
oncogenes = **activated** *”on”cogene*
28
In cancer, are tumour suppressor genes activated or inactivated ?
TSGs = **suppressed**
29
Do both copies of an oncogene need to contain a mutation in order to cause cancer ?
No **just 1 copy** has to be mutated to cause a cancer
30
Do both copies of a tumour suppressor gene need to contain a mutation in order to cause cancer ?
**both copies** must contain a mutation to cause cancer
31
What are the 2 types of retinoblastoma ?
- familial
- sporadic
32
How does presentation of retinoblastoma differ between familial and sporadic types ?
FAMILIAL = both eyes, predisposes person to other/future cancers
SPORADIC = one eye, not associated with onset of other/future cancers
33
What are 2 important oncogenes relating to colon cancer ?
- β-catenin
- KRAS
34
What are 2 important tumour suppressor genes relating to colon cancer ?
- APC
- p53
35
What is the basic/general signalling pathway leading to gene expression ?
- **ligands**
- bind to **receptors** on cell surface
- initiate an intracellular **signalling cascade**
- converge on **transcription factors**
- alters gene expression and cell function
36
What molecule activates the oncogene RAS ?
GTP
37
What is the interaction between RAS and GTP ?
- 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
38
What does activated RAS do ?
**stimulates** downstream pathways resulting in **multiple regulatory processes** for cell division
39
What regulatory effects does the oncogene RAS have on cell division ?
- inhibits apoptosis / allows cell cycle progression
- stimulates protein synthesis
- stimulates cell proliferation
- initiates chromatin remodelling
- enables transcription
40
What effect do oncogene mutations have on RAS ?
**locks RAS in the active form**, allowing for unregulated protein synthesis and avoidance of apoptosis
41
In about what % of all cancers is a RAS a mutation found ?
20-30%
42
In about what % of colon cancers is a RAS a mutation found ?
45-50%
43
When bound to a receptor, what effect does the Wnt signal have on a cell ?
promotes proliferation
44
Are levels of β-catenin high or low in a cell where a Wnt signal has not yet bound ?
**unbound = low** levels of β-catenin
*due to degradation*
45
Are levels of β-catenin high or low in a cell where a Wnt signal has bound ?
**bound = high** levels of β-catenin
46
In the context of colon cancer, what is β-catenin ?
an oncogene
47
In the context of colon cancer, what is APC ?
a tumour suppressor gene
48
Name which CDK molecules drives which part of the cell cycle ?
- 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
What happens to levels of CDKs throughout the cell cycle ?
the stay relatively constant
50
What happens to levels of cyclins throughout the cell cycle ?
They each vary depending on when they’re needed
*they regulate each other*
51
What regulates CDK molecules ?
CKIs = cyclin dependant kinase inhibitors
52
Name one CKI that blocks action of multiple CDKs in the cell cycle …
p21
53
Which cyclin enters the cell into the cell cycle ?
Cyclin D
54
What is the order of cyclins that move a cell through the cell cycle ?
- D
- E
- A
- A
- B
55
Which CDK molecules are associated with cyclin D in the cell cycle ?
CDK 4
CDK 6
56
Which CDK molecule is associated with cyclin E in the cell cycle ?
CDK 2
57
Which CDK molecules are associated with cyclin A in the cell cycle ?
CDK 2
CDK 1 *(CDC 2)*
58
Which CDK molecule is associated with cyclin B in the cell cycle ?
CDK 1
*(a.k.a CDC 2)*
59
In roughly what % of colon cancers is p53 mutated?
50%
60
In what % of ovarian cancers is p53 mutated ?
pretty much 100%
61
Are levels of p53 normally high or low in cells ?
normally **low** due to degradation
62
What is p53 regulated by ?
- kinases
- ubiquitin
- ligases
63
What is p53 ?
a transcription factor that suppresses tumor growth
64
What activates p53 ?
**stress**
- ionising radiation
- UV radiation
- hypoxia
- oncogene signalling
- blockage in transcription
65
What is known as the ‘guardian of the genome’ ?
p53
66
What does p53 do once activated ?
modulates genes effecting multiple downstream pathways …
**- pause cell cycle
- DNA repair
- block angiogenesis
- cause apoptosis**
67
Which gene is a big target of p53 ?
p21
*= a CKI that blocks multiple CDKs in the cell cycle*
68
How does p53’s interaction with p21 help with cell repair?
- 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
How does p53 induce apoptosis ?
stimulates expression of genes that induce cell death
*(Noxa and Puma)*
70
Roughly what % of all UK cancer cases are colon cancer ?
13%
71
Roughly what % of all UK cancer deaths are colon cancer ?
10%
72
Roughly what % of colon cancer patients survive 10+ years since diagnosis ?
57%
73
Are there villi in the large intestine ?
No
74
Are there villi in the small intestine ?
yes
75
What is APC ?
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
How do Wnt, APC and β-catenin interact ?
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
Which cells in the intestinal crypt secrete the Wnt signals ?
Surrounding **stromal cells** at the base of the crypt
78
Where in the intestinal crypt do normal epithelial cells proliferate ?
**at the base of the crypt** near the stromal cells as they release the Wnt
*they migrate up from here*
79
Where in the intestinal crypt do epithelial cells proliferate if they have the APC mutation ?
**anywhere along the crypt** as they don’t rely on Wnt signals for proliferation
80
Roughly what % of colon cancers have an APC mutation ?
80-90%
81
What is the other most common mutation in colon cancers, besides APC mutations ?
β-catenin
*10-20% of colon cancers*
82
Roughly what % of colon cancers have a β-catenin mutation ?
10-20%
83
What does a β-catenin mutation cause ?
the **β-catenin doesn’t get degraded** like it would normally, so the cell is in **constant proliferation mode**
84
Are crypts deeper in the small or large intestine ?
large intestine
85
Where are paneth cells found ?
Base of the crypts in the small intestine
86
What do Paneth cells do ?
secrete defensins
87
What structures form the mid gut ?
- caecum
- ascending colon
- first 2/3 of transverse colon
88
What structures form the hind gut ?
- last 1/3 transverse colon
- descending colon
- sigmoid colon
- rectum
89
Which genes are found to be mutated in Lynch syndrome (HNPCC) ?
MSH2
MLH1
90
What is the normal function of the genes MHL1 and MSH2 ?
code for proteins that **repair faulty DNA**
*(block progression from normal cell to tumour cell = effectively **tumour suppressor genes**)*
91
How does a mutation of MSH2/MLH1 cause progression into cancer ?
Losing their function gives rise to **more frequent mutations/faults within cells during replication**, which accelerates mutations fo other oncogenes/TSGs
92
What are micro satellites ?
**regions of repeated DNA** that change in length (show instability) **when mismatch repair is not working properly**
93
What is mismatch repair ?
a process of recognising and repairing DNA mutations during cell replication
*MSH2, MLH1 code for the proteins that do this*
94
Which genes are involved in mismatch repair ?
MSH2
MLH1
*code for the proteins that do this*
95
What is micro satellite instability testing ?
**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
When did PCR amplification come about ?
1983
97
When was the first human genome sequenced ?
2003
98
What are the 3 subtypes of colon cancer ?
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
What % of colon cancers are
a) POLE ultra-mutated
b) MSI - hypermutated ?
c) non-hypermutated ?
POLE ultra-mutated = <1%
MSI - hypermutated = 9%
non-hypermutated = 90%
100
Which type of colon cancer (hypermutated/non-hypermutated) is more likely to benefit from immune checkpoint therapies ? Why ?
**hypermutated**
101
How do immune checkpoint therapies work ?
**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
What are the main ‘take homes’ to know about colon cancer ?
- **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
What is a liquid biopsy ?
A blood test looking for circulating tumour cells/markers/DNA/RNA
104
What are some pros of a liquid biopsy vs a regular biopsy ?
- less invasive
- cheaper
- allows for early detection of
- allows for early detection of predictive biomarkers
105
Why is it helpful to use liquid biopsies to detect predictive bio markers ?
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
What are organoids + how could they be used to help tackle cancers ?
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**
