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Semester 4 > case 4 - bowel cancer > Flashcards

case 4 - bowel cancer Flashcards

1
Q

what is the majority of CRCs

A

sporadic

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2
Q

what percentage of bowel cancers are FAP

A

1%

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3
Q

what surface of the colon do the polyps line

A

the lumen surface of the colon

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4
Q

what is HNPCC

A

hereditary non-polyposis colon cancer

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5
Q

what is HNPCC

A

hereditary non-polyposis colon cancer

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6
Q

what percentage of CRCs are HNPCCs

A

2-3%

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7
Q

what is Lynch Syndrome

A

when you are predisposed to other cancers

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8
Q

what do these other cancers include

A

ovary, small intestine, urinary tract, skin and brain cancer

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9
Q

what is the difference between FAP and HNPCC

A

there are very few polyps in HNPCC but the progression is fast, 2-3 years instead of the 8-10 years in FAP

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10
Q

what are FAP and HNPCC

A

both familial forms of cancer

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11
Q

what are the hallmarks of cancer

A

evading apoptosis
self sufficiency in growth signals
insensitvity to anti growth signals
sustained angiogenesis
tissue invasion and metastasis
avoiding immune destruction
genomic instability

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12
Q

what is the implication gene type for oncogenesis and TSG

A

diploid

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13
Q

is is stage G1 in the cell cycle

A

cell is born and each chromosome is a single chromatid

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14
Q

what is the S phase of the cell cylce

A

synthesis - DNA replication (replicate the chromosomes)

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15
Q

what happens when the S phase is over

A

each chromosome is represented by two sister chromatids

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16
Q

what happens after S phase

A

G2

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17
Q

what happens after G2

A

mitosis

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18
Q

what happens during mitosis

A

division: chromatids get pulled apart in opposite directions, mean that each new cell inherits one copy of each chromosome in them. once they go back to G1, each cell yet again is represented by one chrmoatid

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19
Q

what are the steps from gene to tissue

A
  1. genome
  2. transcriptome
  3. proteome - via process of translation
  4. cell function - biogenesis and metabolism
  5. tissue architecture - proliferation
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20
Q

what happens if there is mutations in these genes

A

we have changes and this affects cell function and proliferation

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21
Q

what turns into malignancy

A

hyperplasia

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22
Q

what are most tumours made up fo

A

lots of different clones - tumour heterogeneity

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23
Q

what does multi step tumorgenesis involve

A

clonal expansion

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24
Q

what are oncogenes encoded by

A

viruses that can cause cancer e.g SV40 virus

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25
Q

what happens when viral genes are introduced into cells

A

they have a dominant transformative effect e.g Src, Ras, Myc

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26
Q

what is the case of oncogenes

A

it is sufficient to only have one copy of a mutated gene to cause cancer

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27
Q

what are examples of single activating mutations

A

B catenin and KRAS

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28
Q

what are tumour suppressor genes linked with

A

retinoblastoma and Knudson’s two hit hypothesis

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29
Q

what is retinoblastoma

A

a type of cancer that affects children and either comes in a familial or sporadic form

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30
Q

what did Knudson notice

A

that individuals with familial disease had eye tumours bilaterally and were more likely to have other tumours

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31
Q

what is retinoblastoma caused by

A

a mutation on gene 13 (Rb)

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32
Q

what happens with indiviudals with familial retinoblastoma

A

all inherent one mutant copy of this gene
This mutation is recessive but if one cell requires a second copy, Rb function is lost and this not only predisposes them to bilateral eye cancer, but to other cancers as well

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33
Q

what type of gene is Rb

A

a tumour supressor gene

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34
Q

what has to happen in sporadic Rb disease

A

you must first pick up a mutant Rb allelle and then you need a second mutant copy- much more rare event and wont get other cacers

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35
Q

what is the basis of Knudson’s theory

A

in familial disease, only one random hit is required but in sporadic disease, two hits are required

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36
Q

what do the signalling pathways include;

A
  1. ligands
  2. receptors
  3. signalling cascade
  4. transcription factors
  5. alters cellular function and gene expression
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37
Q

what are the different types of cell biological processes

A

growth factor receptors and hormone receptors
Receptor tyrosine kinase
G-protein coupled receptors
Phosphatase
GTpase switches e.g Ras
Cytoplasmic -nucelar shuttling
Serine/threonine phosphorylation cascades
All the elements of transcriptional control
Micro RNAs
Translational control
Sumolyation
(Don’t need to know just be aware)

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38
Q

what is RAS

A

a switch

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39
Q

what does ras bind to

A

GTP

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40
Q

what does RAS do to GTP

A

Ras has GTPase activity, it can hydrolyse GTP

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41
Q

what does it hydrolyse GTP to

A

GDP

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42
Q

what does this release

A

an organic phosphate

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43
Q

what happens when ras is bound to GTP

A

it adopts an active conformation and stimulates downstream pathways

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44
Q

what does ras’s own GTPase activity turn it into

A

GDP/RAS complex which is inactive

the GDP is then exchanged for a fresh molecule of GTP

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45
Q

what happens when these downstream RAS pathways are active

A

leads to stimulation of cell proliferation and protein synthesis

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46
Q

what happens if there is a single mutation in RASS

A

locks it in the active form which means these downstream signals continually on, even in the absence of upstream signals. so when RAS is locked on, proliferation is stimulation

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47
Q

how many copies of Ras need to be mutated

A

only one copy of the RAS gene

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48
Q

what is Wnt

A

a secreted factor that promotes proliferation by binding to its receptor

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49
Q

what is the Wnt complex made up of

A

active GSK-3 beta, APC, beta catennin

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50
Q

what happens when this Wnt complex is activated

A

GSK3 beta phosphorylates beta catenin and leads to degradation.

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51
Q

what happens when Wnt is bound to this complex

A

it disrupts this complex, now GSK-3 beta is iz inactive and beta catenin doesnt get degraded and beta catenin builds up in the cell

moves into the nucleus and drive the processes for cell proliferation

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52
Q

what is beta catenin

A

an oncogene

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53
Q

what is APC

A

a tumour supressor gene

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54
Q

what are the target genes

A

cyclin D and myc

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55
Q

when is entry into the cell cycle regulated

A

G1

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56
Q

what happens during this period

A

cells are responsive to mitogenic GFs and to TGF beta

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57
Q

what happens once it passes the R point in G1

A

it is now committed to compete the entire process of the cell cycle

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58
Q

what happens if you withdraw stimulatory processes beyond R

A

the cell cycle will still complete

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59
Q

what do CDK4 and 6 bind to

A

cyclin D

60
Q

what does this complex activate

A

the cell to drive it through G1

61
Q

what is the CDK2 complex bound to

A

cyclin E

62
Q

what does CDK2/cyclin E complex trigger

A

entry into the S phase

63
Q

what does CDK2 also bind to

A

cyclin A

64
Q

what does this complex do

A

drives the cell through the S phase

65
Q

what does CDK1 bind to

A

cyclin B

66
Q

what does this CDK1 cyclin B complex drive

A

cell into mitosis

67
Q

what happens to the levels of cyclin and the levels of CDK

A

the levels of cyclin moves up and down but the CDK levels stay relatively the same

68
Q

what is the rise and fall of cyclin crucial to

A

the regulation of the cell cycle

69
Q

what inhibits the cyclin-CDK complex

A

CKIs

70
Q

what blocks the activity of multiple CDKs

A

p21

71
Q

what do growth factors signal

A

RAS, which along with Wnt signals, signals beta catenin

72
Q

what does RAS signal

A

fos/jun

73
Q

what does the beta-catenin signal

A

tcf/lef

74
Q

what do both ras and wnt signal

A

signal cyclin d1

75
Q

what happens once cyclin D is synthesised

A

it binds to CDK4, which forms an active protein kinase complex

76
Q

what can this active protein kinase complex phosphorylate

A

a protein called Rb

77
Q

what happens when rb gets phosphorylated

A

it lets go of its binding partner E2F

78
Q

what is E2F and what happens once it is liberated

A

it is a transcription factor and once liberated, it can go onto stimulate the expression of genes like the cyclin E gene

79
Q

what does this expression of cyclin E lead to

A

the cyclin E- CDK2 complex

80
Q

what can this complex go on to do

A

phosphorylate Rb which leads to positive feedback cycle

81
Q

what can this cyclin E -CDK2 complex also do

A

phosphorylates origins of replication to trigger S phase

82
Q

what is Rb in the cell cycle

A

a break, and if you remove this break then you have uncontrolled replication in the cell cycle (tumour supressor)

83
Q

what happens once the second copy of Rb is hit

A

the break is lost

84
Q

what is the most important cell cycle checkpoint

A

p53

85
Q

what is p53

A

a transcription factor
it is normally degraded

86
Q

what is p53 activated by

A

‘stabilisation’

87
Q

what are the ligases

A

kinases and ubiquitin ligases

88
Q

what happens once p53 is activated and stabilised

A

it can lead to
- cell cycle arrest
- DNA repair
- block of angiogenesis
- apoptosis

OR

  • senescence
  • return to proliferation
89
Q

what is a very important target of p53

A

the p21 gene which is a cyclin dependent kinase inhibitor which can block the activity of multiple CDKs

90
Q

what does p21 do

A

puts a block on the cell cycle, giving it enough time to repair and then the cell cycle continues

91
Q

what happens if the damage is too bad to be repaired

A

p53 leads to apoptosis, and stimulates the expression of Bax etc, which induces cell death

92
Q

what is the guardian of the genome

A

p53

93
Q

what is the genome being continuously damaged by

A

xoxidation
Replication errors
UV
X-rays
Chemicals
Mitosis

94
Q

what continuously repairs the genome

A

BER
NER
Proof reading
NHEJ
HR
Checkpoints

95
Q

what is the very important repair mechanism on the context of colon repair

A

the mismatch repair and HNPCC

96
Q

how many cases of bowel cancer are there a year

A

40,000

97
Q

what percentage of people will be alive after their initial diagnosis ten years on

A

57%

98
Q

what is the abnormal cell growths:

A

Hyper proliferation
Adenomatous polyps (small)
Adenomatous polyps (large)
Severe dysplasia (precancerous polyp)
Adenocarcinoma - malignant
Invasive cancer - malignant

99
Q

what are the colonic crypts

A

invaginations where the epithelial sheet has folded back upon itself multiple times

there is an intricate substructure to this structure

100
Q

what kind of cells are there between the Paneth cells in these crypts

A

rapidly dividing stem cells

101
Q

what do these stem cells produce

A

produce two daughter cells one stays behind to maintain the stem cell compartment and the other migrates up and out and eventually is shed off at the top of the lumen

102
Q

what is the most important feature of the tissue

A

it is highly proliferative, and maintained by balancing loss at the top with growth at the bottom

103
Q

what protein do all these stem cells express at the base of the crypts

A

Lgr5+

104
Q

what is the gene that is responsible for FAP

A

5q21

105
Q

what does APC stand for

A

adenomatous polyposis coli and this is the name of 5q21

106
Q

in what percentage of sporadic CRCs is APC mutated in

A

80-90%

107
Q

what type of gene is APC

A

tumour suppressor gene

108
Q

what happens to individuals with the disease

A

they inherit one mutated copy and then the second allele undergoes LOH,

108
Q

what happens to individuals with the disease

A

they inherit one mutated copy and then the second allele undergoes LOH, APC protein function is lost and tumour suppressor function is lost and then will lead to cancer

109
Q

what happens when Wnt is not bound to its receptor

A

the APC complex is attacked and beta catenin is targeted for degradation

110
Q

what happens when Wnt signals bind to their receptors

A

beta-catenin no longer gets phosphorylated and no longer gets degraded, it moves into the nucleus and up regulates cyclin D - proliferation

111
Q

what cells secrete the Wnt signals

A

the surrounding stromal cells

112
Q

what do the Wnt signals engage with

A

the stem cells

113
Q

when is proliferation stimulated

A

when beta catenin is switched on

114
Q

what happens when beta catenin is switched on

A

the cells then migrate up and out of the crypt and because they are still in close proximity to the Wnt signals they keep on proliferating

115
Q

what happens when they are too far up and far away from the Wnt signals

A

beta catenin is switched off and gets degraded. the cells stop dividing and disappear out of the top

116
Q

what happens once the cell loses APC function

A

it is no longer reliant on Wnt signals for proliferation.

117
Q

what does this mean

A

it means that as it migrates up, it can still proliferate, even in the absence of the Wnt signals. so now the APC mutants move up beyond the zone of Wnt signalling, they just dont care

118
Q

what stays on even if there are no Wnt signals and explain how the hyperproliferative zone comes to be

A

beta catenin - the cells dont differentiate, they keep on proliferating and they dont finish migrating, forming a hyperproliferative zone of cells when normally no division would take place

119
Q

where do normal epithelial cells proliferate

A

only proliferate at the bottom when they are close to the secreted Wnt signals.

120
Q

what is the difference to this in APC mutants

A

B-catenin is stabilised even in the absence of Wnt signals, cyclin D is synthesised, driving proliferation even when the cells have migrated beyond the normal proliferative zone

121
Q

how many CRCs have beta catenin mutations

A

10-20%

122
Q

what kind of mutation is a beta catenin mutation

A

single point mutation that stops it being phsophorylated - stops it being degraded.

123
Q

what is an obligate step in colon cancer

A

deregulation of the Wnt pathway

124
Q

where is the HNPCC gene found

A

found on chromosome 2p

125
Q

what is the mismatch repair

A

error in newly made strand
binding of mismatch proofreading proteins
DNA scanning detects nick in new DNA strand
strand is removed
repair DNA synthesis

126
Q

what is silenced by methylation in around 15% of sporadic CRCs

A

MLH1 promotor is silenced

127
Q

what is the mutator phenotype of mismatch repair

A

mutation of MHL1 does not cause cancer.

but rather, by losing MSH2, or MLH1 function, the mutation rate goes up and that accelerates the accumulation in traditional tumour suppressor and oncogenes

128
Q

what is mutated in about 90% of mismatch repair CRCs

A

the TGF beta receptor is mutated

129
Q

what can we see when we sequence genes

A

whole genome - CNV
Exome - mutations
Promoter methylation
RNA - global gene expression profiling
Proteomics (protein level) - net effect of how mutations and changes in gene expression manifest

130
Q

what are the hyper mutated colon cancers

A

the mismatch repair colon cancers

80% dont have mismatch repair defectd

131
Q

what do the hyper mutated tend to be

A

diploid i.e the CNV is low

132
Q

what do the non hypermutated tend to exhibit

A

CIN and therefore are aneuploid i.e the CNV is high

133
Q

what are the specific mutations

A

APC, p53, and K-ras

134
Q

what is the novel b catenin mutation

A

29 cases
deletions
spanning exon 3

135
Q

what is the novel APC mutations

A

35 cases
upstream of exon 9
slicing defect
protein truncation

136
Q

where are mutant proteins expressed

A

on the cell surface

137
Q

what are these mutant proteins recognised by

A

T cells

138
Q

what do tumour cells also express

A

PD-L1 which suppresses T cells

139
Q

what can antibodies do

A

block the PD-1 interaction

140
Q

what does this reuslt in

A

some cancers will benefit greatly from antibody therapies and given immune checkpoint inhibitors to resolve this inteaction

141
Q

what is the antibody which blocks PD1

A

Pembrolizumbab

142
Q

what are the 3 mutation subtypes

A

POLE ultra mutated <1%

MSI - hyper mutated due to micro satellite instability - 9% (mis match repair defect)

MSS - micro satellite stable - 90% (but high CNV due to CIN)

143
Q

what kind of target is the Wnt pathway

A

an obligate and early target, either via APC or beta catenin

144
Q

what tumours are prioritised for immune checkpoint therapy

A

MSI tumours

145
Q

what are liquid biopsies

A

tumours shed cells and DNA into the blood
Minimally invasive and relative inexpensive biopsy
Advances in detection technology e.g NGS, mass spec

146
Q

what are the benefits of liquid biopsies

A

early detection
Predictive biomarkers
Monitor response to therapy

Semester 4 (80 decks)

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