Cancer 4 Flashcards
1
Q
What is unique about Nf1
A
there is complete penetrance - they will always present with some signs of disease
2
Q
What does Nf1 stand for
A
neurofibromin
3
Q
What mutation causes NF1
A
loss of function in neurofibromin
4
Q
what does neurofibromin code
A
RasGAP
5
Q
in NF1, describe how disease/cancer is caused
A
pt inherits loss of function mutation in nf1 - if second hit, no RasGAP present, so when Ras is activated there will be prolonged activation b/c nothing will hydrolyze it back to GDP
6
Q
What genes are involved in hereditary breast cancer
A
BRCA1 & BRCA2
7
Q
what is MOI of BRCA1 and BRCA2
A
AD
8
Q
hereditary breast cancer syndrome for breast cancer accoutn for what percent of csaes
A
5%
9
Q
if it is AD breast cancer what will you see
A
earlier age of onset
Multiple & bilateral disease
Multiple affected family members
Other cancers; ovarian, prostate
10
Q
males who inherit BRCA2 or BRCA1 are at risk for what cancer
A
male breast cancer (BRCA2)
prostate
11
Q
females who inherit BRCA2 or BRCA1 are at risk for what cancer
A
breast
ovarian
12
Q
BRCA genes are involved in what pathway
A
DNA repair pathways
13
Q
describe BRCA role in DNA repair
A
can repair double and single stranded DNA breaks
14
Q
what is MOI of hereditary colorectal cancer
A
AD
15
Q
what percent of cancer is colorectal cancer
A
15% of all cases (in USA)
16
Q
what are two types of hereditary colorectal cancer
A
Familial polyposis coli / Familial adenomatous polyposis (FAP
Hereditary non-polyposis colon carcinoma
17
Q
what mutation causes FAP
A
APC
18
Q
what do mutations inherit in FAP
A
one mutation in APC
19
Q
What does FAP stand for
A
Familial adenomatous polyposis (FAP
20
Q
what are most common mutations for Hereditary non-polyposis colon carcinoma
A
MLH1 & MSH2
21
Q
what is function of MLH1 & MSH2
A
DNA mismatch repair enzyme
22
Q
where are all possible mutations for Hereditary non-polyposis colon carcinoma
A
Mutation MLH1, MLH3, MSH2, MSH6, PMS1, PMS2
23
Q
how does cancer occur in FAP
A
second hit occurs - the cells only have on APC, wherever they get second hit cancer will develop
24
Q
loss of APC means what has happened
A
second hit
25
loss of APC results in what
growth of tumor
26
draw out the stages in evolution of cancer, specifically for colon cancer
pg 121
27
loss of any gene in cancer suggest it is what
tumor suppressor
28
gain of function in any gene in cancer suggests it is what
oncogene
29
what is commonly activated in colorectal cancer
Ras
30
what does DCC stand for
Deleted in colorectal cancer
31
FAP is caused by what
loss of funtion mutation in APC
32
majority of sporadic colorectal cancer is usually caused by what
loss of function mutation in APC
33
Describe role of beta-catenin and APC
Catenin’s link up to cytoskeleton. Catenin involved in cell-cell junctions
If beta catenin is no longer involved in cell-cell junction and it is free in cytoplasm, it can translocate into nucleus and activate TF to transcribe MYC – MYC will transcribe Cyclin D → cell proliferation
APC phosphorylates free beta catenin, when it is phorphorylated targetd for poly-ubiquination and degradation.
34
draw out APC and beta catenin
pg 123
35
what is role of beta catenin
adapter protein - cell adhesion
| can go into nucleus and stimulate transcription of genes
36
Wnt pathway occurs where
occurs at bottom of crypts of colorectum
37
what does Wnt pathway normally do
normally inhibits APC
38
draw out Wnt pathway
pg 125
39
what does Wnt activate
frizzled
40
what does frizzled activate
dishevelled
41
when beta catenin goes ito nucleus it transcribes what
MYC (and therefore cyclin D)
42
proliferation of cells at bottom of crypt is normal or abnormal
normal
| the stromal cells at bottom secrete Wnt
43
in colorectal cancer what happens regarding crypt
| how is this different from what normally happens
the cells migrate up crypt and continue proliferating at top of crypt and tumors will form.
(normally the cells differentiate as they go up the crypt and they stop proliferating. there is Wnt signaling at bottom of crypt therefore inactive APC at bottom of crypt)
44
in 90% of sporadic colorectal cancer where is mutation
APC → accumulation of beta-catenin
45
heterozygous FAP mean what
pts have FAP -
46
at what age should heterozygous FAP undergo routine colonoscopies
15
47
what is total colectomy
entire colorectum is removed
48
HNPCC stands for what
Hereditary non-polyposis colon carcinoma
49
Hereditary non-polyposis colon carcinoma is also known as what
Lynch syndrome
50
males who inherit HNPCC have what risk of colorectal cancer
90%
51
females who inherit HNPCC have what risk of colorectal cancer
70%
52
What is function of MLH1, MLH3, MSH2, MSH6, PMS1, PMS2
DNA repair
53
microsatellite instablitiy
repeats change length as cells go through division
54
what is result of loss of function of DNA repair
lots of replication errors, microsatellites and microsattelite repeats
replication slippage
55
a result of homozygous cells (loss of both allels for DNA repair) results in what
accumulation of point mutations
| replication slippage
56
replication slippage
when it is replicated won't be replicated exactly
57
when gel has more than one band, what does it indicate
slippage
it means as cell replicates the daughter cells will have different size allele (so each individual cell has two alleles) and that continues. THe PCR reaction extracts from a few cells, so a bunch of different sized alleles who up.
58
What does RER + stand for
replication error positive phenotype
59
what does RER+ mean
microsattellite instability
60
why is there slippage
the cell had a second hit, so DNA mismatch repair enzyme has been lost, causes microsattelite instability
61
what is the initial event that causes HNPCC
loss of function of DNA mismatch repair due to second hit
62
p15 and p16 are what
INKs (inhibitor of kinase)
| inhibit CDK4
63
why is there loss of function of TGFBR2 in HNPCC
within coding sequence, it has 10 adenines - slippage likely, if there is slippage will cause deletion which causes frameshift and loss of fuction
64
loss of function of TGF beta receptor
not cause of colorectal cancer
65
what is initiation of cancer of HNPCC
loss of function of DNA repair enzyme
66
Draw out TGFBR2 pathway
pg 138
67
Change in bowel habits; frequency , consistency, bleeding, mucus
Feeling of incomplete defecation (tenesmus), reduction in diameter of stool (rectal ca.)
Melena (upper GI ca.)
Bowel obstruction causing pain, bloating & vomiting of stool-like material.
A tumour in the abdomen, felt by patients or their doctors
smptoms of what
colon cancer
68
almost complete obstruction of bowel what will happen
vomitting of stool like material
69
if colorectal cancer causes invasion of bladder what will happen
haematuria (blood)
70
colorectal cancer invades vagina what symptom
causing pungeant vaginal discharge.
| = late events & large tumour
71
symptoms of liver metastases
Jaundice
Pain in the abdomen, usually epigastric
hepatomegaly
72
constitutional (systemic symptoms) of colorectal cancer
Unexplained weight loss, (most common symptom, caused lack of appetite)
Anemia, fatigue, palpitations
Clinically, pallor and blood tests will confirm the low Hb level.
73
what vaccine has been developed against colon cancer
TroVax
74
what is common therapy of colon cancer
surgical removal of part with cancer followed by chemotherapy
75
what does TroVax do?
causes tumor associated antigen
| boosts immune system to attack the tumor associated antigens
76
loss of what is found in many cancers
p53
77
loss of what is frequently found in sporadic cancers
Rb
78
draw out external signal to RAS/MYC pathway
pg 145
79
how can one have loss of Rb
Mutation / LOH / down-regulation by ↑miRNA (mi-R106a)
80
Are BRCA1 and BRCA2 involed in sporadic breast cancer? explain
No
| it is unusual, usually the hereditary gene is also involved in sporadic cancer
81
describe CGH and cancer
stain chromosomes
extract DNA from tumor cells and label DNA with green fleurocohrome. Label DNA from normal cells with red. take equal amounts and hybridize them onto metaphase spread. where it shows green it means it is amplified
red = more normal DNA than tumor so it is deleted.
yellow = equal amounts
82
in majority of cases in sporadic colorectal cancer mutation where
APC
83
if sporadic colorectal cancer doesn't have APC mutation, where is mutation
beta catenin
84
SMAD4 loss of function in colorectal and also what other cancer
pancreatic
85
what is PTEN
tumor suppressor gene - it's phosphatase that normally removes one of the phosphates from PIP3 reverting it back to PIP2 - it prevents activation of PKB
86
PTEN prevents
activation of PKB
87
Lose PTEN in cancer what happens
lose ability to block pathway - so the pathway is overactive in cancer cells
88
Draw PTEN pathway
151
89
WT-1 is normally involved in what
regulates mesenchymal to epithelial transition - involved in renal differentiation
when there is wound epithelial cells look like mesenchymal - after it is healed supposed to go back to epithelial. in cancer it doesn't go back
90
loss of WT-1 results in what cancer
wilms tumor
91
chromosome instability syndromes describe
not hereditary cancer syndromes
risk of developing cancer
AR conditions - very rare
92
xeroderma pigmentosum where is mtuation
in nucleotide excision repair - gene does not work correctly.
93
if pt is exposed to UV radiation with xeroderma pigmentosum
thymine dimers
| thymine dimers can't be repaired
94
NER stands for what
nucleotide excision repari
95
in order for pts to present XP they have to inherit
bad copy from both parents
96
treatment of XP
reduced exposure
97
what are symptoms of XP
Severe sunburn & blistering following sun exposure
| Thin & dry skin, early development of freckles
98
Ataxia Telangiectasia - what does this word mean
loss of balance and dilation of blood vessels
99
what gene mutated in ataxia telangiectasia
ATM
100
what does ATM stand for
ataxia telangiectasia, mutated)
101
what does ATM do
kinase that can phosphorylated p53 (this stabilizes it)
| it responds to damage
102
what happens to Wnt signaling at top of crypt in colon
there isn't Wnt signaling
103
Wnt signaling pathway normally:
inhibits APC complex, allowing beta catenin to stimulate proliferation (at bottom of crypt)
104
in 10% of sporadic colorectal cancer, where is mutation
APC tumor suppressor is w.t. but is hypermethylated (epigenetics! so still loss of function)
or
point mutation in beta catenin
105
replication splippage leads to what
microsattelite instability
106
In 12% of sporadic colorectal cancer there is loss of which mismatch repair genes?
MLH1, MSH2
107
In 70% oof sporadic colorectal cancer there is a loss of expression of what
DCC
108
In 15% of sporadic colorectal cancer there is loss of what
SMAD4
109
What does SMAD4 signal?
downstream TGFBR2 growth inhibitory pathway
110
Draw out TGF/SMAD pathway
pg 150
111
loss of heterozygosity = (what should I htink of it as)
second hit
| losing w.t. gene
