Cancer 3 Flashcards
1
Q
Can Burkitt lymphoma be inherited?
A
No - sporadic mutation otherwise would not be compatible with life
2
Q
What is happening to MYC gene in Burkitt lymphoma?
A
overexpressed (w.t.)
3
Q
Original B cell that aquired translocation does what in burkitt lymphoma
A
overexpressed, rapidly prliferates
4
Q
What chromosomes have translocation for burkitt lymphoma
A
8 & 14
5
Q
MAR stands for
A
marker chromosome
6
Q
What cell type is burkitt lymphoma
A
B lymphocyte
7
Q
What are two types of burkitt lymphoma
A
african BL
non-endemic
8
Q
What type of burkitt lymphoma is usually found in US
A
Non-endemic
9
Q
30% of non-hodkins lymphoma in US is what
A
burkitt lymphoma
10
Q
How does african bl present
A
in mandible
11
Q
how does non-endemic lymphoma presntn
A
ileocaecal or peritoneal mass
12
Q
Where is translocation for follicular lymphoma
A
14 & 18
13
Q
What is overexpressed in follicular lymphoma
A
Bcl-2 (w.t.)
14
Q
What kind of protein is Bcl-2
A
anti-apoptotic protein
15
Q
What cells affected in follicular lymphoma
A
follicle center B cells
16
Q
CML stands for
A
chronic myelogenous leukemia
17
Q
chrom. most often associated with chronic myeloid leukemia?
A
9 & 22
18
Q
What is found on chromosome 9 affected on
A
ABL gene
19
Q
ABL
A
intracellular kinase involved in signaling pathways that stimulate cell proliferation
20
Q
On chrom 22?
A
BCR gene
21
Q
What is result of t(9;22)
A
BCR-ABL fusion protein - always on, constantly signaling for cell proliferation
22
Q
what is gene fusion product (philadelphia chromosome)
A
BCR-ABL
23
Q
chronic myeloid leukemia - where was translocation aquired
A
cell that aquired translocation is somehwere down lineage
24
Q
acute lymphoblastic leukemia - where was translocation aquired
A
cell down lympohid lieage aquired translocation
25
Describe the chronic phase of CML
intermediate phase, not as long survival
26
what does CML stand for
chronic myeloid leukemia
27
how long can pts be in chronic phase of CML
many years )3 or even 10-15
28
what stage is after chronic phase of CML?
blast phase/crisis
29
describe blast phase/crisis of CML
resembles acute, very very rapid progression. increased cytogenetic rearrangement (more chrom. abnormalities)
30
how do you treat for blast phase
try to get back to chronic phase, treatment usually unsuccessful
31
what drug has been very successful in treating CML
imatinib (generic)/Gleevec
32
any drug that ends in "inib" is what
small moelcule tyrosine kinase inhibitor
33
what does imatinib do
inhibits Bcr-abl tyrosin kinase domain
34
which cells express bcr-abl protein?
only the cancer cells. so only cancer cells are affected
| the other cells have w.t. abl and are not affected
35
why is there chance of relap for pts who have been cured by imatinib?
the cancer cells are constantly mutating - they could mutate so that the drug doesn't work anymore and they can become resistant to the drug
36
What is presentation of CML
anemia, massive splenomegaly
| bruising & bleeding (tiredness, decreased weight, fever, sweats)
37
anemia, massive splenomegaly
| bruising & bleeding (tiredness, decreased weight, fever, sweats) is what?
CML
38
what percentage of leukemia is CML
15%
39
how is fusino protein causing cancer
constituteive activation of tyrosine kinase that is driving excessive prlilferation
40
what does APL stand for
acute promyelcytic leukemia
41
wat type AML is APL
AML M3
42
where is translocation of APL
t(15;17)
43
what is fusion result of APL
PML-RARα
44
RARα
retinoac acid receptor alpha
45
RARα is normally involved in what
WBC differentiation
46
PML is normally
TF, blocks proliferation & induces apoptosis
| tumor supressor
47
when PML-RARα are fused together, fusion protein is
oncogenic
48
describe how PML-RARα is oncogenic
blocks differentiation needed for myeloid differentiation and promotes cell proliferation
49
Where is translocation in ewing sarcoma
t(11;22)
50
what genes fused in ewing
EWS-FLI1
51
FLI1 is what
TF
52
ewing sarcoma affects what ender more
males
53
what is age of onset for ewing sarcoma
10-20 years
54
what is presentation of ewing sarcoma
```
flat bones of pelvis
diaphyses of long tubular bones
(femur, tibia, humerus)
Pain & swelling over tumour
Fever, Weight loss
Anaemia, Fatigue
```
55
how many cases are metastatic at presentation in ewing sarcoma
30%
56
what 3 translocations is there production of fusion protein
CML
ewing saroma
acute promyelocytic leukemia
57
tnovel product of translocation results in what
promotes cell proliferation in same manner as an oncogene.
58
how can amplification activate an oncogene
gene becomes amplified in genome hundreds of times
| should only have 1!
59
N-MYC is amplified in what disease
neuroblastomas
60
N-MYC amplilfication is used as what
prognostic factor - determines how you'll treat
61
MYC is family of
TFs
62
MYC is found amplified in what
many cancers!
| she is using N-MYC neuroblastoma
63
N-MYC amplification results in
neuroendocrine tumour
64
N-MYC amplification is most common in
children
65
what is presentation of N-MYC/neuroblastoma?
50% <2yo
| Mass in adrenals, pelvis, neck, chest, abdomen
66
why would you not want to give child chemotherapy lightly
putting them at greater risk for future mutations due to chemicals
67
why is N-MYC helpful as diagnostic
shows child has poor diagnostic and might want to use more extreme measures
68
amplified N-myc gene sequence can be found where?
at original locus on chrom. 22 or on another chromosome that it inserted into
69
HSR stand for?
homogenous staining region
70
When there is amplified myc on chromosme what is it called
HSR
71
what are double minutes?
extra chromosome pieces full of Myc gene sequence. they are not actually in the chromosome
72
HSR
stain for MYC - can see pic on pg 92
73
if there is overexpression of MYC what protein will there be overexpression of
cyciln D
74
in order to lose tumor suppressor gene, have to lose
both alleles via loss of function
75
gatekeeper control what
control passage through cell cycle
| control checkpoint
76
caretakers job
repair DNA damage, take care of genome
77
explain knudson's 2 hit hypothesis
need 2 mutations. can see on pg 96
78
pts who have inherited cancer syndromes due to tumor supressor gene, what do they inherit
one loss of function mutation in tumor suppressor
79
in order for pts to develop cancer with a tumor supressor gene (if they have inherited one mutated tumor supresor gene)
need sporadic event so the other allele is mutated and loses function
80
hereditary retinoblastoma - how does pt develop cancer so easily
all their cells already have one "hit" so all it takes is another mutation in other allele, much more likely for them to have a hit on both and develop tumor
81
why is retinoblastoma childhood tumor
retinoblast are particuarilly susceptible b/c during early stage in childhood that they are replicating very rapidly, greater chance for mutations
82
inherited cases of tumor suppressor genes are inherited in what manner & why?
AD
| probability the cell will get second hit is very likely - they also usually have multiple tumors
83
in both inherited and sporadic cancer cases, the second hit is
somatic
84
mechanisms for losing tumor suppressor gene - list 6
nondisjunction - one chrom. lost
chromosome lost then the mutated chrom duplicated
mitotic recombination
gene conversion (just gene is replaced_
deletion - so hemizygous for mutated allele
point mutation
85
what does LOH stand for
loss of heterozygosity
86
what does LOH mean
refers to second hit, lose heterozygosity and cell becomes homozygous or hemizygous (loss of w.t.) for mutated allele
87
epigentic cases of 2nd hit, explain
tumor suppressor gene doesn't have a problem it is w.t.
so it's normal but it is silenced b/c it is packaged into heterochromatin
hypermethylation of promoter region
changes in miRNA expression
88
what are the three ways epigenetics can silence tumor supressor
heterochromatin
hypermethylation
miRNA expression (downregulation)
89
miRNA - what are they complementary to?
complementary sequences to messenger RNA
90
miRNA - what can it be used for regarding epigenetics?
another way of controllingn gene transcription
91
miRNA - explain how they work
bind to target, associated with protein complex. binding of miRNA to messenger RNA results in degradation of messenger RNA
92
miRNA - what do they regulate?
they downregulate expression of messenger RNA
93
in cancer what happens with miRNA
overexpression of miRNA that target tumor supressor gene
94
oncomere
oncogenic change of overexpression of miRNA that downregulates expression of tumor supressor genes
miRNA that target tumor supressor gene
95
explain how miRNA is increased/decreased in cancer
increase in miRNA that target tumor supressor
| decrease in miRNA that target oncogenes
96
what does TSG stand for
tumor suppressor gene
97
in glioblastoma how much is miRNA expressed
100x expression
98
what is glioblastoma
most common and very aggressive brain tumor
99
Progressive memory, personality, or neurological deficit (temporal & frontal lobe involvement)
Seizure, Headache, nausea & vomiting, hemiparesis
are symptoms of what
glioblastoma
100
What is treatment for glioblastoma?
palliative
101
when you talk about AR and AD in inherited cancer genetics what does it mean
how it shows up in pedigree
102
multiple tumors
bilateral
early onset
is what?
mendialian inheritance of mutation in cancer - germinline mutation
103
in all AD inherited cancer pts, the pt inherits what
inherits one loss of function mutation
104
List AD inherited cancer syndromes
```
Retinoblastoma
Li-Fraumeni syndrome
Neurofibromatosis type 1
Hereditary breast cancer
Familial polyposis coli (FAP)
Hereditary non polyposis colon carcinoma (HNPCC)
```
105
retinoblastoma is what
rare malignant tumor of retina
106
how much of retinoblastoma are inherited
40%
107
what does it mean that 40% of retinoblastoma is niherited
1 inherited mutation
| 1 sporadic mutation
108
how is retinoblastoma inherited
AD
109
what percentage of retinoblastoma is sporadic
60%
110
if you know pt has on ehit, carries Rb1 mutation, what must happen
watch very closely for tumors
111
when do sporadic vs. inherited retinoblastoma cases occur
sporadic later in childhood. don't need to follow up as often as inherited
112
infants that survive hereditary retinoblastoma have how much of a risk to develop other cancer
400x
| even higher if they were exposed to readiotherapy to treat retinoblastoma
113
draw out pathway that starts with external signal → RAS
pg 108
114
in retinoblastoma, what happens to the signaling pathway that checkpoints G1 to S
there is no Rb so the tumor expressor is not expressed at all, so E2F is always on and constantly stimulates cell proliferation
115
Draw out Rb in resting and proliferating cell
pg 108
116
where is mutation in Li-Fraumeni syndrome
p53 mutation ( 1 allele)
117
how is Li-Fraumeni inherited
AD
118
pts are at risk for developing what cancer in Li-Fraumeni
many cancer
| bone, soft tissue sarcomas, breast cancer, brain tumor, leukemia
119
are sarcomas rare?
yes
| in Li-Fraumeni it is likely to occur
120
what dictates what type of cancer pts with Li-Fraumeni will have
where second hit occurs
121
p53 is most commonly
mutated gene in cancer
122
what is p53
tumor supressor
123
what are 3 important functions of p53
stop cell cycle
repair of genome
kill cell (trigger apoptosis) if DNA damage can't be repaired
124
What is p53
TF
125
do cells always express p53?
yes - it is always being made
126
what happens to p53 if it is not needed
degraded by MDM2
127
if there is DNA damage, what happens to p53
phosphorylated by kinases
128
what is p53's first target
p21 (it transcrives it
129
what does p21 do
block cyclin complexes (any cyclin/CDk complexes in cell cycle)
130
if DNA damage isn't repaired, what does p53 do
levels accumulate, when there are high levels of p53 it transcribes pro-apoptotic genes and cell will die by apoptosis
131
senescence
telomeric repeats determine how much cell can replicate. once they reach threshold they can't replicate again
132
p53 and senescence
detects short telomeres and blocks it from going into cell cycle
133
what doe NF1 stand for
Neurofibromatosis type I
134
what is inheritance of Neurofibromatosis type I
AD
135
what is penetrance of Neurofibromatosis type I
100%
| all pts present with symptoms - signs of condition including benign tumors
136
by what age will pts show symptoms of Neurofibromatosis type I
5
137
what are symptosm of Neurofibromatosis type I
Cutaneous pigmentation
Café au lait spots (nearly all cases)
Freckles (90%)
Lisch nodules (pigmented iris nodules; hamartomas): nearly all cases
Multiple benign neurofibromas (schwaan cell tumours; PNS)
138
What are example gatekeepers
p53
Rb
Nf1
139
What are examples of caretakers
BRCA1
| BRCA2
