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MOD Midterm > Neoplasia: Molecular Basis of Cancer > Flashcards

Neoplasia: Molecular Basis of Cancer Flashcards

1
Q

To go from a normal cell to cancer cell, we need to create a clone; what is the first thing we are going to do in order to do this?

A

we create a mutation that is divergent enough from the normal cell to be promoting cancer, but not too divergent that it kills the cell

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2
Q

after the initiating mutation, what happens next to make cancer?

A

you add on additional driver mutations

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3
Q

What are the four general types of gene classes that are responsible for oncogenesis?

A

proto-oncogenes, tumor-suppressor genes, apoptosis-regulating genes, DNA repair genes

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4
Q

What are germline mutations?

A

heritable; early mutations present as the gametes are providing the genetic material for an embryo to form; all cells in offspring carry 1 mutated allele

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5
Q

What are somatic mutations?

A

non-heritable; involve an original combination of chromosomes that have no mutation whatsoever; mutation only in cells of affected area

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6
Q

How do we make cancer from proto-oncogenes?

A

they gain function and become oncogenes

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7
Q

how do we make cancer from tumor-suppressor genes?

A

they lose function (so there is no tumor suppression)

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8
Q

how do we make cancer from apoptosis-regulating genes?

A

suppress apoptosis/cell death

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9
Q

how do we make cancer from DNA repair genes?

A

they lose function (so if there is DNA damage, they can no longer repair it)

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10
Q

What is the difference between driver vs. passenger mutations?

A

driver mutations are causal; passenger mutations contribute to cancer growth, but does not establish cancer

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11
Q

What is the genetic evolution of cancer?

A

the first mutation allows it to become a malignant clone, but even more mutations can evolve and there can be quite a heterogenous cell population

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12
Q

what are oncogenes?

A

mutated genes that result in excessive cell growth

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13
Q

what are oncoproteins?

A

the result of the genetic mutation

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14
Q

What is the mode of activation in the proto-oncogene PDGFB? and what occurs when this happens?

A

overexpression; astrocytoma

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15
Q

What is the mode of activation for the proto-oncogene ERBB1 (EGFR)? and what occurs when this happens?

A

mutation; adenocarcinoma of the lung

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16
Q

what is the mode of activation for the proto-oncogene ERBB2 (HER)? and what occurs when this happens?

A

Amplification; breast carcinoma

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17
Q

what is the mode of activation for the proto-oncogene KRAS? and what occurs when this happens?

A

point mutation; colon, lung, and pancreatic tumors

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18
Q

What is the mode of activation for the proto-oncogene MYC? and what occurs when this happens?

A

Translocation; Burkitt lymphoma

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19
Q

what is the mode of activation for the proto-oncogene NMYC? and what occurs when this happens?

A

Amplification; Neuroblastoma

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20
Q

What could be the functional product of an activated proto-oncogene (mutated)?

A

abnormal protein, excessive amount of protein, novel protein,

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21
Q

What happens when there is an amplification of growth factor/ growth factor receptor? and what is a common example of this?

A

Her-2/neu (aka ERBB2); this amplification results in too many proteins being expressed

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22
Q

Too much Her2 generates what?

A

too many protein receptors, which signals for cancer cells to divide and multiply

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23
Q

How can we treat amplification of growth factor/growth factor receptor (e.g. Her-2)?

A

we can treat with a receptor antibody called Herceptin

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24
Q

What happens when there are point mutations of KRAS?

A

the system is chronically and dramatically on for the downstream signaling (theres too much downstream signaling)

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25
In a normal state, what is the favored state of RAS?
it tends to be in the inactivated GDP bound state; will be activated in a pulsatile manner- will be activated when it is supposed to be and then turn off again when it is not being used
26
what happens in the mutated RAS associated with cancer?
it defaults to the GTP-bound state- there is activation of the downstream signaling; RAS mutations can cause it to be "stuck" in the GTP-bound state
27
Mutations of RAS that contribute to oncogenesis bind it in a _____________?
constitutively active state (constantly active)
28
What is a characteristic feature of the mutations that occur in RAS?
they contribute to oncogenesis by binding it in a constitutively active state
29
what is PTEN?
a negative regulator of cell signaling- so if cancer wants to have uncontrolled cell growth, it needs to down regulate PTEN
30
What mutation is given to PTEN to allow cancer?
a loss of function mutation - so it can no longer provide its normal inhibitory function
31
What cancer is strongly associated with initiating mutations causing loss of function of PTEN?
endometrial carcinoma
32
What is BCR-ABL and how is it formed?
a hybrid gene; ABL comes from chromosome 9 and joins BCR from chromosome 22
33
what happens when BCR-ABL is formed?
there is now a tyrosine kinase that is now going to be extremely active inside the cell (its a non-receptor tyrosine kinase)
34
what happens when the non-receptor tyrosine kinase is upregulated?
it is directly feeding into the signaling pathways creating cellular proliferation
35
What is BCR-ABL known as and what is it associated it?
the philadelphia chromosome; commonly associated with CML
36
What does oncogene addiction mean?
when tumor genesis is extremely dependent on a particular oncoprotein (e.g. BCR-ABL)
37
Why is knowing particular oncogene addictions important?
for treatment- if you are dependent on this mechanism, it is a target for therapy for cancer
38
What is a very effective form of treatment for CML? and why?
tyrosin kinase inhibitors (imatinib); because of oncogene addiction
39
Is oncogene addiction very common with different cancers?
no; CML is a very specific circumstance where we are able to cut out the supplier with this one little snip
40
What is MYC?
the master transcriptional regulator; this gets out of hand with several tumors; you don't want too much MYC because it leads to cancer
41
What is the most common extracranial solid tumor in children?
neuroblastoma
42
There are two ways the cyclins can become carcinogenic. What are these?
we can turn on the "on" switch or we could turn off the "off" switch
43
What normally inhibits the cyclin pathway?
p16
44
what can germline loss of function of p16 lead to?
familial melanomas
45
what cyclin is overexpressed in certain cancers such as mantle cell lymphoma?
cyclin D1
46
what are three examples of tumor suppressor genes in normal cells?
RB, TP53, and APC
47
what happens when RB, TP53, or APC become mutated?
they can no longer function as normal, so they cannot suppress tumors
48
How do RB and TP53 shut down proliferation?
by causing senescence and apoptosis
49
What is Knudson's hypothesis?
two mutations involving both alleles of RB are required to produce retinoblastoma; in germline (familial) mutations, only one additional somatic hit is needed; in sporadic cases, a particular cell has to have 2 somatic mutations to knock out both genes
50
germline mutations of RB mean all cells have a pre-existing mutation; these cells are at high risk of what?
tumorigenesis by succumbing to a second hit
51
What is RB a key negative regulator of?
the G1/S cell cycle transition
52
What does RB exist as in quiescent cells?
in an active hypophosphorylated state
53
what does RB exist as in cells passing through the G1/S cell cycle transition?
inactive hyperphosphorylated state
54
when RB is hyperphosphorylated, what helps usher in the growth cycle?
the cyclins
55
what do high levels of cyclins lead to?
hyperphosphorylation of RB and therefore inhibition of RB
56
what happens if you have a loss of function of RB?
inappropriate activation of the cell cycle
57
What is TP53 known as?
the guardian of the genome
58
What is the most frequently mutated gene in human cancers?
TP53
59
what cancers are classically positive for p53 mutations?
serous adenomas of the ovary
60
what happens if there is a loss of function mutation in p53?
there will be no cell cycle arrest; no DNA repair; no senescence--> leads to malignant tumors
61
We treat cancers with radiation and chemotherapy; these should work by inducing DNA damage, but what happens if the p53 is not working/mutated?
these tumors have a higher requirement for therapy
62
What syndrome is associated with the germline TP53 mutation?
the Li-fraumeni syndrome
63
what differentiates a germline mutation from a somatic mutation of p53?
younger age, diverse tumors, and a family history
64
Besides TP53 and RB, what is another tumor suppressor gene we discussed?
APC: adenomatous polyposis coli
65
germline mutations of APC are associated with what?
familial adenomatous polyposis- polyps develop early and extensively; colectomy in early adulthood or cancer is consider inevitable by 40 years of age
66
What is special about germline mutations of APC?
they can occur de novo; so you cannot rely on a family history
67
APC is a component of what signaling pathway?
WNT signaling pathway
68
what is a major function of the APC protein?
to hold beta-catenin function in check
69
what happens during WNT signaling?
it blocks the formation of the destruction complex- so beta-catenin can translocate from the cytoplasm to the nucleus and cause cell proliferation
70
What happens if there is no APC/ mutated APC?
the destruction complex will not form- Beta-catenin will be able to signal cell proliferation
71
What is the Warburg effect?
aerobic glycolysis
72
What does autophagy in cancer allow?
doesn't really help with growth, but it does help with survival
73
How do cancer calls evade cell death?
they mutate/down regulate TP53 and they upregulate BCL-2
74
What cell death pathway is important for killing cancer cells?
the intrinsic apoptotic pathway
75
What is the opposite of fertility?
senescence
76
What determines senescence?
telomeres
77
What do stem cells have that prevent senescence?
telomerase- an enzyme that protects their telomeres
78
What is the relationship with cancer and telomeres?
cancer also uses telomerase so that it will never be unable to replicate
79
What are cancer stem cells?
like normal stem cells- they can self renew- give rise to heterogenous populations of daughter cells and proliferate extensively
80
Solid tumors cannot grow more than a few mm unless they induce what?
angiogenesis
81
Tumors set up their vascular system how?
by switching the tumor microenvironment from antiangiogenic to proangiogenic (an angiogenic switch)
82
What is a proangiogenic factor?
HIF1
83
what is the effect of HIF1?
VEGF and FGF
84
how could you treat cancer when thinking about angiogenesis?
block VEGF- this would block the process of angiogenesis from occurring
85
What are the three major steps in invasion and metastasis?
Getting through the basement membrane, getting into the vessels, getting out of the vessels
86
How does the tumor initiate getting through the basement membrane?
there will be dissociation of tumor cells from each other
87
how do the tumors cells dissociate from each other?
an epithelial to mesenchymal transition
88
what are the hallmarks of epithelium?
in epithelial tumors, there are cadherins that are responsible for binding these cells to each other
89
what occurs during the epithelial to mesenchymal transition?
the silencing of the E-cadherins
90
After the epithelial to mesenchymal transition, what occurs next?
the degradation of the ECM basement membrane and connective tissue
91
how do cancer cells accomplish the degradation of the ECM basement membrane and connective tissue?
with enzymes called Matrix Metalloproteinases
92
what occurs after the degradation of the ECM basement membrane and connective tissue?
attachment and locomotion and invasion into the vessel
93
What is the major cell responsible for the immune defense against tumors (tumor antigens)?
CD8+ Cytotoxic T lymphocytes
94
Although we have CD8+ CTLs to help defend against tumor cells, some tumor cells have a way around this. What do they do?
antigen loss (failure to produce tumor antigen) and class I MHC-deficient tumor cells--> both lead to lack of recognition by t cell; tumor cells can also produce immunosuppressive proteins or expression of inhibitory cell surface proteins --> leads to inhibition of t cell activation
95
What is an example of an immunosuppressive protein or expression of inhibitory cell surface proteins that tumor cells present to t cells to inhibit their activation?
PD-1 Ligand
96
How can we treat tumor cells with the over expression of inhibitory cell surface proteins?
by using PD-1/PD-1 Ligand antibodies--> immune checkpoint inhibitors
97
what does failure of the mismatch repair lead to?
unstable, persistent microsatellites in the DNA (microsatellite instability)
98
What is Lynch syndrome?
germline loss of function mutations in a mismatch repair gene (remember that failure of the mismatch reapir leads to microsatellite instability)
99
what do lynch syndromes include?
colorectal, stomach, pancreas, ovary and uterus, prostate gland, and the urinary tract
100
How might DNA damage (like strand breaks) be repaired?
by the homologous recombination repair (HRR)
101
what are the responsible genes for HRR?
BRCA-1 and BRCA2
102
what is a treatment for acute promyelocytic leukemia?
all trans retinoic acid (since the PML/RAR complex doesn't "like" retinoic acid anymore
103
What are the 2 major mechanisms of epigentics?
DNA methylation and Histone modification
104
what is the role of miRNA (micro RNA)?
to regulate RNA
105
what happens if we down regulate miRNAs?
the translation of RNA will go up (and this includes oncogenic RNA)
106
when is an example of when cancer utilizes down regulation of miRNAs?
with BCL-2s--> miRNAs are in part responsible for keeping BCL-2 in check; so when you have downregulation of the miRNAs for BCL2, you will have upregulation of the actual BCL2 molecule

MOD Midterm (22 decks)

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