Cancer Biology Flashcards
1
Q
Which genetic alteration is pancreatic cancer commonly a/w?
A
K-RAS at codon 12
Mnemonic: Pankreas
2
Q
Which genetic alterations are cutaneous melanomas commonly a/w?
A
BRAF
3
Q
Which genetic alterations are basal skin carcinoma and medulloblastoma commonly a/w?
A
PTCH
Mnemonic: BiTCcH
4
Q
Which genetic alterations are thyroid cancers commonly a/w?
A
RET proto-oncogene
5
Q
Which genes are a/w HNPCC?
A
- Mismatch repair genes (most common ones in bold)
– MLH1
– MSH2, MSH3, MSH6
– PMS1, PMS2
6
Q
How does APC lead to polyps?
A
During differentiation from stem cells to crypt cells, APC-gene (aka β-catenin) gets turned on. This leads to a progenitor-like phenotype, causing abnormal, continued proliferation → polyp formation
7
Q
Which famous syndrome is a/w p53 mutation?
A
- Li Fraumeni syndrome
– a/w breast, lung cancers, brain tumors, sarcomas
8
Q
What is APC gene?
A
It is a tumor suppressor gene a/w colon (FAP), stomach, and intestine tumors.
9
Q
Which CDKs phosphorylate RB1 protein?
A
CDK4/6
10
Q
What other cancers are patients with familial retinoblastoma at risk for?
A
- Osteosarcomas
- Lung Ca
- Kidney Ca
- Bladder Ca
11
Q
Is p53 inactivated by mutations only?
A
- No, it can be inactivated in two other ways:
– Viruses with proteins that inactivate p53
– Deletion in INK4A-ARF locus (common in cancers). The ARF (aka p19) region makes proteins that control p53 activation through MDM2 inactivation.
12
Q
Where on DNA does p53 bind?
A
It binds to single-strand regions generated in damaged DNA, including those at telomeres.
13
Q
Is p53 activated or inactivated by DNA damage?
A
Activated
14
Q
Which downstream proteins does p53 activate?
A
p21, GADD45A, Bax, MDM2, PCNA, NFκB, and others.
15
Q
How does p53 cause apoptosis?
A
It activates BAX, BID, and PUMA.
16
Q
What is the function of MDM2?
A
- Negative self-regulator of p53
– Produced by p53 itself
– MDM2 binds to p53 to cause p53 degradation
17
Q
What’s the first step for ATM after radiation damage to DNA?
A
- Auto-phosphorylation
- It then Phosphorylates a number of effector proteins
18
Q
What is the function of ATM as it related to DNA repair?
A
It coordinates DNA repair by activating repair enzymes, including p53 through phosphorylation.
19
Q
How does CHK2 interact w/ CDC25C to regulate the cell cycle?
A
- ATM activates CHK2
- CHK2 phosphorylates CDC25C phosphatase, inactivating it and inhibiting cell cycle
– CDC25C phosphatase normally removes inhibitory phosphates from cyclin-CDK complexes promoting cell cycle progression
20
Q
How does p53 affect the G2-M transition?
A
p53 inhibits CDC25C → prevents G2-M transition.
21
Q
What is the main mechanism of lymphoma cell death following radiation?
A
- p53-mediated apoptosis
- p53 mutations make them radioresistant
22
Q
How do p53 mutations affect lymphocyte and thymocyte radiation sensitivity?
A
This mutation makes them more radioresistant.
23
Q
What is the function of p53?
A
It is a tumor suppressor gene and plays a role in cell cycle regulation and apoptosis.
It also plays a vital role in DNA damage surveillance and almost all forms of DNA repair, including NHEJ, HRR, MMR, BER, and NER.
24
Q
What is the function of BRCA1/2?
A
- Tumor suppressor genes.
- Play a role in homologous recombination.
25
Which cancer is a/w ABL1 mutation?
CHRONIC myeloid leukemia
26
What is the function of ABL?
It is an oncogene activated through chromosome translocation, forming BCR-ABL (9:22)
27
What's the function of the PI3K-Akt-mTOR pathway? What're the steps?
- Function:
-- Anti-apoptosis
-- Pro growth
-- Pro angiogenesis
-- Pro ribosome biogenesis
- Some activators:
-- VEGF
-- IGFR
-- HIF1
- Steps:
28
What is the function of PTEN?
- Tumor suppressor gene
- Counteracts PI3K
-- PI3K: PIP2 → PIP3
-- PTEN: PIP3 → PIP2
29
What're some drugs that target the mTOR pothway?
- Everolimus
- Temsirolimus
30
What is the function of NF1?
It is a tumor suppressor gene a/w neurofibroma, and sarcoma.
31
What is the function of WT1?
- Tumor suppressor gene and a transcription factor
- When mutated or absent, it leads to the development of Wilms tumor.
32
Which main proteins regulate p53?
- ATM
- ATR
- DNA-PK
33
Approximately what % of cancers have p53 inactivation?
≥ 50%
34
Which domain of the p53 protein is acted on by viral inactivating proteins?
DNA-specific binding domain, the same region affected by mutations in the majority of cancers.
35
Which domain of the p53 protein is mutated in the majority of cancers?
DNA-specific binding domain
36
Which viruses contain proteins that inactivate p53?
1. HPV (E6)
2. Adenovirus (E1B55K).
3. SV40 (large T)
Such proteins are absent in EBV virus.
Mnemonic: **HAS** proteins
37
Which kind of viruses contain proto oncogenes?
Retroviruses contain altered/mutated proto-oncogenes, usually acquired through their vertebrate hosts.
They were instrumental in the study of oncogenes.
38
What are exons? What are introns?
Exons → coding regions
Introns → non-coding regions
39
What are the most common ligands for EGFR?
- EGF
- **TGF-α**
40
What is EGFR? What are the different types of EGFR, its ligands, and its function?
- Cell surface tyrosine kinase receptor family. Members:
-- EGFR (Her1; ErbB)
-- EGFR2 (HER2; ErbB2)
-- EGFR3
-- EGFR4
- Activated by the epidermal growth factor (EGF) ligand and TGF-α.
- Enhances cell proliferation
-- Pathway: See figure
41
What're the molecules involved in the EGFR pathway?
- In order:
-- EGFR
-- Ras/Raf
-- MAPKK (Mek)
-- MAPK (Erk)
- Figure:
42
Does EGFR exist as a homo or a heterodimer?
Homodimer
43
What mechanism normally inactivates tumor suppressor genes?
Loss of heterozygosity, since they act in a recessive manner.
Also inactivated by epigenetic silencing
44
What mechanism(s) activate oncogenes?
- Deletion
- Point Mutation
- Retroviral integration
- Gene amplification
- Chromosome rearrangement
45
What is the function of the promoter region?
Determines whether a gene is transcribed or not.
46
What is the function of BRCA1/2?
They are tumor suppressor genes.
They play a role in homologous recombination.
47
Why are levels of p16 elevated in HPV-driven cancers?
- Normal p16 negative feedback loop fails
-- RB is inactivated by E7 and becomes insensitive to p16 levels
48
Which cancers are a/w p16-INK4A mutations?
- Pancreatic
- Esophageal
- Malignant Melanomas
PEMs
49
What is the role of p16-INK4A?
- Protein product of the p16 tumor suppressor gene
- Inhibits CDK 4/6:cyclin D/E complex
- Prevents RB phosphorylation
- Limits cellular proliferation
50
How is p53 usually modified?
- Phosphorylation
- Acetylation
51
What is the role of p14-INK4A?
- Inhibits MDM2-mediated degradation of p53
- ↑ p53 → cell cycle inhibition
52
Which cancer is a/w ALK translocation?
NSCLC
53
Which cancer is a/w amplified C-MYC?
- Burkitt Lymphoma
- Leukemias
54
Which cancer is a/w amplified L-MYC?
SCLC
55
Which cancer is a/w mutated Notch1?
T cell acute lymphoblastic leukemia
56
Which cancer is a/w KIT and/or PDGFR receptor kinase activations?
≥ 90% gastrointestinal stromal tumor (GIST)
57
Which drug targets the KIT and/or PDGFR receptor kinase activations?
Imatinib (Gleevac)
58
What is the oncogene addiction model?
Some tumors rely on the continued activity of a single oncogene for growth and survival.
Inactivation of this gene can halt the progression of such cancer.
59
What kind of enzymatic activity does telomerase exhibit?
- Reverse transcriptase.
- Telomerase complex has an RNA template from which a repeating TTAGGG sequence is reverse transcribed and added to the ends of the DNA.
- Mnemonic: Telomere adds TAGs to chromosome ends
60
Do all tumor cells have deficiences in DNA repair?
No
61
Why are levels of p16 elevated in HPV-driven cancers?
The p16 negative feedback loop fails. RB is inactivated by E7, and becomes insensitive to p16 levels.
62
Which notable chromosomal instability disorder is not a/w cancer?
Cockayne's syndrome: stunted growth, impaired nervous system development, photosensitivity, and premature aging.
63
What causes Cockayne's syndrome?
Deficiency in nucleotide excision repair, akin to what happens in XP.
64
Which cancer is a/w Bloom's syndrome?
- Leukemia
- Lymphoma
Mnemonic: B**l**oom's
65
Which cancer is a/w Fanconi's anemia?
Leukemia
66
Which cancer is a/w Nijmengen breakage syndrome?
Leukemia
67
Which cancers are a/w ataxia telangiectasia?
- Leukemia
- Lymphoma
68
How is ATM activated following radiation?
- Autophosphorylation
-- Inactive dimer to an active monomer
69
How does ATM interact with MDM2?
It phosphorylates MDM2, preventing it from inhibiting p53.
70
How does ATM interact with H2AX?
It phosphorylates H2AX, resulting in γH2AX formation, which is a marker of DNA damage.
71
How does ATM regulate the cell cycle?
It activates CHEK2, which phosphorylates CDC25 phosphatase, which can now not dephosphorylate CDK1 (a step necessary for G2-M progression)
72
How does the MRN complex interact with ATM?
MRN activates ATM.
73
What is the function of NF-κB?
Irradiation → activation
Transcription factor → inhibits apoptosis
Activation → tumor progression
74
How do mutations in the Ras family affect the Ras proteins?
- Prevent GTPase activity.
- Ras proteins are active and inactive when bound to GTP and GDP respectively. By preventing GTPase activity, mutations can lead to continuous activation of the RAS protein and its downstream signalling.
75
Which cellular compartment is a/w the RAS enzyme?
RAS enzymes are located on the inner surface of the plasma membrance
76
Are mutations in genes of the Ras family oncogenic or tumor suppressing?
- Oncogenic
- Mutated in almost 25% of all cancers
77
What kind of protein is RAS?
A small GTPase
78
What are the phenotypic characteristics of people with ataxia-telangiectasia?
- Progressive ataxia
- Telangiectasias of the sun-exposed regions
- Dysphagia
- Dysarthria
- Chronic lung diseases
- 24% increased risk for leukemias and lymphomas
- Hypogammaglobulinemia
79
What is the inheritance pattern of a **loss of function mutation** in tumor suppressor genes on a **pedigree** level?
- Autosomal dominant
- One copy of the mutated gene inherited from the parents is present in all body cells.
-- During life, this person will very likely lose the normal gene copy (loss of heterozygosity) in at least a few cells in their body.
-- This will lead to cancer, giving the impression of dominance
80
What's the inheritance pattern of a **loss of function mutation** in tumor suppressor genes on a **cellular** level?
- Autosomal recessive
- One copy of a tumor suppressor gene is enough to suppress tumor growth
81
What is the inheritance pattern of a gain of function mutation in oncogenes on a pedigree and cellular level?
Dominant in both
82
What is DCC and what's its function?
DCC (disseminated colon carcinoma) is a tumor suppressor gene
Often altered in colon cancer
83
How do levels of p21 change in irradiated cells?
↑ 2/2 ↑ p53 expression
84
Is neurofibromatosis a/w inactivation of tumor suppressor genes or activation of oncogenes?
Inactivation of tumor suppressor genes
85
What is the function of BCL2?
- Anti-apoptotic protein
- Counters the release of cytochrome c from mitochondria
86
Which virus produces E6 and E7 proteins?
HPV
87
What does E6 do?
Inhibits p53
88
What does E7 do?
Inhibits RB
89
What happens to tumor cells (or normal cells) with wt p53 after irradiation?
Genotoxic insult → Senescence
90
What defines a stem cell?
- Ability to self renew
- Ability to produce daughter cells that have limited mitotic potential and are destined to differentiate
91
What is chromothripsis?
A catastrophic event is where portions of chromosomes break apart and join together randomly. It can result in many oncogenic changes in a single event.
92
What is a driver mutation?
A mutation that occurs early on in the development of cancer.
Usually occurs in a recessive or dominant oncogene.
93
What is clonal evolution?
Changes in the genetic makeup of tumors over time
94
What drives clonal evolution?
Mutations, such as through imperfect DNA repair.
Mutations that are disadvantageous are selected out.
Mutations that are advantageous become enriched.
95
What are mutational signatures?
- Distinct patterns of alterations in DNA bases.
- Only considers point mutations.
- Signature refers to the fact that these patterns can be specific to certain mutagens, such as aging, smoking, etc
- By knowing the pattern, you can deduce the identity of the mutagen
96
What influences the mutational signatures of DNA?
Specific mutagen
Bases surrounding the base of interest
DNA damage repair processes at work
97
How do mutations in the RAS family affect the proteins?
They usually prevent GTPase activity.
RAS proteins are active and inactive when bound to GTP and GDP respectively. By preventing GTPase activity, mutations can lead to continuous activation of the RAS protein and its downstream signaling.
98
What are some hallmarks of cancer?
Sustained proliferative signaling
Replicative immortality
Resisting cell death
inducing angiogenesis
activating invasion and metastasis
99
What are some characteristics of cancer stem cells?
- Small subset of cancer cells
- Can give rise to cancer stem cells or non-stem cells
- More radioresistant and chemoresistant than proliferative tumor cells
- Reside in specialized niches that impede chemo and radiation activity, eg hypoxic regions
- Often increase after radiation
- Have high anti-oxidant levels
- Slow cycling
- High MDR1 expression
- Reprogramming
100
How is the tumorigenic capacity of cancer cells quantified?
By injecting them in mice and determining the number required to cause tumors in 50% of sites (TD50).
It inversely correlates with TCD50
101
What are Yamanaka factors? What's their significance?
They can induce pluripotent cells from mature cells, and include:
1. c-**M**yc
2. **O**ct3/4
3. **K**lf4
4. **S**ox2
Mnemonic: Yamanaka **MOKS**
102
How did cancer stem cell theory gain fame?
When it was discovered that AML patients have tumor-initiating cells that grew tumors in NOD/SCID mice.
103
Why are Till and McCulloch famous?
They discovered that bone marrow-derived colonies arose within 10 days in the spleens of WBI mice.
104
Which stem cells reside in the intestinal crypts?
1. Rapidly active intestinal stem cells (LGR5+)
-- radiosensitive
2. Quiescent, reserve intestinal stem cells
-- Can re-enter the cell cycle to help repopulate the crypt
105
How long does it take for the stem cell compartment in the intestinal crypts to regenerate (aka crypt turnover time)?
3-5 days
106
How does the radiosensitivity of cancer stem cells compare to non-stem cells?
More radioresistant
107
Why are cancer cells more radioresistant?
- A higher level of free radical scavengers
- Abnormal developmental pathways
- Hypophosphorylation of checkpoint kinases
- Hyperactivation of anti-apoptosis pathways
108
Can differences in metabolism be used to improve the diagnosis or treatment of cancer with radio-chemotherapy?
No
109
What cancer is a/w RET/PTC1 type of rearrangement?
Papillary Thyroid Cancer
110
Mutations in what gene has been consistently linked to radioresistance?
RAS
111
Oncogenes are a/w what kind of epigenetic change?
- Hypomethylation
- Acetylation
112
Which epigenetic therapy is being investigated for cancer treatment?
**Decitabine**, which can re-activate silenced genes
Mnemonic: De-silences genes
113
Tumor suppressor genes are a/w which epigenetic change?
- Hypermethylation
- Deacetylation
114
What is Provenge?
It is a cancer vaccine, used to treat metastatic, castrate-resistant prostate cancer. Very costly.
115
What is the advantage of using nanodevices?
They can be engineered to avoid biological or biophysical barriers
116
Which cancer is a/w N-myc (MYCN) amplification?
Neuroblastoma
Lung carcinoma
117
Which cancer is a/w MET amplification?
Renal cell carcinoma
118
Which syndrome and cancer is a/w RET amplification?
- MEN 2A and B
- Papillary thyroid cancer
119
How does p53 cause G1-S arrest?
- ↑ p53 → ↑ p21
- p21 → cyclin E/CDK2 (G1-S checkpoint) inhibition
120
How does RB1 control the cell cycle?
- RB is normally complexed w/ E2F
- For division, CDK 4/6 w/ Cylins D/E phosphorylate RB1, causing it to detach from E2F
- E2F is a transcription factor that activates genes responsible for the G1-S transition
121
What is an HSR?
- Homogeneously staining region
- HSR is a region within a chromosome where an oncogene has multiplied several times.
122
What is a double minutes?
- Extrachromosomal DNA
--"Mini-chromosomes"
-- Contain copies of oncogenes in large numbers
- Detected in many tumors
123
What is erb? Which cancers are a/w erb?
It is an oncogene (of the EGFR family) a/w GBMs and SqCC
124
Which cancers are a/w K-Ras amplification?
- Ca:
-- Lung
-- Ovarian
-- Bladder
-- Colon
-- Pancreatic
- Commonly mutated at codon 12 → constitutive K-Ras activation
125
What cancer is a/w N-RAS?
H&**N** Ca
126
What is an allograft or syngeneic animal model?
Transplant tumors from one mouse to another
127
What is a xenograft animal model?
Transplant human tumors into immunodeficient mice
128
What is a transgenic mouse?
A mouse that can rapidly develop tumors 2/2 some genetic changes.
129
What is a PDX mouse?
A human tumor and surrounding tissue are harvested from a patient and transplanted onto a mouse (PDX mouse).
130
What is the downstream RAS on Jun kinase?
- ↑ Ras → ↑ Jun kinase (JNK)/ Stress kinase (SEK-1) → apoptosis inhibition, ↑ proliferation
131
What is the downstream RAS pathway affects chromatin remodeling?
- Ras → Raf → MEK → ERK → Msk1 → chromatin remodeling
-- remodels chromosomes **MSK** (musculoskeletal system)
132
What is the downstream RAS pathway affects protein synthesis?
- Ras → PI3K → Akt → mTOR → protein synthesis
-- Mnemonic; **m**RNA → **m**TOR
133
What are the downstream effects of RAS activation on cellular proliferation?
- Ras/Raf → Mek (MAPKK) → Erk (MAPK) → cellular proliferation
134
What is the downstream effects of RAS activation on survival transcription?
RAS → PI3K → survival transcription
135
What is a homodimer?
A receptor made of two identical subunits (proteins)
136
What is a heterodimer?
A receptor made of two distinct subunits (proteins)
137
Is TGF-β Receptor a homo or heterodimer?
Heterodimer (two different protein subunits)
**2 → β**
138
What is the receptor for TGF-β?
TGF-β Receptor
139
Are dominant oncogenes tumor-specific?
Not really, the same oncogenes can be activated in many different tumors.
140
Are tumor suppressor genes tumor-specific?
Yes!
141
What is an autocrine tumor?
A tumor that makes its own growth factors
142
What are the functions of myc?
It has multiple functions, many of which cause immortalization, proliferation, and apoptosis.
143
What are collaborating oncogenes?
Two oncogenes, acting on different pathways, act together to create a tumor.
144
What is the collaborating oncogene for Ras?
Ras-Myc
145
What is the collaborating oncogene for erbB?
- erbA
-- erbA-erbB
146
How can NFκB be activated?
- NFκB and IκB are bound together as a dimer
- Mutation in either can lead to constitutive activation
- Constitutive IκB activation can also lead to constitutive NFκB activation
- Radiation (stressor) can induce IκB inactivation, causing NFκB activation (temporary activation)
147
What is loss of heterozygosity (LOH)?
Cells start out heterozygous for a gene. However, the normal variant of the gene is lost, leaving the cell with the mutant copy only → loss of heterozygosity (LOH)
148
Where on DNA does p53 bind?
It binds to single-strand regions generated in damaged DNA, including those at telomeres.
149
What genes are most commonly mutated in colon cancer?
- MLH1
- MSH2, MSH6
- PMS1, PMS2
150
Which syndrome/cancers is/are a/w ATM mutations?
- Ataxia telangiectasia
- Leukemia, lymphoma
151
Which syndrome/cancer is a/w XP?
- Xeroderma pigmentosum
- Skin cancers
152
What is the downstream effect of caspase 9?
- Caspase 9 → Caspase 3 activation
- Caspase 9 → Caspase 7 activation → PARP inhibition → DNA repair inhibition
153
What are the downstream effects of caspase 3?
- Caspase 3 → DNA-PKcs inhibition → DNA repair inhibition
- Caspase 3 → DNA fragmentation (contributes to blebs)
- Caspase 3 → caspase 6 → Lamin A (cell shrinkage)
- Caspase 3 → Lamin B (cell shrinkage)
154
How does stress response (radiation, etc) lead to apoptosis?
155
How do cyclins and CDK levels vary throughout the cell cycle?
156
What is the role of Chk1/2 in cell cycle control?
They control the G2 → M transition
157
What is the human telomere repeat sequence?
TTAGGG
158
How does telomere length vary with cell division in germ cells, stem cells, normal cells, and cancer cells?
159
What is a molecular marker for senescence?
SA-β-gal
160
What is miRNA (micro-RNA)?
- Hairpin-like RNA's that are produced in the nucleus
- Move into the cytoplasm and regulate messenger RNA
-- inhibit mRNAs → block translation
161
What is a passenger mutation?
162
What is a driver mutation?
163
Which cancers are most a/w microsatellite instability?
- Endometrial (>25% MSI)
- Colon & gastric (10-20% MSI)
- Rectal (5-10% MSI)
- Adrenocortical, ovarian, esophageal, prostate, cervical (2-5%)
164
Does the number of driver mutations required for a particular cancer vary by cancer type?
Yes!
165
What's the function of Von Hippel-Lindau (VHL) protein?
- VHL regulates HIF
- In the presence of O2, 4prolyl hydroxylases (PHDs) add hydroxyl groups to HIF leading it to binds to VHL → HIF ubiquitination and destruction
- Defects in VHL lead to ↑ HIP levels, which can cause malignant development
166
If a cancer staging system changes in such a way that the cancers previously characterized as II are now III, how will the prognosis of stages II and III change?
The prognosis of both will improve!
167
Changes in which genes lead to a loss of cancer cell adhesion?
- E-CAD
- N-CAM
168
What two functional changes are required for cancer invasion and metastases?
- Loss of adhesion
- Extracellular matrix degradation
-- via Matrix Metalloproteinases (MMPs)
169
What're the functions of Chk1/2?
- Cell cycle checkpoint molecules
- Promote cell cycle arrest
170
What cells or cellular features underlie the abscopal effect?
T-cells and dendritic cells
171
What cells or cellular features underlie the bystander effect?
- Cell-to-cell gap junction communication
- Factors secreted by neighboring irradiated cells
172
How does HIF impact cellular metabolism?
- Increases glycolysis & inhibits oxidative phosphorylation
-- Up-regulates GLUT-1 transporter (↑ cellular glucose uptake)
-- Induces pyruvate dehydrogenase kinase 1 (PDK1), which Inhibits pyruvate dehydrogenase (PDH), preventing Actyl Co A formation and initiation of Krebs cycle (↓ oxidative phosphorylation)
-- Downregulates e- transport chain (mitochondrial respiration)
-- Increases lactic acid formation (↑ anaerobic metabolism)
-- Increases lipid metabolism (alternative to glucose)
173
Why are mammalian cells more radiosensitive than lower eukaryotes or prokaryotes?
- 2/2 larger DNA content (genome)
-- Larger target for radiation, making it more susceptible to damage
174
Which proto-oncogenes are usually activated by point mutations?
- RET
- Ras (N-, K-, and H-)
- neu
