Chapter 7 Pt 2 Flashcards
Driver mutations will often occur in what genes?
What type of mutations are usually associated with them?
- Growth promoting protooncogenes: only need mutation of 1 to promote neoplasia
- Tumor suppressor genes: inhibit growth; NEED mutation of BOTH to cause neoplasia: LOF mutation
- Genes that regulate apoptosis: GOF or LOF mutations
- DNA repair genes: LOF mutations
What is a oncogene?
Cause unregulated cell growth
Mutations from proto-oncogene => oncogene are often what?
They usually occur through what 3 mechanisms:
Gain-of function
- Point mutation=> constitutionally active of product
- Gene amplification => overexpression of the product
- Gene rearrangement (translocation) => inappropriate expression of the gene
** if a autocrine loop occurs: the growth factor gene is not altered or mutated. Oncoproteins are increasing signalling to overexpress and cause the autocrine loop
What proteins are encoded by protooncogenes?
- Growth factors
- Growth factor receptors
- Signal transducers
- transcription factors
- Cell cycle components
What is a oncoprotein?
Oncogenes encode proteins call oncoproteins, which resemble the normal products that proto-oncogenes make, except they have a mutation in their normal regulatory element (NLE). Thus, they are autonomous and their activity does not depend on external stimuli.
If a patient has 1 tumor suppressor allele, can they be protected from neoplasia?
Yes. In order to cause neoplasia, you need a mutation of BOTH tumor supressors.
Is it worse to have a mutation in 1 proto-oncogene or 1 tumor suppressor cell.
1 protooncogene. 1 proto-oncogene CANNOT protect us against cancer.
In order to cause a cancer, we need to lose BOTH tumor suppressors.
How do tumors and GF relate?
Tumor can make growth factors, which they respond to themselves via an autocrine loop. The growth factor itself enough to cause a mutation, but it can increase the chance of acquiring mutations as they are proliferating
Receptor tyrosine kinases can be constituionally active by what mechanisms?
- Point mutation
- Amplification
- Gene rearragement (translocation)
What are the important TK receptors to know?
- ERBB1
- ERBB2
- ALK
ALK, a receptor tyrosine kinase, has a subset family called what?
mechanism?
Assx tumor
TRK neurotrophin gene
Mechanism: Pt mutation
Assx tumor: neuroblastoma
What is a RAS?
RAS is a signal transducer that relays signals from [receptor tyrosince kinases nucleus]
-protooncogene
It sends signals via 2 pathways: MAPK and P13K/AKT.
RAS/P13K and other components of the pathway usually have what types of mutations?
gain of function (point mutation)
90% of RAS mutation occur in what tumors
- pancreatic
2. Cholangiocarcinomas (bile duct)
50% of RAS mutation occur in what tumors
- Colon
- endometrial
- thyroid
CET
30% of RAS mutation occur in what tumors
- Lung adenocarcinomas
2. myeloid leukemias
N-RAS
- Melanoma
2. Hematologic
H-RAS
- Kidney
2. Bladder
K-RAS
- Colon
- Lung
- Pancreatic
What percent of tumors have a mutated RAS gene?
15%
What is BRAF?
BRAF is a serine/threonine signal transducer that relays information from tyrosince kinase receptors via the RAS signaling (MAPK).
tumors caused by BRAF
100% of hairy cell leukemias
80% of benign nevi
>60% of melanomas.
How do treatments of BRAF and RAS mutation differ?
Because RAS genes are so often mutated, we have been trying to find targeted therapy specific for these proteins. However, because they differ so greatly and their mode of signaling, it is been hard.
Meanwhile BRAF inhibitors has proven to be effective in cancers that have a mutated BRAF. Those that without a BRAF mutation do not respond
What is the mechanism of BRAF?
- Point mutation (GOF)
2. Translocation
What is BCR and ABL
ABL codes for a tyrosine kinase that is tightly regulated.
When it is translocated from Chr 9=>22, it forms a fusion gene with BCR.
[ABL-BCR] fusion gene can then +TK activity via BCR moiety of ABL in the cytoplasm.
Describe BCR-ABL mechanism and assx tumor
Mechanism: translocation 9 =>22:
BCL-ABL fusion gene via the BCR moiety => + constit. active [BCR- ABTK TK] in the cytosol => causes myeloid cells to divide more quickly => buildup of premature leukocytes
Assx tumors: Chronic myelogenous leukemia and acute lymphoblastic leukomia
Assx tumors with BCR-ABL translocation fusion gene
- Chronic myelogenous leukemia
2. Acute lymphoblastic leukemia
What activates the non-receptor tyrosine kinase activity of ABL?
BCR moiety.
How can we treat chronic myelogenous leukemia (CML)?
How well does the treatment work?
BCR-ABL inhibitors
Tx works well: low toxicty and high therapetic efficacy
suffix -blast means what?
a familial cancer (inherited/genetic) cancer that is seen in bbs
What is the ultimate consequence of a deregulated mitogenic (mitosis) signaling pathway?
increase + of nuclear transcription factors => increase expression of pro-growth genes and cyclins => allow the tumor to have growth autonomy
What is MYC
What pathway does it work through?
MYC is a protooncogen, located in the nucleus that codes for transcription factors, that activates the expression of pro-growth genes and cyclins => allow the tumor to have growth autonomy
Works through the RAS/MAPK pathway
What 5 things does MYC do when activated?
- increase the expression of pro-growth genes and cyclins
- allow the tumor to have growth autonomy
- Increase the expression of telomerase
- work with other transcription factors to reprogram somatic cells => pluripotent cells.
- At least partially responsible for the Warburg effect
What does Dr. Putthoff consider MYC to be?
The master transcription regulator of cell growth
c-MYC
Mechanism: t(8:14), a translocation that involves IgH
Assx tumor: Burkitts lymphoma (B-cell lymphoma)
L-MYC
Mechanism: amplification
Assx tumor: lung cancer (small cell carcinoma
N-MYC
Mechanism: amplification
Assx tumor: neuroblastoma
The fastest growing tumors have (name?) have the highest amounts of what?
Burkitts lymphoma
MYC
What is one cancer we should always assx MYC with?
Burkitts lymphoma
What is central to malignant transformation?
LOSS OF CELL CYCLE CONTROL. At least 1/4 key regulators of the cell cycle is dysregulated (Rb, CDK4, cyclin D, P16/INK4A) in a vast majority of cancers
At least 1/4 of the following cell cycle regulators are dystfunctioned in a vast majority of cancers
- CDK4
- cyclin D1,2,3
- P16/INK4A
- Rb
mutations of P16/INK4, CDK4, cyclin D, or any upstream regulators, can cause what to be inactive, even if there is no mutation in the gene itself?
Rb
Loss of the control cell cycle can occur through what mechanisms?
- LOF of tumor supressor genes ( Rb/TP53) or cyclin dependent kinase inhibitors (CKDIs)
- GOF of cyclin dependent kinases (CDK4) or cyclin D.
Loss of the control cell cycle can occur
- LOF of tumor suppressors or CDKI, which do what?
- GOF of CDK4 or cyclin do, which do what?
Tumor suppressors prevent the G1-S
CDKIs: inhibit cyclin dependent kinases/cyclin complexes
CDK4 and cyclin D: form a complex => phosphorylates Rb (inactivates)=> preventing E2F from binding, allowing it to cause cell cycle to go from G1=>S
CDK4
Mechanism: amplification or point mutation (gain function)
Assx tumor: glioblastoma, melanoma, sarcomas
cyclin D1 (CCND1)
Mechanism: (11:14) translocation
Assx tumor: mantle cell lymphoma, multiple myeloma, breast and ESO cancers
If a child has 1 inherited mutatnt RB allele in all somatic cells, how will they present?
In order to get a neoplasm via tumor supressor, BOTH must be gone.
Thus, the child will be normal, however, they will have an increased risk of developing cancer.
What are the 2 important tumor suppressors?
Rb
p53
What is the pattern of inheritance for Rb
AD: increase risk of cancer that is associated with a germline rotation
AR: LOF in Rb
What inhibits the G1=>S phase and is directly or indirectly inactivated in most human cancers?
Rb
How does Rb inhibit the cell cycle from going from G1=>S
- Unphosphorylated Rb: bound to E2f, inhibiting the cell from going G1-S
- Phosphorylated Rb: E2F TF unbinds, and allows the cell to go from G1 =>S
What are the different ways to compromise Rb
- Viral oncoprotein HPV E7 will bind to the same spot E2F binds to, preventing it from binding, allowing it to be free and cause G1=>S
- LOF in BOTH Rb
- LOF in cyclin dependent kinase inhibitors (CDKIs) => prevent inhibition of CDK4 or cyclin D => can then phosphorylate Rb => inactivate it
- GOF in mutations that increase CDK4 or cyclin D
When Rb is phosphorylated, it is _________.
When Rb is hypophosphorylated, it is _____.
Phosphorylated => inactive
Hypophosphorylated => active
What familial and sporadic tumors are associated with Rb?
Familial: familial retinoblastoma syndrome
Sporadic: retinoblastoma and osteosarcoma
What chromosome is Rb located?
Chr13q14
Describe the knudson 2 hit hypothesis hypothesis for Rb
Knudson 2 hit hypothesis says that in order for ppl to get a cancer caused by a tumor suppressor gene; the person will have to have BOTH Rb genes knocked out. This ouccurs in 2 ways
- Familial (inherited): all somatic cells inherit 1 mutated RB (first hit) and the 2nd hit is aquired (sporadic) hit of the other normal Rb gene Bc the 2nd hit seems inevitable, most people who inherit 1 mutation => more likely to get bilateral retinoblastoma. AD pattern.
- Sporadic: Both normal alleles acquire a LOF mutation. very rare. causes unilateral retinoblastoma
What types of cancers are more likely to become bilateral? Familial or sporadic?
Familial.
What is considered “GUARDIAN OF THE GENOME”?
TP53; it is the CENTRAL MONITOR OF STRESS
What does TP53 do?
TP53 is the guardian of the genome. It is a tumor suppressor that prevents G1=>S (arrests cell cycle)
TP53 detects what?
Then does what?
Detects: anoxia, DNA damage, inappropriate signaling due to oncoproteins
It will then repair DNA. If DNA cannot be repaired => cellular senescence or apoptosis.
What is one weird thing that p53 does?
inhibit angiogenesis
p53
mechanism
assx tumor
Mechanism: LOF of TP53 on Chr 17q13.1 OR inactivated by HPV E6 => DNA is not repaired (genetic instability) => driver mutation accumulate in ONCOGENES => increases risk of malignancy.
Assx tumors:
Familial tumors: Le-Fraumeni syndrome
Sporadic cancers: most human cancers
Inheritance of p53
AD
How does p53 works
Trigger
Sensed
Trigger: anoxia, DNA mutation, fucked up signaling d.t mutated oncoproteins
Sensed by: ATM/ATR kinases => phosphorylate p53, free it from MDM2 inhibitor
p53 upregulates CDKinhibitor p21
p21 then causes arrest at G1-S CP allowing cells to
1. repair dNA
if does not occcur: cellular senscence or apoptosis
If apoptosis: increase BAX; inactivate Bcl12 => cytochrome C leaks out => apoptosis
Once a cancer is established, what does p53 tell us?
how a cell will respond to treatment
- Tumors with normal wild type alleles of p53= > easier to cure bc p53 can supress tumors
- Tumors with mutated p53 cannot repair DNA => resistant to chemo and radiation
What tumors often have wild type normal p53 alleles, making them easier to cure?
- acute lymphoblastic leukemia
2. Testicular teratocarcinomas
What tumors often have mutated p53 alleles, making them harder to cure?
- Lung cancer
- Colorectal cancer
cannot repair DNA=> apoptosis and resistant to radiation and chemo
What happens if we inherit 1 mutated TP53?
increased liklihoof to get malignant tumor bc they only need 1 more hit
What is Li-Fraumeni syndrome (mneuomic)?
Familial form of TP53 (inherited one mutated TP53; acquired another) => li fraumeni syndrome => 25x more likely to deevlop multuple carcinomas and sarcomas by 50YO.
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SBLA cancers: sarcomas, breast/brain tumors, leukemias and adrenal CTX carcinomas
Ppl wih Li-Fraumeni syndrome are more prone to get what cancers
SBLA
sarcomas
brain tumors/ breast cancer
leukemia
adrenal gland carcinoma
What is NF1
a tumor suppressor that encodes neurofibromin 1, a GTPase that inhibits RAS signaling
NF1
What is the mechanism?
inheritance
Famial syndromes
Sporadic syndromes
germline LOF => causes neurfibromatosis type 1
AD
familial: neurofibromastosis type 1:
Sporadic: neuroblastoma, juvenile myeloid leukemia
