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.