Molecular Aspects of Neoplasia Flashcards
What is a driver vs passenger mutation?
Driver mutation - genetic mutation providing a growth advantage to a precursor cell
Passenger mutation - genetic mutation providing no appreciable effect on cellular growth
What are the three types of driver mutations which can lead to tumor progression (increased virulence)?
Mutations or epigenetic changes in:
- Proto-oncogenes -> dominant growth promoters
- Tumor suppressor genes -> recessive (two changes required) growth inhibitors
- Apoptosis-regulating genes -> inhibition of apoptosis leads to increased cell number over time
What class of mutations predisposes to these driver mutations?
Defects in DNA repair genes -> genomic instability
Is a given tumor one homogenous group of cells? Why?
No, as they continually acquire driver mutations progressing to higher virulence, different sections of the tumor will multiply and make up a large portion. Each section has one “mother cell” which spawns a large group of cells with a growth advantage before the next major mutation
How does a tumor induce self-sufficiency in growth signals? What type of mutation is this?
Typically, by activation of protooncogenes to oncogenes which produce oncoproteins, increasing cellular proliferation
This is a “dominant” mutation since it is gain-of-function
Give a few proto-oncogenes which can be mutated for a self-sufficiency in growth signals.
- Overexpression of growth factor genes -> autocrine growth factors
- Growth factor receptors -> I.e. EGFR2/HER2
- Signal-tranducing proteins -> i.e. Ras
- Nuclear transcription factors -> i.e. MYC translocation or overproduction
- Overexpression of cyclin / CDK’s
How can cell over-proliferation predispose to further mutations?
Rapidly diving cells accumulate mutations faster
-> often, hyperproliferation conditions will lead to dysplasia and eventual carcinoma
Why does overexpression of HER2 result in increased cell proliferation?
Not only an increased responsiveness to growth factors, but activation of receptors without growth factors
-> if they are high enough density, they will dimerize without a growth signal
What is the most common type of Ras mutation?
Point mutations leading to resistance to GAPs (GTPase-activating proteins, like NF-1)
-> mutant RAS proteins remain in GTP-bound, active state with continuous mitogenic signalling
What gene is translocated from chromosome 9 to chromosome 22 in CML? What is the result?
ABL gene -> encodes some tyrosine kinase involved in mitogenesis
BCR-ABL fusion gene product is made with increased tyrosine kinase activity
Why can translocation of a protein like MYC lead to increased expression?
If it is under control of a frequently active promoter, transcription will be greatly increased
Are tumor suppressor genes oncogenes? Why or why not?
No -> when they are active, their are not pro-growth.
You need “two hits” to knock out their function and lead to uncontrolled cell growth -> recessive
What is normally the second alteration which allows for “Insensitivity to Growth-Inhibitory Signals”?
Loss of heterozygosity, most frequently due to DNA methylation
-> one copy of the tumor suppressor gene has already been knocked out by a deletion / point mutation
What are the two main pathways by which tumor suppressor genes are knocked out?
- Inherited mutation in one of the gene (this predisposition is considered dominant, but overall it’s recessive since you need a ‘second hit’ to knock out protein functioning) -> i.e. Li-Fraumeni syndrome, with germline mutations in TP53
- Sporadic malignancies -> both alleles are knocked out sporadically
What are the two most commonly altered tumor suppressor genes? Which is most common?
- TP53 gene - most common - loss of normal p53 function - “guardian of the genome” -> genetically damaged cells are able to propogate
- Rb gene - loss of RB function in inhibiting the G1->S transition, normally preventing E2F from dissociating in its hypophosphorylated state - “gatekeeper of G1/S”
What type of gene is the APC gene and how does it predispose to cancer?
Tumor suppressor gene
APC normally binds onto Beta-catenin, a protein associated with E-cadherin, inhibiting B-catenin from pushing colon epithelial cells thru the cell cycle.
APC dissociates whenever WNT growth signal comes in. If APC is mutated, it will dissociate even in the absence of WNT -> APC mutations are the drivers for most colon carcinomas
What type of genes are NF-1 and p21?
Tumor suppressors
NF-1 = GTPase-activating protein p21 = CDKI
How do cancer cells promote growth through cellular metabolic alterations?
Via the Warburg effect -> metabolic switch to glycolysis in aerobic conditions -> rapid, inefficient energy production with carbon skeletons from glucose going towards synthesizing macromolecules / organelles rather than full oxidation.
What pathway of apoptosis is most frequently mutated in cancer, and how is this done?
Intrinsic (mitochondrial) pathway
Increased expression of anti-apoptotic genes -> Bcl-2
Decreased expression of pro-apoptotic genes -> BAX/BAK
How do cells acquire limitless replicative potential?
- Telomere maintenance by reactivation of telomerase activity
- Evasion of senescence by inhibiting p53 / Rb
- Capacity for self-renewal, there are “cancer stem cells”
