9.15.16 Lecture Flashcards
Describe the typical gain-of-function cancer mutation.
Single overactivity mutation event that creates an oncogene to promote cell transformation; acts in a dominant manner.
Describe the typical loss-of-function cancer mutation.
Underactivity mutation; need mutations in both copies of a tumor suppressor gene, promoting transformation; acts in a recessive manner.
Genes mutated in cancer can be made overactive in many ways. Describe these.
- Deletion or point mutation in coding sequence leads to hyperactive protein made in normal amounts.
- Regulatory mutation leads to normal protein greatly overproduced.
- Gene amplification leads to normal protein greatly overproduced.
- Chromosome rearrangement in a nearby regulatory DNA sequence causes normal protein to be overproduced.
- Chromosome rearrangement via fusion to actively transcribed gene produces hyperactive fusion protein.
Mutation of ___ receptor can make the receptor active even in the absence of its ligand, and consequently ongogenic.
Epidermal growth factor
Describe the outcomes of a normal, healthy individual, an individual with hereditary retinoblastoma, and an inidividual with nonhereditary retinoblastoma.
Normal individual may have occasional cell inactivation of 1 of 2 good Rb genes, no tumor is produced. Individual with hereditary retinoblastoma inherits mutant Rb gene. Occasional cell inactivates its only good Rb gene, leading to excessive cell proliferation and a retinoblastoma. This individual typically has multiple tumors in both eyes. The individual with nonhereditary retinoblastoma has an occasional cell inactivate 1 of 2 good Rb gene. This happens again to the remaining good Rb gene, leading to excessive cell proliferation and retinoblastoma. 1/30,000 people develop 1 tumor in 1 eye.
Both genetic and epigenetic mechanisms can inactivate tumor suppressor genes. Describe the genetic mechanisms by which this may occur.
Nondisjunction leading to chromosome loss, chromosome loss followed by duplication, mitotic recombination, gene conversion during recombination, deletion, and point mutation.
Describe the epigenetic mechanisms that can inactivate tumor suppressor genes.
DNA methylation and packaging the gene into condensed chromatin.
Oncogenes typically involve ___ mutations. Tumor suppressor genes typically involve ___ or ___ mutations that abort protein synthesis by creating stop codons.
Missense; truncating; missense.
Many caners have disrupted genomes; this can be represented by ___ plots, which show what three things?
Circos; highly amplified regions, intrachromosomal rearrangements, interchromosomal rearrangements
Describe the difference between driver and passenger mutations.
Driver mutations (~10/cancer) are seen at a higher frequency, may be present in all cells of a given tumor; causal factors. Passenger mutations (~300/cancer) are more sporadic and many not be present in all tumor cells due to heterogeneity; phenotypic factor.
Mutations in the ___ pathway drive cancer cells to grow. Most normal cells need signals (___) that drive cell-cycle progression and signals (___) that drive cell growth.
PI3K/Akt/TOR; mitogens; growth factors
Describe the PI3K/Akt/TOR pathway.
Glucose binds to a glucose transporter. Glucose transport increases, leading to an increase in glycolysis. This increases pyruvate, which increases the TCA cycle in the mitochondria. This increases release of citrate into the cytosol, leading to the formation of acetyl CoA. This leads to lipid synthesis, which leads to membrane biosynthesis for cell growth. In addition, growth factors bind, activating receptor tyrosine kinases. This activates the PI-3 kinase, which activates Akt, which activates mTOR, which increases protein synthesis and increases glycolysis.
The PI3K/Akt/TOR pathway becomes abnormally activated ___ in tumor progression.
Early
___ occurs as cells form microcolonies.
MET
EMT transition of transformed cells is induced by extracellular ___ and ___, which originate from where?
TGFbeta; Wnt; activation by proteases of pro-TGFbeta in ECM, secretion of TGFbeta/Wnt from untransformed cells or by secretion from tumor cells themselves.
