Genetics Of Oncogenes Flashcards
What is cancer?
Aberrant cell growth
Caused by a series of acquired mutations affecting a single cell and its clonal progeny
The mutations usually target genes that regulate proliferation, differentiation and survival of cells
Describe Darwinian micro evolution
- All cancer cells originate from a single cell
- accumulation of mutations with each successive proliferation
- With each cumulative mutational event the mutated cells gain a growth advantage
Outline tumor progression
Normal—> hyperplastic—> dysplastic—> neoplasticism—> metastatic
The property of progressive aggressiveness is selected for in cancer
Tumor progression results from waves of mutation followed by clonal expansion
What are the cancer results from Darwinian evolution on a microscopic scale?
Initial mutation - creates a cell that undergoes clonal expansion
Within the clonal expansion cells, there is a cell that undergoes a second mutation
This cycle repeats to establish tumor heterogeneity
Summarize the age dependency of cancer (all types combined)
Most occurs with the 5th to 6th power of age, suggesting the result may come due to multiple independent events
Explain evidence for monoclonality
- Examination of X-inactivation pattern in cancers
- tissues are mosaic for X-inactivation
-BUT, cells from cancer tissue have the same copy of the inactivated X-inactivation chromosome
Strongly suggests that they are derived from a single
- Chromosomal abnormalities of cancers
- Chromosomal aberration occurs(translocation)
- Cancer develops
- All cells in the tumor contain the genetic aberration - Multiple myeloma produce a monoclonal immunoglobin
- Multiple myeloma is a malignancy of B-cell (precursors of antibody producing plasma cells)
- All myeloma cells in a patient produce the same antibody molecule
- Also evidence for monoclonality of cancers
What are the fundamental changes for cancer formation?
- Proliferation without external stimuli because of oncogenes activation
- Non responsive to growth inhibition because of tumor suppressor genes inactivation
- Metabolic switch to aerobic glycolysis for rapid growth
- Resistance to programmed cell death
- Unrestricted proliferative capacity.
- Induce angiogenesis
- Loss of cell to cell adhesion and contact inhibition of growth allowing invasion and metastasis
- Evasion of the immune system
How do mutations take Place?
Exogenous, I.e. viruses, chemicals
Endogenous- products of metabolism (these are the environmental exposures)
Environmental exposures lead to non lethal genetic damage( and so does germ line and spontaneous damage)
Non lethal mutation initiated mutation developing malignant phenotype
What can lead to cancer formation?
Mutations in any of the following four classes if normal regulatory genes can lead to cancer formation m
- DNA repair
- Apoptosis regulating gene
- Proto-oncogenes
- Tumor suppressor genes
What are proto-oncogenes?
- Normally they encode proteins that promote cell growth
- Mutations activating proto-oncogenes can result in one of two things:
- Excessive increase in one or more normal function
- Creating a completely new function on the affected gene product (Gain of Function)
Usually a single copy mutation is sufficient to cayse cancer despite the presence of a normal copy (oncogenes are dominant)
What are tumor suppressor genes?
- Usually produces genes that inhibit cell cycle and preventing proliferation
- Mutations usually result in a Loss of Function
- Both alleles must be affected before malignant transformation can take place (tumor suppressor genes behave in a recessive manner
What are apoptosis regulating genes?
Mutations that can cause either:
- Gain of function in genes that suppress apoptosis (anti-apoptotic )
- Loss of function in genes that promote apoptosis (pro-apoptotic
What are DNA repair genes?
Mutations in these genes impair the cell’s ability to recognize and repair non lethal genetic damage
Explain the major cellular proliferative pathway
MAP kinase pathway under normal condition
- Growth factor presence outside the cell
- Binding of growth factor to its soecufuc growth factor receptor
- Receptor auto phosphorylation
- Exchange kf GTP for GDP on RAS
- RAS binds to RAF and begins a phosphorylation cascade
- Upregulation and downregulation transcription of different genes favoring cell survival and proliferation
What is the effect of mutations in dna repair genes?
Increase in frequency of mutations in cells
Describe the cellular growth control pathway (MAP KINASE)
- Instructions come from outside the cell (growth factors)
- Growth factors bind to cell surface tyrosine kinase receptors
- Trigger signal transduction pathways which involve intracellular kinases
- And proteins with GTPase activity
- Then activate DNA-binding proteins which in turn activate gene expression to drive DNA replication and cell division
What are the components of the MAP KIJASE?
- Growth factor binds to receptor in the membrane
- Triggers cascade of activation of GTP binding proteins (ras)
- Phosphorylation of intracellular proteins by intracellular kinase
- Activating transcription factors which in turn activate genes in driving cell division
Mutation in any one of the genes/ proteins in this pathway results in oncogenes
Explain proto-oncogenes in the map kinase
- Peotioncogenes produce proteins that regulate cell proliferation
- Mutations May occur at one of the five proteins along the signal transduction pathway
- Oncogenes are mutant or misregulated forms of proto-oncogenes
- Mutations of a proto-oncogene results in the production of a mutant protein that stimulates cell division
- Mutation May also involve increased expression of the gene resulting in production of large amounts of a protein That stimulates cell d8vision
Describe growth factor receptor (tyrosine kinase)activation
- Ligand binds to binding sites, causing receptor tyrosine kinase receptor to be phisphorylated and dimerizes-activation of lip tyrosine
- Then phosphorylation of additional residues
What can cause growth. Factor receptor to be rendered constitutively active?
Truncation sorry point mutations can render a GF receptor constitutively active- even in the absence of a signal
Proto-oncogenes are normaal versions of genes can contribute when mutationally activated, or when inappropriately expressed
This leads to oncogenes that are mutant versions of these genes
What are examples of oncogenes due to reciprocal translocation?
Burkitt lymphoma -activation of Myc
Chronic myeloid leukemia- activation of abl
Explain burkitt lymphoma
- Myc oncogene is fused to immuglobulin locus (t8:14)
- Myc is a transcription factor important for (G1/S) transition
- Level of oncogene expression is increased as Myc is now under the regulation of IgH promoter (Active promoter)
- Increased Myc production
- B-lymphocytes undergo rapid cell divisions (due to high levels of Myc protein) resulting in malignant phenotype
What is the pharmaceutical use for Imanetib in Ph+CML?
- Imaniteb mesylate is a powerful tyrosine kinase inhibitor specific fir a few tyrosine kinase including Bcr-abl
- Effective against the bcr-abl fusion protein which is stuck in its activated form (constitutively active)
- Imanitib binds to the active site of the fusion protein, bcd-abl(tyrosine kinase ) and prevents its activity
Explain the activation of Ras proto-oncogene
- Ras is a GTPase involved in the major cell proliferative pathway(MAP KINASE)
- Ras activated by binding GTP
- it initiates a phosphorylation cascade that activates cellular proliferation
- It is quickly inactivated by intrinsic GTPase activity (GTP—> GDP)
- A constant stimulation is required to continue to grow
Explain oncogene activation of Ras
- Oncogenesis depends on Ras hyper-activity (over activity)
- Ras-GTP activates growth pathway
- Ras-GDP inactive (no growth)
- Many mutations inhibit GTPase activity= Ras becomes constitutively active (Ras is active even in the absence of a growth factor)
- Singkd point mutations at Gly12 or Gln61 have been isolated from tumor cells that result in constitutive activation of ras
Explain gene amplification of an oncogene: double minutes
- Double minutes are extrachromosomal fragments of DNA containing an amplified oncogene (Multiple/hundreds of copies of the oncogene)
- Seen in aggressive tumors where the amplified region includes an oncogene
- Eg: EGFR is often amplified as double minute chromosomes in advanced gliomas-visualized with FISH probes
Explain oncogenesis by gene amplification
Homogenously staining regions
Abnormal homogenouslystaining regions (Hsrs) of chromosomes in cancers often contain amplified oncogenes (Multiple/hundreds of copies of the oncogene)
Contrast double minutes and hsrs
Double minutes are extrachromosomal fragments of DNA
Whereas, hsrs are amplified oncogenes attached to the chromosome
Oncogene amplification as double minutes or hsrs result in overproduction of the oncoprotein resulting in an increased stimulation for the cell to divide
How does HER-2 overexpression lead to sporadic breast cancer?
Human epidermal growth factor receptor 2
About 30% of breast cancers have HER-2
THIS can be detected by FISH probes, and HER-2 detected as double minutes
What are the pharmaceutical applications of HER-2?
Important to know HER-2 expression profile for management
- HER2+ tumors have increased HER2 receptors on the tumor
- Herceptin drug (antibody to HER2)(trastuzumb)
- antibody binds to HER2 and prevents binding of growth factor to HER2
- Addition of herceptin to the treatment, results in decreased tumor cell proliferation
Is herceptin effective for all HER2 tumors ?
Herceptin is very effective for HER2+ tumors but not effective for treatment of HER2- tumors
