Genetics of Oncogenes Flashcards
cancer
Manifestation of mutations
usually of somatic origin
threshold model does not apply for cancer
Tumor progression
Normal->Hyperplatic(hyperplasia)–>Dysplastic(phenotypic differences)–> neoplasia(abnormal diffision, tumor growth)–> Metastatic
What does tumor progression result from?
Waves of mutation followed by clonal expansion
What alterations in malignant transformation lead to Increases survival and growth?
Self-sufficiency in growth signals
Insensitivity to growth-inhibitory signals
evasion of apoptosis
escape from immune attack
limitless replicative potential
What alterations in malignant transformation lead to Metastasis?
loss of contact inhibition of growth
loss of cell-cell adhesion
ability to invade other tissue
What alteration in malignant transformation lead to increased mutation rate
breakdown in DNA repair and genomic stability
What alteration in malignant transformation lead to cancer energy supply?
Sustained angiogenesis
Oncogenes
Normally stimulate growth
Tumor suppressor
inhibit growth
DNA Repair
normally limit mutations
Proto-oncogenes
Produce proteins which promote cell growth or prevent apoptosis
Mutation and or over/mis expression causing cell growth
Usually gain of function mutation resulting in cancer
mutation in ONE copy sufficient to cause cancer
Tumor suppressor genes
Produce proteins that inhibit the cell cycle preventing cell proliferation
Usually a Loss of Function mutation resulting in cancer
mutations in TWO copies required to cause cancer
Mutator Genes
Mutations in DNA repair genes
what is the difference between proto-oncogenes and oncogenes?
Proto-oncogenes are normal version of genes that can contribute to cancer when mutationally activated or inappropriately expressed.
Oncogenes are the mutant versions of the genes
What do proto-oncogenes produce
proteins that regulate cell proliferation
Burkitt lymphoma is caused by what
activation of myc
Chronic Myeloid leukemia is caused by what
activation of abl
Burkitt lymphoma
Blood malignancy
myc oncogene is fused to immunoglobulin locus
Myc gene and role in Burkitt Lymphoma
- Myc is a transcription factor important for G1/S transition
- Level og oncogene expression is increased as myc is under the regulation of IgH promoter
- leads to increased myc production
- B-lymphocytes undergo rapid cell divisions resulting in malignant phenotype
what is this an image of?
BCR-Able translocation in chronic myeloid leukemia
what is this an image of?
The philadelphia chromosome translocation t(9;22)(q34;q11)
Imaniteb and anticancer application
Is a powerful tyrosine kinase inhibitor- for Bcr-abl
Effective against the bcr-abl fusion protein which is stuck in its activated form
Binds to the active site of the fusion protein, bcr-able, and prevents its activity.
What is this an image of?
Pharmaceutical application of Imaniteb
Activation of Ras proto-oncogene
A GTPase involved in the major cell proliferative pathway(MAPKinase)
- activated by binding to GTP
- Initiates a phosphorylation cascade that activates cellular proliferation
- quickly inactivated by intrinsic GTPase activity ( GTP->GDP)
- Constant stimulation is needed to grow
- Initiates a phosphorylation cascade that activates cellular proliferation
Oncogene activation of Ras
- Ras GTP activates the growth pathway while Ras GDP is the inactive form where no growth occurs
- Many mutations inhibit the GTPase activity that will allow Ras to stay active, even in the absence of a growth factor
- Ex) single point mutation at Gly12 or Gln61
- Many mutations inhibit the GTPase activity that will allow Ras to stay active, even in the absence of a growth factor
Double minutes
Extrachromosomal fragments of DNA containing an amplified oncogene
Ex) EGFR is often amplified as double minute chromosome(seen in red in the image) in advanced gliomas which can be visualized by FISH Probes
What is Her-2
Human Epidermal Growth Factor Receptor 2
HER2+ tumors and Herceptin relationship
HER2+ tumors have increased HER2 receptors on the tumor
Trastuzumab is a Herceptin drug that binds to those receptors so that growth factors can not bind
results in decreased tumor cell proliferation
Only effective for HER2+
