Molecular oncogenesis Flashcards
What is the key molecular basis for cancer?
Non-lethal genetic alterations
Examples of genetic alterations (4)
- Point Mutations
- Balanced translocations
- Gene deletions
- Gene amplification/overexpression
What are methods for laboratory detection? (5)
- Conventional cytogenics
- Fluorescent-labeled DNA probes
- PCR
- Immunohistochemistry
- Nucleic acid sequencing
What are gene tarets for cancer and what kind of mutation leads to cancer for each? (5)
- Proto-oncogenes - Activations
- Tumor suppressor genes - Inactivation
- Antiapoptosis genes - Activation
- Apoptosis genes - Inactivation
- DNA repair genes - Inactivation
What is a proto-oncogene?
Genes involved in regulating normal cell growth
Normally expression is under tight controls
Functions usually are: GFs, GF Receptors, Signal transducer, TFs, Cell-cycle regulators
What is an oncogene?
Gene involved in autonomous, unregulated cell proliferation
Constitutive expression, no regulation
Mutant allele results in gain of function
Formed from the combination of a proto-oncogene and a genetic alteration
How are growth factors used by tumors?
Tumors can gain ability to produce necessary GF or develop GF receptors to increase sensitivity
What is the SIS oncogene?
β-PDGF production, ovrexpressed in astrocytomas and osteosarcomas
What is the normal behavior of a GF receptor vs the abnormal behavior?
Normal has transient activation: Dimerization and tyrosine kinase activity
Abnormal: Constitutive activation
What is ERB B2 (Her-2-Neu) and what does it indicate in breast cancer? How do we treat it?
Type of GF receptor, overexpressed often in breast cancer
It is a poor prognostic sign, indicating unresponsiveness to estrogen therapy.
Trastuzumab used to trigger a body immune response against a HER2+ cancer cell
Which cancer is c-KIT important for and what drug is used to treat it and its mechanism of action?
Affects gastrointestinal stromal tumors
Treated with Imatinib mesylate which is a tyrosine kinase inhibitor
What are signal transducing proteins?
Receive signals from receptor-ligand complex
Transiently transduce signal into organelles
What is RAS and what does a mutation do to it?
Why is it important?
What are specifc RAS variants?
Signal transducing G-protein, mutation inhibits the GTP-ase activity
Ras SNPs account for 15-20% of all tumors making it the single most common abnormality of oncogenes in tumors and a chemo target
K-Ras in pancreas, colon CA; H-Ras in bladder, kidney CA
What is c-ABL and what genetic alteration can happen?
Tyrosine kinase signal transduction, not receptor linked
t(9;22) Philadelphia Chromosome creates a bcr-abl fusion product
Results in loss of regulatory control so chronic myelogneous leukemia (CML) and Acute lymphoblastic leukemia (ALL)
What are transcription factors?
Proteins that bind to DNA and control transcription of genes (either activation or inhibition)
What is c-Myc, what disease state does it have, and what is the genetic alteration?
c-Myc: Continued expression of the MYC gene resulting in cell proliferation
Increased expression in Burkitt Lymphoma
t(8;14), attaching MYC to Ig gene.
What is n-Myc, what disease state does it have?
Amplified Myc oncogene
Amplification in neuroblastoma (25-30%)
Poor prognosis
What are cyclins?
Transient, unstable proteins that activate CDKs
What are CDKs?
Cyclin-dependent kinases which are constitutively expressed but require cyclin activation. Phosphorylate proteins necessary for transition through the cell cycle.
What is the role of cyclin D? What is a genetic alteration that results from this and the possible disease states related to this?
Activates CDK4, CycD-CDK4 complex phosphorylates Rb protein to encourage passage into S-phase
Mutation of t(11;14) results in a Cyclin D1-IgH causing overexpression of D1.
Mantle cell lymphoma, minor population of plasma cell myeloma and hairy cell leukemias.
This is detectable via cytogenetics, immunohistochem.
What are tumor suppressor genes?
Normal genes responsible for controlling cell proliferation
What is the two-hit hypothesis and the cliche example used?
Mutations in both alleles are required for oncogenesis due to the resulting loss of function.
Often given in the context of retinoblastoma, where the familial involves a germline mutation where one of the alleles already inactivated and only one more “hit” is required, while the sporatic or purely somatic form would require two “hits” still.
What is APC and what is the disease state and mechanism associated with it?
APC is a tumor suppressor gene which acts by destroying/down-regulating β-catenin.
APC mutation results in β-catenin accumulation, which complexes with TCF to stimulate transcription of many growth factors
Results in 100s of adenomas, notably in familial adenomatous polyposis (FAP)
FAP results in 500-2500 mucosal polyps in the colon of adolescents, young adults
Need to perform a colectomy to preventmalignant transformation of polyps
What is p53, what is its function, and what is the syndrome affiliated with it?
p53 is a tmor supressor gene important for cell cycle arrest and initiation of apoptosis following the detection of cell DNA damage.
Li-Fraumeni syndrome is the inheritance of a mutated p53 allele resulting in a 25-fold risk of developing cancer by 50 y/o
Mainfests with a wide variety of cancers at younger than expected ages
