Molecular Oncogenesis Flashcards
What are typical genes that are altered that can cause cancer?
- Proto-oncogenes
- Tumor Suppressor
- Anti-apoptosis
- Apoptosis genes
- DNA repair
How can growth factors and their receptors contribute to cancer?
Some cells gain the ability to produce growth factors that will continually allow them to proliferate
Typically growth factor receptors are expressed intermittently, but an alteration may overexpress allowing frequent activation - Tyrosine Kinase activation of many pathways.
What is commonly over expressed in astrocytoma and osteosarcoma?
SIS gene is altered and overexpresses Beta-PDGF
What gene product is amplified commonly in breast cancer and what drug therapy can be used against it?
ERB-B2 produces overexpression HER2 tyrosine-kinase growth factor receptors.
Trastuzumab antibody that blocks the receptor from binding the growth factor
If a patient was identified to have a c-KIT gene mutation producing GISTs what might be a viable therapuetic?
Imatinib - blocks tyrosine kinase activity
If a patient has analysis performed his cancer and it identifies a RAS mutation, what does that mean?
Secondary messenger mutation that can continue giving a growth signal, even when there is no stimulus.
–Usually a GTPase (breaks down GTP when in active form), so may be unable to deactive the GTP-activated protein.
How does a c-ABL gene contribute to cancer?
The abl-gene is translocated from the #9 chromosome to #22 where it combines with bcr-gene and loses regulation of the tyrosine kinase receptor.
What drug therapy can be used on a c-ABL gene translocation?
Imatinib - blocks the tyrosine kinase activity
What is a major transcription factor associated with cancers that is mutated?
MYC-oncogene, activates many genes and when altered causes constant stimulation.
What is a common abnormality of the c-MYC gene?
Translocation from #8 to #14 and it’s placed next to the Ig-gene, which is stimulated frequently also activating the c-MYC gene causing frequent activation.
–Burkitt Lymphoma, B-cell tumors
How is the n-MYC different from the c-MYC and what does it indicate?
n-MYC can amplify itself constantly signaling activation, frequently involved in neuroblastoma. If n-MYC is found indicates poor prognosis. Tested for via FISH analysis.
What is Cyclin D’s relationship with Rb protein?
As the cell is growing in G1 phase a build up of CyclinD activates CDK4, which phosphorylates Rb allowing the cell to transition into S-phase.
How can Cyclin D1 be involved in cancer?
Translocation of #11 to #14 fusing IgH-D1, causing an over expression and increased cell cycle progression.
What is the two hit hypothesis?
Tumor suppressor genes have a pair of genes and must be altered to promote cancer growth.
How does the Rb gene regulate the cell cycle?
Rb binds E2F until Cyclin D activates CDK4, that phosphorylates Rb releasing E2F that allows progression of the cell cycle. If Rb dysfunctional then E2F can continually activate cell cycle progression
What is the etiology of Familial Adenomatous Polyposis?
Inherited mutations of APC, which are involved in the breakdown of B-catenin that regulate gene expression. Usually B-catenin is bound to APC until stimulus allows APC to release for desired transcription, when mutated constant stimulation.
An individual 25y/o has been being evaluated for sarcoma and they tell him he has Li-Fraumeni Syndrome, what is the cause of his cancer?
Li-Fraumeni Syndome is when there is an inherited mutated p53 gene increasing chance of cancer by 25x.
Normal functions of p53:
- initiation of apoptosis following DNA damage
- causes cell cycle arrest
What is the role of BCL-2 in apoptosis and where is it frequently found mutated?
Anit-apoptosis gene over expressed in my lymphomas
- Altered in Translocation 14 –> 18, causing inhibition of normal apoptosis
- *Follicular Lymphoma
What are the types of chemical carcinogens and examples?
Direct Acting on DNA - Alkylating Agents
Indirect Acting, procarcinogens, that are processed into a carcinogen by cytochromes that can then effect DNA
What are the two modes of metabolizing polycyclic hydrocarbons?
- CYP1A1
- Glutathione-S-Transferase
What are the most potent chemical carcinogens?
Polycyclic Aromatic Hydrocarbons, they are initiators that cause permanent DNA damage.
What types of cancer are usually from ionizing radiation?
Thyroid cancer
Leukemias
How can microbes promote cancers?
- Viral genome integration causing over expression of viral products or host genes
Ex. HPV, Hepatitis - Recurrent inflammation and regenerate causes accumulation of damage leading to cancer
Ex. Hep B and C, H. Pylori
What kind of microbe can be the cause of Burkitt Lymphoma?
EBV infection in an immunocompromised individual.
Why and how can H. Pylori cause gastric adenocarcinoma?
Host Inflammatory response, regeneration –> metaplasia
How does Hep B and C increase your chance of hepatic cancer?
Chronic hepatic injury due to constant regeneration increased risk of mutations and ultimately cancer.
