LECTURE NOT FIRST AID Cancer Genetics Flashcards
What are cyclin dependent kinases and how do they work?
Passage through the cell cycle is controlled by the activity of a group of intracellular enzymes termed cyclin-dependent kinases, which form complexes with regulatory proteins termed cyclins.
When CDKs complex with the cyclins, CDKs gain the ability to phosphorylate different proteins to regulate the cell.
Studies of cancers show that in order for a cell to become malignant, it needs to leave the cell regulations controlled by the CDKs, so they need to escape regulation of DNA damage repair, signal transduction networks, and cell cycle control.
Most of these genes to mutate in order to escape this control are the ones active during the shift from G1 to S. Which genes used during this shift are the ones usually at fault?
RB and p53
Proto-oncogenes vs. oncogenes
Proto just means its a gene that could become oncogenic, i.e., a gene that control cell proliferation for normal cell growth.
Oncogene means that proto-oncogene isn’t regulated anymore so it’s just replicating stuff like crazy.
Discuss what causes Burkitt’s Lymphoma
t(8;14) that causes the active promoter of the Ig Heavy chain to be slapped right next to the coding region of the myc-gontrol gene, which is usually under strict control.
Discuss what causes CML (chronic myelogenous leukemia)
t(9;22) - Leads to unrestricted growth of granulocytes in the bone marrow.
It fuses BCR and ABL to make a gene that leads to a hybrid protein that constitutively activates tyrosine kinase , leading to unregulated activation of cell growth pathways (mostly from the ABL product, which is usually tightly controlled).
What is contact inhibition?
In culture, cells that touch each other stop replicating.
Cancer cells do not stop, they have lost this inhibition.
Discuss retinoblastoma (you’ll want to be vaguely familiar with this disease)
The first tumor suppressor gene to be cloned was the gene responsible for familial
retinoblastoma.
Retinoblastomas are retinal cell tumors, and often develop in young children (between birth and 4 years of age). About 60% of the cases are sporadic, but the rest are inherited in an autosomal dominant manner. In comparison to sporadic cases, familial retinoblastomas usually develop at younger ages, often in both eyes. These patients also show a 400-fold increased risk of other tumors, particularly osteosarcomas, as young adults.
Discuss the two-hit hypothesis
The two-hit hypothesis (Knudson hypothesis) was proposed as an explanation for the two forms of these cancers, familial and sporadic. Sporadic retinoblastoma arises when, by chance, both copies of the RB1 gene have been inactivated by somatic mutation. This should be rare, because it depends on the occurrence of two low frequency events in the same cell. In the familial form, an inherited mutation inactivates one copy of the RB1 gene. The other copy of the gene is normal, and indeed most of the retinal cells do not form tumors. Tumors arise when the
other allele is inactivated by somatic mutation.
How does RB1 work?
RB1 plays a critical role in regulating the progression of cells through the cell cycle. It binds an important transcription factor, E2F, that directs the transcription of genes for enzymes involved in DNA synthesis. When bound to RB1, E2F is inactive and DNA synthesis is blocked. When RB1 is phosphorylated by CDKs, it releases the transcription factor and DNA synthesis can proceed
How does p53 work?
If the cell senses the
presence of DNA damage, the p53 transcription factor is activated. This leads to the expression of a Cdk-cyclin inhibitor, which binds the Cdk-cyclin complex and prevents it from phosphorylating RB1.
This gives the cell time to repair itself.
p53 can also cause the cell to initiate apoptosis after extensive DNA damage has occurred.
What is Li-Fraumeni syndrome?
Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome due to a germline mutation in p53. In contrast to most inherited cancer susceptibility disorders, patientswith this syndrome can develop a wide variety of tumors, including bone and soft tissue sarcomas, breast cancers, brain tumors and leukemias, with half the patients developing a first cancer by age 30.
What do BRCA1 and BRCA2 do?
BRCA1 and BRCA2 are involved in regulating the cellular response to double-strand DNA breakage. BRCA1 is involved in DNA repair and/or DNA damage signaling for checkpoint activation. BRCA2 is likely to be directly involved in repairing the double-strand DNA break.
What is chromothripsis?
The multistep model for cancer development suggests that genomic changes that lead to cancer happen one step at a time, resulting in the loss of tumor suppressor genes and the activation of oncogenes.
In 2011, a striking new phenomenon, termed chromothripsis (meaning chromosome shattering into pieces in Greek), was reported, which suggests that all these changes may happen as a single step in some cancers.
One key feature of Chromothripsis is that a single chromosome can contain many rearrangements as if this chromosome was cut into many pieces and then randomly stitched back together. Chromothripsis has been found in about 2-3% of cancers. Interestingly, about 25% of studied bone cancers displayed evidence of chromothripsis
How does Chromothripsis occur?
The mechanism of chromothripsis has been revealed recently, and it has been shown to involve the formation of micronuclei.
During mitosis, an error in chromosome segregation can lead to a lagging chromosome not properly attached to the mitotic spindle. After nuclear envelope forms around this single chromosome, a micronucleus is formed. The nuclear envelope for the micronucleus is not stable and can collapse, triggering DNA damage and problems in DNA replication.
This explains well why a single chromosome contains so many mutations.
