Lecture 21: The Genetics of Cancer Flashcards
(51 cards)
1
Q
what are the two unifying themes about cancer genetics?
A
- cancer is a genetic disease
- different inheritance pattern than other genetic disorders
2
Q
cancer is a genetic disease caused by
A
- mutations in genes that regulate cell division, or activate cell death
- environmental factors
3
Q
how does cancer have a different inheritance pattern than other genetic disorders?
A
- inherited mutations can predispose to cancer (germline)
- mutations causing cancer occur in somatic cells
- mutations accumulate in clonal descendants of a single cell
4
Q
describe two changes in signalling systems can lead to cancer
A
- protein that stimulates cell division starts working more
- protein that blocks the cell from dividing stops working
5
Q
cancer phenotypes include (4)
A
- uncontrolled cell growth
- genomic and karyotypic instability
- potential for immortality
- ability to invade and disrupt local and distant tissues
6
Q
molecular changes causing uncontrolled cell growth
A
- autocrine stimulation
- loss of contact inhibition
- loss of apoptosis
7
Q
autocrine stimulation
A
- when autocrine stimulation is absent, the cell receptor responds to the binding of a ligand produced elsewhere
- when autocrine stimulation is present, the cell receptor responds to the binding of a ligand produced in the cell
8
Q
loss of contact inhibition
A
- contact inhibition present: normal cells stop dividing once they cover a surface and touch neighbouring cells.
- contact inhibition absent: cancer cells continue to divide even after touching neighboring cells.
9
Q
loss of apoptosis
A
- following irradiation, most normal cells recognise the DNA damage that has occurred, leading to cell death
- following irradiation, most cancer cells continue dividing despite the DNA damage that has occurred
10
Q
how can defects in DNA repair machinery lead to genomic instability?
A
- replication occurs
- mismatch is created by DNA polymerase
- in a normal cell, this mismatch is corrected by mismatch repair and the following round of replication results in a normal DNA sequence
- in a cancer cell, the mismatch is not correct and the following round of replication results in a mutated DNA sequence
11
Q
karyotypic instability
A
- increased rate of chromosomal aberrations
- this includes gains/losses of chromosomes, chromosomal rearrangements, and formation of abnormal structures (eg dicentric chromosomes)
12
Q
draw and explain the graph for immortality of cancer cells
A
number of passages (X-Axis): where you take a cell, grow it, move it to another plate, and repeat
cumulative cell number (Y-axis)
- in normal cells, as number of passages increases after a certain point, cumulative cell number plateaus
- in cancer cells, they lose the ability to stop passaging so the line is straight
13
Q
3 steps for the spread of cancer
A
- angiogenesis: the formation of blood vessels to distribute nutrients to all the cancer cells
- metastasis: where cancer cells break through the basement membrane and go to another body part
- evasion of immune surveillance
14
Q
multi-hit model of carcinogenesis
A
proposes that cancer arises through the accumulation of multiple genetic and epigenetic alterations in clonal copies of a single cell
15
Q
evidence for the clonal origin of tumours
A
- scientists explored this through X-inactivation in females
- they looked at proteins on the X chromosome
- in normal tissue, there was a mixture of cells with proteins from both X chromosomes
- in tumour cells, there was a mixture of cells with proteins from only one X chromosome
16
Q
two main pieces of evidence for the multi-hit nature of cancer
A
- lung cancer death rates: males started smoking around 1930 and lung cancer death rates peaked around 1990. females started smoking around 1950 and lung cancer death rates peaked around 2000.
- incidents of cancer increase exponentially between age 0 and age 80
17
Q
give an example of the familial genetic predisposition to certain types of cancer
A
- retinoblastoma is caused by inherited mutations in the RB gene
- individuals who inherit a single RB- mutant allele are more prone to this cancer as loss of heterozygosity through WT mutation is more likely
18
Q
two general types of cancer producing mutations
A
a) oncogenes
b) tumour suppressor genes
19
Q
oncogenes
A
- members of signal transduction systems that produce proteins promoting cell proliferation
- cancer occurs when an oncogene obtains a gain-of-function mutation in ONE allele
20
Q
tumour-suppressor genes
A
- members of cell cycle checkpoint control and DNA repair mechanisms
- produce protein that inhibits cell proliferation or protects the genome
- cancer occurs when a tumour-suppressor gene obtains a loss-of-function mutation in BOTH alleles
21
Q
approaches to identifying oncogenes
A
- tumour-causing viruses
- transform normal mouse cells with human tumour DNA
- genome wide functional genes
22
Q
role of tumour-causing viruses in identifying oncogenes
A
- Retroviral DNA integrated near proto-oncogenes in cellular DNA.
- The viral promoter overactivated these genes, turning them into activated oncogenes.
- Deletion and fusion events also captured proto-oncogenes into the viral genome.
- Studying these viral fusion genes revealed which host genes could drive cancer.
23
Q
role of transformation of normal mouse cells with human tumour DNA in identifying oncogenes
A
- human tumor DNA transformed normal mouse cells, causing them to grow uncontrollably.
- By isolating the integrated human DNA, scientists identified specific mutated proto-oncogenes
24
Q
oncogenic changes: constitutive activation - Bcr/c-abl
A
Bcr: signaling molecule involved in regulating cell growth and cytoskeletal organization.
Abl: regulating cell differentiation, division, adhesion, and response to DNA damage.
- normal chromosome 2 (containing abl)
- normal chromosome 22 (containing bcr)
- both chromosomes break and swap segments
- changed chromosome 9 now does not contain abl, whilst changes chromosome 22 (Philadelphia Chromosome) contains bcr-abl which is now constitutively active -> cancer
25
oncogenic changes: constitutive activation - oncogenic forms of RAS
RAS is involved in the cell proliferation pathway
- in a normal cell, the binding of a growth factor to a receptor activates RAS, causing proliferation
- in a cancer cell, proliferation occurs even without the growth factor
26
oncogenic changes: constitutive activation - Her2 gene amplification
Her2 regulates cell growth
- in normal cells, each cell has 2 copies of Her2
- in breast cancer cells, each cell has more than 2 copies of Her2, leading to multiple copies of the Her2 receptor on the surface of the cell and the cell being able to activate itself for cell growth
27
how can tumour suppressor genes be identified?
through genetic analysis of families with inherited predisposition to cancer
28
how does inheritance of mutant suppressor alleles lead to increased chance of cancer?
- one normal allele is sufficient for normal cell proliferation in heterozygotes
- however, the wild-type allele in somatic cells of the heterozygote can be lost or mutated, leading to abnormal cell proliferation
29
events causing loss of heterozygosity in somatic cells of RB+/RB- individuals
- nondisjunction (loss)
- uniparental disomy
- mitotic recombination
- gene conversion
- deletion
- point mutation
30
what are the usual functions of tumour suppressor genes whose mutations decrease the accuracy or rate of cell proliferation
1. negative regulators of cell proliferation
2. components of cell cycle checkpoints (before S phase, after G2)
3. involved in DNA damage repair
4. promote apoptosis when DNA damage is excessive
31
how do cell cycle checkpoints ensure genomic stability?
checkpoints monitor the genome and cell-cycle machinery before allowing progression to the next stage of the cell cycle
32
G1 to S checkpoint
DNA synthesis can be delayed to allow time for repair of DNA that was damaged during G1
33
G2 to M checkpoint
mitosis can be delayed to allow time for repair of DNA that was damaged during G2
34
spindle checkpoint
monitors formation of mitotic spindle and engagement of all pairs of sister chromatids
35
describe the role of p53
1. p53 is a transcription factor that is activated by UV or ionising radiation
2. induces expression of CDK inhibitor, p21
3. p21 inhibits the activity of CDK4 - cyclinD complexes
4. if these complexes are inhibited, then Rb is not phosphorylated
5. Rb remains unphosphoryalted so it can inhibit E2F, preventing entry into the S phase of the cell cycle
36
if Rb is phosphorylated
E2F is no longer inhibited, so the genes necessary for DNA synthesis are activated
37
how does loss of P53 function lead to genomic instability?
- inactive p53 means p21 is not induced
- p21 cannot inactivated CDK4/cyclin D so this complex phosphorylates Rb
- E2F is constitutively phosphorylated, causing the cell to enter the S phase
- if mutations in the DNA have occurred, these are not repaired before mitosis
38
how does chemotherapy work?
targets proliferating cells:
- disrupts DNA replication
- prevents formation of the mitotic spindle
39
problem with chemotherapy
drugs used in chemotherapy target rapidly dividing cells; however, they also affect normal dividing cells, leading to adverse side effects
40
strategies to target the unique molecular properties of the cancer cells
- design drugs that specifically bind and inactivate oncogenic proteins
- mobilise the immune system to eradicate cells that overexposes a particular oncogene
41
oncogene protein inactivation: Gleevec
- typically the Bcr/c-Abl enzyme binds to ATP and a target protein, leading to chronic myelogenous leukaemia
- Gleevec binds to the ATP active site, inhibiting it
42
monoclonal antibodies to growth factor receptors: Herceptin
- typically, abundant Her2 in cancer cells leads to dimerization, turning the signal transduction pathway on and leading to cell proliferation
- Herceptin attracts the immune system cells to attack the cancer cells. this prevents dimerization and recruits killer T cells, turning the signal transduction pathway off and stopping cell proliferation
43
strategies tailored for tumour suppressor genes
- many tumour suppressor gene products are involved in DNA repair/DNA damage checkpoints
- in many cells excessive DNA damage induces programmed cell death
strategy: utilise the ultra sensitivity of cancer cells to DNA damage to elicit self-destruction by inducing programmed cell death
44
strategies tailored for tumour suppressor genes: LOF-PARP inhibitors
PARP inhibitors block the action of poly(ADP-ribose) polymerase, needed to mend nicks in DNA
without PARP, nicks in DNA -> double stranded breaks -> self-destruction by apoptosis
45
how are PARP inhibitors an example of tumour selective cytotoxicity?
in a normal cell with a functional homologous recombination (HR) pathway. there is HR-mediated DNA repair of the double-strand breaks, enabling cell survival. some cancer cells do not have this
46
why are PARP inhibitors not for all cancer cells?
- they increase genomic instability
- in cells with dysfunctional apoptotic pathways, this may simply lead to the accumulation of new cancer associated mutations
47
personalised medicine
customising medicine by designing the most effective drug therapy and treatment strategies based on the specific genetic profile of a patient
48
how can we solve the problem of whole-genome sequences of cells derived from different regions of the same tumour having somewhat different genomes (heterogeneity)?
- possibly most effective treatments would be directed against the common (early_ mutations to target all the cells
- help find the driver mutations and 'druggable' targets
49
how can we use immunotherapy to prevent the evasion of immune surveillance?
monoclonal antibody can prevent the interaction between tumour cells and T cells so that the T cell can no longer recognise the tumour cell
50
car-t cell therapies
Car T cells have a chimeric antigen receptor which can recognise the cancer cell
51
challenges with immunotherapy
- easier to implement for hematopoietic cancers (unique antigens)
- can induce a cytokine storm (life-threatening)
