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BIOL253: Genetics > Cancer > Flashcards

Cancer Flashcards

1
Q

What is the definition of cancer?

A

heterogeneous group of around 200 diseases characterised by:

  • uncontrolled cell growth
  • invasion and metastasis
  • undifferentiated cells
  • dysregulation of cell signalling responses
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2
Q

What is carcinogenesis?

A

the process of cancer formation driven by mutations and epigenetic changes in somatic tissues

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3
Q

Define hyperplasia and dysplasia?

A

Hyperplasia = increased cell division

dysplasia = cells change form

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4
Q

What is the difference between a benign and malignant neoplasm?

A

Benign neoplasm = in situ localised cell overgrowth

malignant neoplasm = invasion of surrounding tissue and ability to metastasise

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5
Q

What are the names of the cancers derived from the following tissues?

1) Epithelium
2) Stromal tissue
3) Blood

A

1) carcinoma (90% of all human cancers)
2) sarcoma
3) leukaemia, lymphoma

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6
Q

Why are actively dividing cells predisposed to forming tumours?

A

rapid cell division so increase in probability of unrepaired DNA replication errors so increase in probability of mutations

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7
Q

Are are tumour cells different?

A

Yes but they are monoclonal (meaning they derived from the same starting cell - but have picked up mutations along the way so are not identical)

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8
Q

Describe how mutation drives the formation of cancer

A

1) mutation in single cell leading to reduced control of cell division and clonal expansion producing a benign tumour
2) rapid division increases rate of other mutations and results in development of another mutations that confer growth advantage and result in clonal expansion, rapid division, and escape of checkpoints to form a malignant tumour
3) malignant tumour invades surrounding tissue and cancer cells can enter the bloodstream or lymphatics where they are transported to secondary sites within the body

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9
Q

What is the difference between a driver mutation and a passenger mutation?

A

A driver mutation directly or indirectly confers a selective growth advantage to the cell allowing for increased proliferation and evasion of checkpoints

A passenger mutation doesn’t confer a selective growth advantage in any way, but may affect morphology or metabolic pathways

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10
Q

What are the three positive and three negative regulators of cell proliferation?

A

Positive regulators:

1) classical oncogenes (stimulate proliferation)
2) telomerase (stimulates proliferation)
3) anti-apoptotic genes (inhibit apoptosis)

Negative regulators:

1) classical tumour suppressor genes (inhibit proliferation)
2) indirectly acting tumour suppressor genes (E.g. in genome maintenance) (inhibit proliferation)
3) apoptotic genes (stimulate apoptosis)

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11
Q

How is the balance between cell proliferation and apoptosis regulated?

A

endogenous and exogenous signals activate signalling pathways that may stimulate proliferation (E.g. mitogen signalling activates transcription factors that express proliferative genes) or arrest cell cycle (E.g. growth inhibiting factor signalling activates transcription factor that results in expression of cell cycle inhibitors)

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12
Q

List the events of the cell cycle including the checkpoints

A

G1 phase = growth before chromosome replication
(G0 = quiescent cells)
RESTRICTION POINT CHECKPOINT (favourable environment - if not = remain in G0)
S phase = DNA synthesis produces two identical sister chromatids
S-PHASE CHECKPOINT
G2 phase = growth and preparation for mitosis, mitotic spindle begins to form
G2/M CHECKPOINT (all DNA replicated, favourable environment - if not - remain in G2)
M phase = mitosis and cytokinesis
METAPHASE TO ANAPHASE CHECKPOINT (all chromosomes attached to spindle correctly)

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13
Q

What proteins drive the progression through the cell cycle?

A

cyclin dependent kinases (Ser/Thr kinase activity only present when bound to its cyclin)

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14
Q

How do cyclin and CDK levels vary throughout the cell cycle?

A

Cdk proteins are constitutively expressed throughout the cell cycle

Cyclin expression oscillates (rise and fall) throughout the cell cycle so they are only expressed when the Cdk activity is required.

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15
Q

What are the cyclin/CDKs present at each stage of the cell cycle?

A

G1-Cdk = cyclin D - Cdk 4/6

G1/S-Cdk = cyclin E - Cdk2

S-Cdk = cyclin A-Cdk 2 (SPF)

M-Cdk = cyclin B - Cdk 1 (MPF)

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16
Q

How do cyclin-Cdk complexes drive cell cycle progression?

A
  • activate the next cyclin-Cdk complex (E.g. by promoting expression of the next cyclin)
  • proteolysis of key enzymes
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17
Q

How is M-Cdk activity regulated?

A

1) association with cyclins
2) activation by phosphorylation of Thr160 by Cdk-activating kinases (CAKs)

3) phosphorylation status of Try15 and Thr14 of M-Cdk
- Wee1 kinase phosphorylates Try15 and Thr14 = inhibit
- Cdc25 phosphatase dephosphorylates Tyr15 and Thr14 = activates

4) CDK inhibitor proteins (CDKIs) inhibit Cdks

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18
Q

How does G1-Cdk drove progression through the restriction point checkpoint?

A

in G0 and early G1 = transcription factor E2F is bound to, and inhibited by, Rb protein.

Mitogens bind to receptor, results in conformational change that results in phosphorylation of the cytoplasmic domain of the receptor. Activation of signalling pathway that results in activation of Ras and leads to a MAPK signalling cascade that ends in transcriptional response:
- activation of Myc transcription factor leads to cyclin D expression

Cyclin D then associates with Cdk4/6 to form the G1-Cdk.

  • G1-Cdk phosphorylates the Rb protein, causing E2F to be released.
  • E2F activates transcription of genes involved in the G1/S transition (E.g. cyclin E, cyclin A, enzymes for DNA synthesis)
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19
Q

What type of gene is Rb?

A

tumour suppressor (Rb protein binds to E2F and prevent cell cycle progression until sufficient growth factor signalling)

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20
Q

How does the M-Cdk/MPF promote the G2/M transition?

A
  • induces spindle assembly
  • initiate chromosome condensation
  • ensures sister chromatids are attached to opposite spindle poles
  • promotes breakdown of nuclear envelope
  • rearranges the actin cytoskeleon
  • rearranges the Golgi apparatus
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21
Q

How is the regulation of the G2/M transition regulated?

A

Phosphorylation status of M-Cdk/MPF:

  • Wee1 kinase phosphorylates Y15 and T14 to inhibit activity of MPF
  • expression of Cdc25 phosphatase in late G2/M phase results in removal of inhibitory phosphates and activation of MPF
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22
Q

How do cyclin-Cdks drive cell cycle forward by proteolysis of key proteins?

A
  • Phosphorylate cell cycle regulators = substrates for the SCF ubiquitin ligase complex
  • phosphorylate ubiquitin ligases to activate them (E.g. APC - anaphase promoting complex)
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23
Q

What two things does progression through the cell cycle depend on?

A

1) activation of specific Cdk activity (specific to phase)

2) elimination of proteins from previous cell cycle phases by ubiquitin mediated proteolytic degradation

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24
Q

Describe the action of SCF ubiquitin ligase complex controls the G1/S phase transition?

A

has three subunits: Skp1, Cullin, and F-box protein

  • p27 Cdk inhibitor (CDKI) inactivates S-Cdk/SPF during G1
  • phosphorylation of p27 by the G1/S-Cdk to target it for polyubiquitination by SCF and subsequent degradation in the proteasome
  • S-phase SCF ubiquitinates G1 factors (involved in replication origin licensing) that prevent entry into S phase, and targets them for proteasomal degradation
  • Cyclin E (of G1/S-Cdk) is targeted for degradation by SCF aswell
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25
Q

How is M-Cdk/MPF activity regulated by the APC ubiquitin ligase?

A

Cdc20 expression in G2 phase binds to APC, activating it, promoted by phosphorylation by M-Cdk
- results in ubiquitination of cyclin B of MPF by APC and subsequent degradation by the proteasome.

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26
Q

How does the APC-Cdc20 ubiquitin ligase promote the metaphase to anaphase transition?

A
  • M-Cdk/MPF phosphorylates APC to allow binding to Cdc20
  • APC-Cdc20 degrades securin, which activates separase
  • Separase cleaves cohesin complex holding the two sister chromatids together, promoting anaphase
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27
Q

How does APC-Cdh1 ubiquitin ligase ensure exit from mitosis and control of G1?

A

Exit from M phase:

  • Degradation of M-Cdk cyclin B by APC-Cdc20 during M phase results in reduced phosphorylation of APC so dissociation between APC and Cdc20
  • APC binds alternative activator Cdh1, which continues to ubiquitinate M-Cdk cyclin B for degradation allowing exit from M phase

Control of G1 phase:

  • APC-Cdh1 remains active in early G1
  • Increase in G1/S-Cdk (Cyclin E - Cdk2) phosphorylates and inactivates Cdh1
  • APC remains inactive until activated by association with Cdc20 in M phase.
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28
Q

What are responses when errors are detected by cell cycle checkpoints?

A

1) activation of DNA repair
2) cell cycle arrest
3) inhibit further DNA synthesis (S-phase checkpoint)

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29
Q

What is the structure of a checkpoint pathway (E.g. for a DNA double-stranded break)

A
  • damage specific sensors bind to the damaged DNA (MRN and KU for DSB)
  • sensors activate transducer regulatory kinases to initiate the damage response (ATM for MRN and DNA-PKCS for KU)
  • transducers activate effectors, which perform checkpoint functions (E.g. DNA repair proteins, proteins that arrest cell cycle)
  • prolonged arrest leads to apoptosis in multicellular organisms
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30
Q

Describe the activation of the spindle checkpoint (metaphase to anaphase checkpoint)

****Cdc20??******

A
  • lack of attachment, incorrect attachment or chromosomes to spindle - monitored by spindle assembly checkpoint
  • APC-Cdc20 is the main effector and is activated to prevent transition into anaphase and mitotic exit
31
Q

How do mitogens promote cell division/passage through restriction point in normal cells?

A
  • Mitogen signalling activates TOR kinase signalling pathway that results in increase in protein synthesis to increase the size of a cell.
  • mitogens stimulate cell division by activating cyclin-Cdks (mitogen signalling results in MAPK phosphorylation cascade that activates transcription factors that increase expression of G1 and S phase cyclins) - E.g. Myc transcription factor increase expression of cyclin D (G1 cyclin)
32
Q

What is an oncogene? what happens when mutated?

A

Stimulates cell proliferation or inhibit apoptosis as a proto-oncogene

when mutated, this leads oncogenes that increase the activity of a protein

33
Q

What are the 10 hallmarks of cancer?

A
  1. Self-sufficiency in growth signalling
  2. ability to evade growth suppressors
  3. Activating invasion and metastasis
  4. Enabling replicative immortality
  5. Inducing angiogenesis
  6. resistance to apoptosis
  7. de-regulating cellular energetics
  8. Avoiding immune destruction
  9. Genome instability and mutation
  10. Tumour promoting inflammation
34
Q

Oncogenic mutation are genetically ___________

A

dominant (mutation of a single allele is sufficient to contribute to carcinogenesis)

35
Q

What are the six major classes of cellular oncogenes?

A
  1. mitogens
  2. mitogen receptors
  3. signal transduction component
  4. transcription factors
  5. cell cycle drivers
  6. cell death inhibitors.
36
Q

What are the three types of oncogenic mutations (turn a proto-oncogene into an oncogene) and what are their results?

A

1) Translocation (gene moved to new locus so now under control of a poorly controlled or constitutively active promoter) = excess protein
2) Gene amplification (multiple copies of the gene) = excess protein
3) Point mutation (more common) = hyperactive or degradation-resistant protein

37
Q

Give an example of a mitogen receptor oncogene:

- name, types of mutation, results of mutation

A

name = EGFR (epidermal growth factor receptor)

Types of oncogenic mutations:

  • amplification = more receptors = increased signalling
  • deletion = truncated receptor lacking extracellular domain = constitutively active in absence of mitogen

Results:
- promotes self-sufficiency in growth signalling by constitutive activation of pathway from EGFR

38
Q

Give an example of a signal transduction component oncogene:

- name, types of mutation, results of mutation

A

name = Ras protein

  • small GTPase (hydrolyses GTP to GDP to inactivate itself)
  • mitogen binds to receptor causing GDP exchanged for GTP, activating Ras
  • Ras activates signalling cascade via Raf kinase

Types of oncogenic mutation:
- mutations at codons 12, 13, and 61 = prevent GTPase activity = constitutively active Ras

Results:
- promotes self-sufficiency in growth signalling by constitutive activation of pathway from Ras

39
Q

Give an example of a transcription factor oncogene:

- name, types of mutation, results of mutation

A

name = Myc protein
- stimulates cell growth and division in response to mitogen signalling

Types of oncogenic mutation:

  • gene amplification = increased expression of Myc = hundreds of copies resulting from rearrangements that bring sequences from several chromosomes together
  • point mutation = stabilises Myc = resistant to degradation
  • translocation = under control of more active promoter so increased expression

Results:
- promotes self-sufficiency in growth signalling

40
Q

What is the cause of Burkitt’s Lymphoma?

A

Translocation brings the MYC gene under control of sequences that normally drive the expression of antibodies in B cells - MYC mutant B cells proliferate to form a tumour

41
Q

Give an example of a cell cycle regulator oncogene:

- name, types of mutation, results of mutation

A

name = Cyclin D - Cdk4 (G1-Cdk)

  • CCND1 gene encodes cyclin D
  • CDK4 gene encodes Cdk4

Types of oncogenic mutation:
- amplification:
- amplification of CCND1 results in over-expression of
cyclin D
- amplification of CDK4 results in over-expression of
Cdk4
= inappropriate expression of G1-Cdk = unregulated phosphorylation of Rb = release of too much E2F = increase transcription of cyclin E and cyclin A = drives progression through restriction point in absence of mitogen signalling
- mutation within CDK4 results in Cdk4 resistant to p16 inhibition so promotes inappropriate entry into S phase

Results:
- promotes self-sufficiency in growth signalling

42
Q

What are the characteristic changes of a cell undergoing apoptosis?

A

cell shrink and condense

cytoskeleton collapses - results in blebbing of plasma membrane

nuclear envelope disassembles

nuclear chromatin condenses and breaks into fragments

cell surface chemically altered - signals for engulfment by neighbouring cell or macrophage

43
Q

What are the two pathways of apoptosis?

A

Extrinsic pathway - triggered by extracellular signal proteins binding to cell surface death receptors

Intrinsic pathway - release of mitochondrial proteins into cytosol that are normally present in the intermembrane space

44
Q

How is the intrinsic pathway of apoptosis regulated by Bcl2 family proteins? and how do mutations in these genes lead to cancerous phenotype?

A

Anti-apoptotic proto-oncogenes activated to increase the levels of Bcl2 blocks apoptosis and results in immortalised cells that resist cell death.

Pro-apoptotic tumour suppressor gene activated to increase the levels of Bax, which forms a Bax-Bax homodimer which induces apoptosis

Mutations leading to cancerous phenotype:

  • oncogenic mutation within anti-apoptotic gene can result in constitutive expression of Bcl2 and result in cancerous phenotype
  • mutation within the pro-apoptotic gene can switch off the tumour suppressor gene and lead to decreased activation of pro-apoptotic pathways result in cancerous phenotype

= both lead to cells resisting apoptosis

45
Q

How does oncogene MDM2 result in cancerous phenotype?

role, types of mutation, results of mutation

A

Role:
A ubiquitin ligase that regulates levels of p53 (a tumour suppressor gene that prevents progression through the cell cycle when DNA is damaged, can promote apoptosis)
- no DNA damage = MDM2 ubiquitinates Lys residues in p53 C-terminal domain = degradation, remaining p53 is exported from nucleus
- DNA damage = kinase activity (ATM, ATR, CHK2) results in phosphorylation MDM2 and p53 = prevents interaction = allows p53 tetramerises and accumulation

Types of oncogenic mutation:
- Amplification of MDM2 prevents accumulation of p53 (associates with more p53 and mediate degradation at a higher rate)

Results:

  • Evasion of growth suppressors
  • resistance to apoptosis
46
Q

How does oncogene telomerase result in cancerous phenotype?

role, types of mutation, results of mutation

A

Role:
- prevents shortening of telomeres
(In most somatic cells, telomerase in inactive - so, if telomere length becomes critical, cells withdraw from the cell cycle)

Types of oncogenic mutation:
- mutation results in overexpression = reactivates telomerase to prevent telomere shortening and allow indefinite cell division.

Results:
- replicative immortality

47
Q

What is a tumour suppressor gene?

A

normal role of TSG products is inhibition of cell division:

  • negative regulation of proliferative signalling
  • inhibition of cell division
  • pro-apoptosis
48
Q

How can mutations within a tumour suppressor gene lead to cancer?

A

Mutations resulting in a decrease in the normal activity of the tumour suppressor protein lead to loss of cell division inhibition

49
Q

Mutations in classical tumour suppressor genes are genetically ___________

A

Recessive (both alleles need to have the mutation to get an increased risk of cancer)

50
Q

What is retinoblastoma?

A
  • retinal cancer arising in immature retinal cells
  • affects 1 in 20000 children (routine screening in UK)
  • 87% of children worldwide with retinoblastoma die (almost exclusively in countries lacking good screening)

can be sporadic = no family history, unilateral, single tumour in one eye

can be hereditary = bilateral, multiple tumours (disease appears dominant)

51
Q

What is Knudson’s two hit mutation hypothesis?

A

Hereditary retinoblastoma
- one mutation is inherited, second mutation is sporadic

Sporadic retinoblastoma
- both mutations are sporadic

52
Q

Mutations in which gene cause retinoblastoma?

A

RB tumour suppressor gene

53
Q

How can the second hit mutation cause the loss of the second wildtype RB allele?

A

Can occur at the chromosome level resulting in loss of heterozygosity:

  • loss of chromosome carrying wildtype allele and replaced by duplication of the chromosome carrying the mutated allele
  • mitotic recombination between non-sister chromatids (most common)

Can occur at the gene level resulting in loss of gene but not loss of heterozygosity:

  • gene inactivation
  • epigenetic silencing (chromatin rearrangement that affects transcription)
54
Q

What is the normal role of the RB?

A
  • Binds to E2F and prevents its activation
  • G1-Cdk activation results in phosphorylation of Rb, releasing E2F, which acts as a transcription factor to increase expression of the genes required for G1/S transition (E.g. cyclin A, cyclin E)
55
Q

What are the consequences in rb/rb cells?

A
  • Rb protein is often truncated causing it to be unstable and unable to bind to E2F
  • E2F free to activate genes required for G1/S transition and S phase = cell progression and proliferation
  • results in sustained proliferative signalling
56
Q

What is the most commonly mutated gene in humans cancers?

A

p53 (approximately 50% of all sporadic cancers)

57
Q

what is p53?

A

A tumour suppressor gene that encodes for the p53 protein (a transcription factor). Its main function is to arrest the cell cycle to allow time for DNA damage repair

58
Q

How is p53 an effector of DNA damage checkpoints?

A

p53 acts downstream of effectors and transducers of DNA damage pathways:

  • ATM, ATR, CHK2 = phosphorylate Ser to activate N-terminal
  • MDM2 = ubiquitination of C-terminal Lys
  • p300 = acetylation of C-terminal Lys
59
Q

How does p53 accumulate in response to DNA damage?

A
  • no DNA damage = MDM2 interacts with p53 and ubiquitinates Lys residues in p53 C-terminal domain = degradation, remaining p53 is exported from nucleus
  • DNA damage = kinase activity (ATM, ATR, CHK2) results in phosphorylation MDM2 and p53 = prevents interaction = allows p53 tetramerises and accumulation
60
Q

What are the results of p53 accumulation?

A

Interacts with proteins:
- such as p300 (which acetylates histones to enhance transcription and acetylates p53 C-terminal Lys)

Promote transcription of target genes that promote cell cycle arrest and cell death:

  • p21 tumour suppressor gene, which binds to and inhibits the activity of Cyclin E - Cdk2 (G1/S-Cdk) to prevent progression through the cell cycle
  • GADD45, which binds to PCNA and blocks function as processivity factor (during S-phase replication checkpoint)
  • 14-3-3sigma tumour suppressor gene, which sequesters Cdc25 phosphatase required for activation of M-Cdk = arresting cells at G2/M boundary
  • Bax tumour suppressor gene, which is pro-apoptotic
  • FAS death receptors on cell surface to promote extrinsic apoptosis pathway
  • APAF1, which activates caspases involved in the intrinsic apoptosis pathway
61
Q

How do mutations in the p53 gene result in cancerous phenotype?

A

Mutation results in decreased level of p53:

  • no activation of DNA damage checkpoint
  • no cell cycle arrest (DNA repair doesn’t occur and cells keep dividing)
  • balance between Bax and Bcl2 shifts towards Bcl2 anti-apoptotic pathway and cell immortality
62
Q

Failure of checkpoints leads to what?

A

genetic instability, which can lead to accumulation of different mutations

63
Q

Failure of the spindle (M) checkpoint can lead to what?

A

Aneuploidy

64
Q

Failure of the chromosome duplication checkpoint can lead to what?

A

Polyploidy

65
Q

Failure of DNA damage checkpoint can lead to what?

A

Translocation (can result in oncogenes)

Deletion |(loss of TSG, constitutively active oncogene)

Amplification (oncogenic if occurs within a proto-oncegene)

66
Q

How can p53 activity be lost via inactivating mutation?

A
  • may be caused by specific environmental exposure:

Skin cancers = UV signature mutations C –> T or CC –> TT transition

Lung cancers = mutations in DNA bases subject to attack by polycyclic hydrocarbons in tobacco smoke

67
Q

Describe how some p53 mutations have a dominant negative effect

A

mutation of once copy is sufficient to disrupt the p53 protein function because the mutated subunits still tetramerise and disrupt the function of the entire protein and prevent activity.

68
Q

How can p53 activity be lost via degradation?

A

Cervical cancer

  • main cause is HPV types 16 and 18 (account for 70% of cases)
  • HPV produces oncoproteins E6and E7
  • E6 binds to p53, targeting it for degradation and preventing accumulation of p53 in response to DNA damage
  • E7 sequesters Rb, resulting in constitutively active E2F, which drives the cell through the G1/S checkpoint
69
Q

What are the two main ways that p53 activity can be lost?

A
  • inactivating mutation (skin and lung cancers)

- degradation (cervical cancers)

70
Q

Give four examples of gatekeepter TSGs (directly involved in restraining cell proliferation)
- name and consequence of mutation?

A

p53 = mutation results in loss of G1/S and G2/M checkpoints

p21 = mutation results in loss of G1/S and S checkpoints

RB = mutation promotes proliferation and activity of E2F

Bax = mutation results in failure to promote apoptosis of damaged cells

71
Q

Give two hereditary cancer syndromes that result from loss of gatekeep TSGs
- name of syndrome, mutant gene, inheritance, and main types of cancer

A

syndrome = Retinoblastoma
Mutant gene = RB1
Inheritance = dominant (inherit one mutant gene to create high risk of cancer susceptibility)
Types of cancer = retinoblastoma and osteosarcoma (later in life)

Syndrome = Li-Fraumeni Syndrome
Mutant gene = p53
inheritance = dominant
Types of cancer = Sarcomas, breast, leukaemias, adrenal, brain

72
Q

What is the difference between a gatekeeper and a caretaker TSG?

A

Gatekeeper TSG = directly involved in restraining cell proliferation

Caretaker TSG = maintains the integrity of the genome

73
Q

Mutations in which type of TSGs are commonly associated with familial cancer (and rarely seen in sporadic cancers)?

A

Mutations in caretaker TSGs

74
Q

Give three examples of hereditary caretaker mutations that are associated with increased cancer risk?

A
  1. Lynch syndrome
    - autosomal dominant inheritance of a mutant allele of one of the mismatch repair genes (MSH2, MLH1, PMS1, PMS2)
    - tumours show LOH
  2. Xeroderma pigmentosum
    - autosomal recessive inheritance of defective nucleotide excision repair capability - cannot repair UV inflected DNA damage
  3. Familial breast cancer
    - dominant inheritance of mutation within BRCA1 or BRCA2 nuclear protein genes (promote repair of DSBs by high-fidelity homology directed repair mediated by Rad51)
    - -> tumours show LOH (abnormal chromosomes due to DSB repair by NHEJ)

BIOL253: Genetics (6 decks)

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