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Undeleted > molecular basis of cancer > Flashcards

molecular basis of cancer Flashcards

1
Q

5 general characterisitcs of cancer

A
  1. increased and uncontrolled growth
  2. immortality
  3. loss of differentiation
  4. invasion
  5. metastasis
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2
Q

what begins cancer

A

non-lethal genetic damage

  • inherited or env.
  • single cell and expansion from it
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3
Q

what are genetic requirements for CA

A

multi-step hits

- change must be permanent and passed on

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4
Q

where does heterogeneity in CA come from

A

tumor progression and selection for those best able to survive

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5
Q

2 general ways genes are altered in CA

A
  1. mutation (inherited or aquired)

2. epigenetics

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6
Q

4 types of mutations

A
  1. point
  2. deletions/insertion
  3. amplification.copy number alteration
  4. translocation
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7
Q
  • 8 key features of molecular basis of CA
A
  1. self-sufficiency of growth signals
  2. insensitivity to growth-inhibitory signals
  3. defects in DNA repair
  4. evasion of apop
  5. limitless replicative potential
  6. sustained angiogenesis
  7. ability to invade and metastasize
  8. evasion of host immune system
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8
Q

3 types of oncogenes involves in self-sufficiency of growth signals

A
  1. oncogenes - promote cell growth in abscence of growth signals
  2. proto-oncogenes - non-mutated “normal” genes
  3. oncoprotein - product of oncegenes
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9
Q

what do oncogenes lead to

A

acceleration of normal growth patterns

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10
Q

5 steps to normal cell prolif that can be hijacked

A
  1. binding of GF to receptor
  2. transient and limited activation of GF receptor
  3. transmission of transduced signal
  4. induction and activation of nuclear regulatory factors
  5. entry and progression through cell cycle
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11
Q

5 types that oncoproteins may be

A
  1. growth factors
  2. GF receptors
  3. signal transduction molecules
  4. nuclear regulatory proteins
  5. cell cycle regulators
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12
Q

what is normal function, mutation, and clinical implication of Her2-neu

A

normally - growth factor receptor
mutation - many additional copies
clinical - many breast cancers over express and is associated with poor outcome

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13
Q

what is normal function, mutation, and clinical implication of Ret

A

normally - glial growth factor receptor in neuroendocrine cells - important for tissue migration in fetus
mutation - translocation and fusion product seen in thyroid CA, aquired point mutations
clinical - MEN type 2 and familial thyroid CA

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14
Q

what is normal function, mutation, and clinical implication of Ras

A

normally - receptor associated signal transduction molecule, normally self-limited by GTPase
mutation - mutated forms in many CA and continued signalling
clinical - testing for Ras in lung CA predicts responses

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15
Q

what is normal function, mutation, and clinical implication of Abl

A

normally - signal transduction molecule that can be activated without receptor binding
mutation - chromosomal translocation causes Bcr-Abl which is constinutively active (philly)
clinical - chronic myloid leukemia and acute lymphoblastic leukemia, target of imatinib

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16
Q

what is normal function, mutation, and clinical implication of Myc

A

normally - nuclear regulatory protein, early response gene, increase in activity
mutation - amplification or translocation
clinical - amplification seen in breat, colon and lung, translocation seen in burkitts lymphoma

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17
Q

what is normal function, mutation, and clinical implication of Cyclin-D

A

ormally - cell cycle regulator - acts with cyclin dependent kinases to move the cell through the cell cycle
mutation - amplification or translocation
clinical - amplification seen in breast, esopha. and liver CA, translocation seen in melanoma and sarcomas

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18
Q
  1. what is responsible for insensitivity to growth inhibition
A

tumor supressor genes (brakes) - loss of function in mutations

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19
Q

3 things a tumor supressor gene does

A
  1. regulate or halt cell growth
  2. checkpoints and brakes on cell cycle
  3. linked to apoptosis pathways
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20
Q

5 things that a tumor supressor may be

A
  1. transcription factor
  2. cell cycle inhibitor
  3. signal transduction molecule
  4. cell surface receptor
  5. regulator of cellular response to DNA damage
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21
Q

4 key tumor supressor genes

A
  1. Rb ( cell cycle inhib)
  2. Cyclin dependent kinase inhibitor (p16)
  3. APC (inhibitor of cell transduction)
  4. p53
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22
Q

2 main cell cycle checkpoints for DNA damage

A
  1. G1/2 (Rb, p53, ATM, ATR)- assess damage and commit to replication or not
  2. G2/M (p53) - reassess and repair before mitosis
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23
Q

what is normal function, mutation, and clinical implication of Rb

A

normally - cell cycle regulator
- blocks entry of cell into S phase
- bind E2F and stops transcription
- if activated then release E2F and transcription occurs
mutation - 2 hits required to mutate Rb - may be inherited or aquired
clinical - retinoblastoma

24
Q

what is loss of heterozygostiy

A

heterozygosity does not affect cell behavior, but need both changed to get outcome

25
Q

what is normal function, mutation, and clinical implication of cyclin dependent kinase inhibitor

A

normally - inhibits CDK to stop cell cycle at various points

clinical - mutations seen frequently in CA

26
Q

what is normal function, mutation, and clinical implication of APC

A

normally - inhibitor of cell signal transduction by degradation of B-catenin from WNT signalling
clinical - germline mutation leads to familial adenomatous polyposis, may also be involved in sporadic colon CA via 2 hit hypothesis

27
Q

POINT 3 what are defects in DNA repair

A

normally check DNA and repair if something is wrong

28
Q

4 important DNA repair genes

A
  1. p53
  2. mismatch repair genes
  3. nucleotide excision repair genes
  4. homologous recombination repair genes
29
Q

normal functions of p53

A

prevents propagation of of genetically damaged cells - quiesence, senescence, apop

30
Q

how does p53 work

A

normally complexed to MDM2 and when cell stressed will release p53

31
Q

clinical implication of p53

A

most common target of mutations

li fraumeni- germline mutation leads to many cancers

32
Q

what are key genes in HPV

A

E6,7,2

33
Q

how do low and high risk HPV strains differ

A

low risk - DNA remains in ring outside cell

high risk - integrated into cell

34
Q

what is funciton of E2

A

supresses activity of E6 and E7

35
Q

what is function of E6 and E7

A

E6 - binds to p53 - activates telomerase

E7- binds to Rb- displaces E2F

36
Q

what is net result of HPV mutations

A

inactivate 2 key tumor supressor genes leadin g to cell proliferation

37
Q

what is normal function, mutation, and clinical implication of mismatch repair genes

A

normally - correction of chance errors that occur in DNA rep
mutation - loss of mismatch leads to microinstability
clinical - sporadic colon CA and lynch syndrome - increased risk of colon and endometrial CA

38
Q

what is nucleotide excision repair

A
  1. UV dameg causes pyramindine crosslinking
  2. these must be removed by exision
    if not - xeroderma
39
Q

what is homologous recombination repair

A

chemical crosslinking causing DNA crosslinks

- BRCA1 and 2 are part of repair pathway

40
Q

what is non-homologous end-joingin pathway

A
  • salvage pathway
  • broken chromosomes joined end to end
  • increase instability
41
Q
  1. evasion of apoptosis - normal function of apoptosis
A

damaged cells that cannot be repaired in G1 will undergo apop

42
Q

what is BCL-2

A

anti-apoptotic factor

- 85% of lymphoma show over expression of BCR-2

43
Q

why do cells normally stop replicating

A
  1. reach hayflick limit
  2. progressive shortening of telomeres
    - then p53 shuts down
  3. in absence of p53 itll try and end-join
    - causes instability and cell collapse
44
Q

where is telomerase normally expressed

A

germ cells and not somatic cells

45
Q

what is importance of telomerase in CA

A

activity present in 90%+ of CA

46
Q
  1. why is angiogenesis needed
A
  1. provide nutrients

2. access for metast

47
Q

what is normal angiogenesis

A

balance between angiogenic and anti-angiogenic factors

48
Q

how does tumor make angio

A

increase angiogenic factors - eg VEGF

inhibit anti factors - p53

49
Q
  1. what is ability to invade and metastasize
A
  1. invasion of cellular matrix

2. vascular dissemination and homing of tumor cells

50
Q

4 requirements for cells to invade and met

A
  1. dissociation of neighbour cells
  2. degradation of ECM
  3. attachment of novel ECM components
  4. migration of tumor cells
51
Q

how does CA dissociate neighbor cells

A

breaks in cadherins of adjacent cells

52
Q

how does CA degrade ECM

A

may secrete proteolytic enzymes or induce other cells to do so

53
Q

how does CA attach to ECM

A

remodelling of ECM leads to generation of novel binding sites

54
Q

how does CA move

A

multiple genes and factors at work

55
Q

what do tumor cells do in blood stream

A
  1. may clump or associate with platelets
  2. activate coagulation factors
  3. exit at distant sites
56
Q

2 ways tumors pick where to go

A
  1. drainage sites

2. specific tropisms for some CA

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