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Block 2 Cancer > Cancer Driver Genes > Flashcards

Cancer Driver Genes Flashcards

1
Q

PanCancer Atlas project

A

looking at cancer genes, genetic, and epigentic changes and altered signaling pathways; this project aims to better understand oncogenic processes that control cancer development and progression

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2
Q

DNA sequencing of diff cancers showed

A

cancer contains large number genomic abnormalities including

  • point mutations
  • indels
  • copy # changes
  • chromosomal abnormalities
  • most mutations in non coding regions some in protein coding gene mutations too
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3
Q

Driver genes

A
  • small subset of genes mutated in cancer
  • when mutated or dysregulated confer selective growth or survival advantage to cells expressing them and promote tumorigenesis
  • can be activated proto-oncogenes (oncogenes) or inactivated tumor suppressor genes
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4
Q

Passenger genes

A

majority of mutated genes found in tumors; these do not specifically give tumor cells a growth or survival advantage and therefore do not drive tumorigenesis

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5
Q

can a passenger gene become a driver gene

A

yes if changes in tumor microenvironment occur and passenger gene now provides growth or survival advantage to tumor cell

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6
Q

oncogenes

A
  • positive regulators of cell proliferation and survival
  • derived from photo-oncogenes which are converted to oncogenes and promote tumorigenesis independent of viruses
  • mutations that activate proto-oncogenes are dominant mutations -> oncoprotein gaining new fx or no longer tightly regulated
  • can encode proteins or non-coding regulatory RNAs (ex miRNAs)
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7
Q

potential proto-oncogenes

A

genes that normally regulate cell proliferation, cell differentiation, and cell survival

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8
Q

Oncogene categlories

A
  1. Growth factor signaling components
  2. Cell cycle related
  3. Epigenetic regulators
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9
Q

Growth factor signaling components

A

growth factors, growth factor receptors, signaling intermediates and transcription factors

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10
Q

cell cycle related

A

cell cycle regulators, differentiation (cell fate) regulators, and regulators of apoptosis

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11
Q

epigenetic regulators

A

alter transcription of cancer related genes

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12
Q

oncogene study

A
  1. initially IDed as genes carried by cancer-causing animal retroviruses but these only = small fraction cell-derived oncogenes
  2. study genes activated in tumors bc chromosomal translocations or gene amplifications
  3. transgenic animals express individual or combo genes -> tumors
  4. whole genome sequencing and functional analysis of genes
  5. monitor changes to cell growth in culture (changes= properties of transformed cells)
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13
Q

properties of transformed cells

A

Specific properties that enable tumor cells to proliferate and survive in vivo

  1. loss of contact inhibition
  2. Anchorage independence
  3. Reduced growth factor requirements
  4. moropholigcal changes
  5. limitless replicative lifespan
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14
Q

Loss of contact inhibition

A

transformed cells can proliferate and grow on top of each other

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15
Q

anchorage independence

A

no longer anchorage dependent, don’t have to attach to ECM to survive and proliferate

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16
Q

reduced growth factor requirements

A

can make their own (autocrine stimulation) or activate growth factor signaling pathway

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17
Q

morphological changes

A

rounder with fewer attachments to substratum

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18
Q

limitless replicative lifespan

A

inactive tumor supressor genes and reactivate telomerase so can replicate indefinetely

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19
Q

Hall marks of cancer and transformd cells

A
  1. Sustaining proliferative signaling: Reduced growth factor requirements and loss of anchorage dependence
  2. Evading growth suppression- loss of contact inhibition
  3. Enabling replicative immortality: limitless replicative lifespan
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20
Q

Proto-oncogene conversion or proto-oncogene activation

A

process by which proto-oncogenes converted to oncogenes
usually by mutations that modify the coding region (produce oncogenic altered protein) or deregulate expression (normal protein overexpressed or expressed when it normally wouldn’t be)

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21
Q

gene amplification

A

results in increase porto-oncogene DNA copy number; coding recon of amplified gene not mutated but expression of gene deregulated (protein over expression)

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22
Q

Transolocation

A
  • proto-oncogene located near strong transcriptional enhancer bc translocation this increases porto-oncogene transcription (becomes oncogene bc expression is deregulated)
  • translocation breakpoint in coding region of proto-oncogene and of another gene produce fusion protein w/ parts of both; if activity proto-oncogene increased then oncogene (bc change in protein coding region)
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23
Q

bcr-abl oncogene

A

example of fusion oncoprotein; this is target to Gleevec

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24
Q

Other causes of proto-oncogene activation

A
  1. simple mutations
    - point mutations
    - small insertions or deletions in coding or noncoding regions
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25
Q

Ras

A

this is signaling intermediate mutation slows rate at which GTP is hydrolyzed keeping ras in active state; mutation = point mutation c-ras -> onc-ras

26
Q

myc

A

this is transcription factor; mutation at the-58 -> increased protein stability

27
Q

oncogenesis and the cell cycle

A
  • cell cycle regulators converted to oncogenes stimulate cell cycle transit and cell proliferation (Cyclin D, Cyclin E, cdk4)
  • genes that block cell cycle exist (inhibit apoptosis (bcl12) or prevent cancer from differentiating (myc)) are potentially oncogenes
28
Q

epigenetic regulators as oncogenes

A

cancer associated mutations in genes that modify epigenome (DNA methylation partners, histone tail modifications ect) deregulate transcriptional networks -> disrupt homeostasis

  • mutated or misrelated DNA methytransferases
  • Mutated misregulated histone modifying enzymes (ex. histone deacetylases and histone lysine methyltransferases); repress transcription of tumor suppressor genes
29
Q

Precision cancer medicine

A

no two tumors are the same b/c tumor characterized by intra-tumor heterogeneity, driver mutations, and tumor microenviornments which affect tumor phenotype and tumor response to conventional and targeted therapies so precision cancer medicine DNA sequces tumors to ID driver mutations and active cancer signaling pathways to tailor treatments of genomic profile of tumor

30
Q

Oncogene addiction

A

tumors dependent upon continued expression of single oncogene, therapies directed against these = most affective

31
Q

Tumor heterogeneity increases

A

likelihood that new drug resistance mutations preexist or will arise in subpopulation of tumor cells also increases

  • targeted driver genes may acquire additional mutations that block drug binding or increase gene copy number so drug can’t inhibit all target protein
  • tumor may also bypass targeted protein by activating downstream effectors
  • tumor may use alternative signaling pathway to compensate for loss of targeted pathway
32
Q

preclinical animal models

A

allow for testing of tumor’s initial response to a drug, ID biomarkers correlated with drug efficacy and study mechanism of drug resitance

  • Patient derived xenographs (PDX)
  • 3D organotypic cultures
33
Q

PDX

A

fresh piece tumor or tumor cell under skin of immune compromised mouse

34
Q

organotypic cultures

A

consist of tumor derived cells embedded in 3d matrixx and maintained for extended period of time using culture conditions optimized for specific tumor type

35
Q

Tumor supressor genes

A

inhibit tumorigenesis (inhinbit tumor cell proliferation and stimulate apoptosis)

36
Q

Evidence that tumor suppressor genes exist:

A
  1. Somatic cell hybridization experiment
  2. Occurrence of characteristic chromosomal deletions
  3. Viral oncogene action
37
Q

Somatic cell hybridization experiments

A

normal cell fused with tumor cell in vivo daughter cell does not produce tumors unless lost specific chromosomes

38
Q

occurrence of characteristic chromosomal deletion

A

Recurrent chromosomal deletions associated with specific cancers
ex. BRCA1 and 2 (breast cancer) and APC (colon cancers)

39
Q

Viral oncogene action

A

same 2 cell proteins (tumor suppressors) inactivated by oncoprotein from diff DNA tumor viruses
exs.
1. SV40 (T antigen inactivates TSGs, Rb, p53
Adenovirus proteins E1A and E1B inactivate Rb and P53 respectively
inactivation of tumor suppressor proteins -> cancer

40
Q

Retinoblastoma

A

2 types inherited and sporadic

  • inherited form multiple tumors in both eyes b/c have on functional copy of Rb so need one mutation to inactivate wild type and have tumor formation (being born with inactivated TSG increases risk for developing cancer and increases chance of developing it at earlier age)
  • sporadic get single tumor in single eye because would need two mutations to occur in single retinoblast to get tumor (this = two hit hypothesis)
  • Rb gene located on chormosome 13*
41
Q

Inactivation of tumor suppressor genes

A
  • in general inactivation of both copies of the gene must occur to fully inhibit tumor suppressor fx
    1. Mutations that inactivate a TSG
    2. Epigenetic silencing of TSG transcription
    3. Degradation of TSG mRNAs by oncogene miRNAs
    4. Sequestration of TS protein
42
Q

mutations that inactivate TSG

A

mutations inactivating both copies of TSG usually occur independely “loss of heterozygosity”= alterations in chromosomal banding patterns that accompany the conversion of a cell containing a deletion in on copy of a TSG to one that has acquired a deletion in the second copy of the same TSG

43
Q

Epigenetic silencing of TSG transcription

A

Misregulated DNA methytrnasferases hypermethylate; repression of TSG transcription

44
Q

Degradation of TSG mRNAs by oncogenic miRNAS

A

miRNAS act as oncogenes and target TSG mRNA for degredation

45
Q

Sequestration of TS protin

A

oncoprotein bind to and inactivate specific TS proteins ex. E1A, E1B, papilloma E7 and E6 oncoprotein

46
Q

Rb

A
  • first TSG identified
  • contains 2 pocket domains (A and B) through which it interacts with lg # of proteins including viral oncoprotein that inactivate Rb and transcpriton factor E2F and histone deacetylases and other chromatin modifiers
  • contains numerous phosphorylation sites that regulate activity of Rb
47
Q

Rb regulates

A

cell cycle transit and cell differentiation

  • Rb regulates cell proliferation by controlling the activity of E2F during G1 phase of cell cycle
  • Rb knockout mice die during embryogenesis; several tissues and organs fail to develop normally; also have impaired differentiation (bc cells can’t leave cell cycle in absence of Rb
48
Q

Rb function complexity

A

main view of Rb interaction has been studied in terms of E2F but in truth it interacts with many other cellular proteins and plays mediating action; no Rb -> major defects in cell cycle but all the cell changes associated with Rb are not yet understood

49
Q

Rb regulation

A

normally regulated by phosphorylation (proliferative and anti proliferative signals act by altering extent of Rb phosphorylation
- anti proliferation signals activate CKI blocking Rb phos keeping Rb active in inhibitory state

50
Q

Anti-proliferation signals and Rb

A

anti-proliferation signals like cell cell contact, specific soluble factors (TGFB inhibits epithelial cells) and oncogenes activate CKIs (cyclin-dependent kinase inhibitors) which block Rb phosphorylation keeping Rb in active state which = inhibitory -> E2F remaining inactive and DNA synth and cell proliferation blocked

51
Q

How do cancer genes escape anti-proliferation signals

A

alteration in one of Rb pathway genes (some are tumor suppressors others act as oncogenes)

  1. reduced expression or inactivation of Rb (tumor suppressor)
  2. Overexpression of cyclin D or cyclin E (oncogenes)
  3. Point mutations in cdk4 that prevent CKI binding (oncogene)
  4. reduced expression or inactivation of CKIs often p16 (tumor suppressor)
52
Q

p53

A
  • Guardian of the genome
  • maintains genome and prevents tumorigenesis
  • p53 protein contains a nuclear localization signal and DNA sequence specific binding site; functions as transcription factor
  • under normal conditions it is unstable with short half life and present in v low levels in the cell
  • post translationally modified (phosphorylated) in response to activating signal stabilizing it so it accumulates in cell and fxs
53
Q

evidence that p53 is a tumor suppressor gene

A
  1. p53 inactivated by DNA viral oncoproteins and this is required for viral-mediated cell transformation
  2. Li-Faumeni syndrom in ppl = inherit 1 inactive copy p52 associated w/ increase incidence of several types cancer
  3. p53 knockout mice develop multiple tumors (ex lymphomas sarcomas)
  4. p53 mutated in >50% all human cancer
54
Q

What does p53 respond to

A
  • responds to many types cellular stress including those experienced by tumor cells
55
Q

what does p53 do once activated

A
  • stimulates transcription of genes that regulate DNA repair, metabolism, autophagy, and translation
    -growth arrests cells by indiucing transcription of p21
    induces apoptosis via Bax and other genes
56
Q

p21

A

cyclin dependent kinase which prevents Rb from being phosyphorylated (inactivates it)
-p21 transcription induced by p53

57
Q

Bax

A

proapoptotic gene this is one of proapoptotic genes p53 induces

58
Q

Guardian of the genome

A

p53

  • facilitates the repair DNA damage and prevents the replication and survival of abnormal cells
  • temporarily arrests normal cells containing non-lethal mutations until DNA damage repaired
  • transformed cells expressing oncogenes or oncogene induced stress p53 promotes permanent growth arrest (senescence) or apoptosis
59
Q

main roles p53

A
  • kills or growth arrests cells express oncogenes
  • sensitizes tumor cells to killing effects of telomere shortening, hypoxia, and other stresses
  • protects genome by preventing cells from accumulating additional mutations that -> tumor progression
60
Q

almost all cancers

A

have mutations or epigenetic alterations that directly or indirectly block p53 from functioning

Block 2 Cancer (10 decks)

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