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BIOM 4150 Cancer Biology- Final > 10- Cancer Genetics/ Epigenetics > Flashcards

10- Cancer Genetics/ Epigenetics Flashcards

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1
Q

What are the 2 types of tumor suppressor genes/ examples of each?

A

Gatekeeper gene ex) RB/ APC/ NF1
Caretaker gene ex) TP53

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2
Q

What is a gatekeeper gene?

A
  • TS gene that operates to hinder cell proliferation or further cell differentiation/ cell death
    > prevents generation of neoplastic cells
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3
Q

What is a caretaker gene?

A
  • TS gene that encodes a protein responsible for maintaining the integrity of the genome
    > prevents generation of neoplastic cells
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4
Q

What is the main difference between oncogene activation/ TS inactivation?

A

Oncogene activation = dominant
TS inactivation = recessive (need both alleles mutated)

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5
Q

What is a tumor suppressor gene?

A
  • gene whose partial/ complete inactivation leads to ↑ likelihood cancer
  • gene responsible for constraining cell proliferation
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6
Q

What is an oncogene?

A
  • gene that can transform cells
  • gene whose activation leads to cancer
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7
Q

Where/ how can TS inactivation occur?

A

Familial/ Inherited > occurs in germ line
Sporadic > in somatic cells

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8
Q

What was the first tumor suppressor discovered?

A

RB > Retinoblastoma

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9
Q

What was Knudson’s hypothesis?

A

RB: Knudson’s “two-hit” hypothesis
- both alleles of gene need to be inactivated for RB tumors to arise (recessive)

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10
Q

What was interesting about retinoblastoma?

A
  • bilateral cases develop faster/ earlier (suggestive of single mutation)
    > familial (born with 1 mutant allele/ only need 1 mutation)
  • unilateral cases develop later in life (suggestive of 2 mutation events)
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11
Q

If the odds of having 2-independent mutations in the same cell are small (10^-12), how were patients getting Rb?

A
  • loss of heterozygosity (LOH)
  • development in a cell of only 1 version of an allele instead of normal 2
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12
Q

What are the mechanisms of LOH? (loss of heterozygosity)

  • besides mutation, how can wt Rb alleles be eliminated from genome?
A
  1. Mitotic recombination
  2. Gene conversion (copying mutant allele)
  3. Chromosomal non-disjunction (trisomy > could have 2 wt/ 2 mutant)
  4. Gene silencing (transcriptional inactivation
  5. Deletion > development of hemizygosity > only 1 copy of gene
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13
Q

What is FAP/ APC?

A
  • in normal colon, polyps develop with age/ rarely become cancerous
  • in FAP colon, thousands/ 100% chance of becoming cancerous
  • FAP arises due to mutation in APC gene (accounts for 1% of CRC)

FAP = Familial Adenomatous Polyposis
APC = Adenomatous Polyposis Coli = gatekeeper gene

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14
Q

How does APC mutation lead to FAP?

A
  • APC = inhibitor of Wnt signalling
  • with APC loss > accumulation of B-catenin in cytosol > ↑ Wnt/ B-catenin signalling> ↑ survival/ proliferation
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15
Q

What syndrome is associated with loss of TP53?

A

Li-Fraumeni

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16
Q

What is NF1?

A
  • loss of neurofibromin > neurofibromatosis (cafe au lait spots)
  • NF1 = Ras-GAP (switches Ras off)
  • loss of NF1 > overactive Ras signalling
17
Q

Why is NF1 not a typical tumor suppressor?

A
  • Knudson’s 2 hit hypothesis: loss of both alleles required for phenotype
  • NF1+/- cells with 50% functional protein (1 wt allele) show ↑ growth signalling through Ras compared to NF1-/-
    = Haploinsufficiency- loss of 1 allele sufficient to induce neurofibroma phenotype
18
Q

Why is sporadic cancer due to mutated proto-oncogenes common but familial cancer due to mutated proto-oncogenes rare?

A
  • embryonic lethality ↑ spontaneous abortions
19
Q

What is an oncogene familial syndrome?

A

H-ras > Costello syndrome

20
Q

What is haploinsufficiency/ how does it change the 2-hit hypothesis?

A
  • loss of 1 allele sufficient to induce phenotype (dominant)
  • Knudson’s 2 hit hypothesis: loss of both alleles required for phenotype
21
Q

What are epigenetic changes?

A
  • inherited changes in gene expression that do not depend on alterations of DNA nucleotide sequence
    > changes in behaviour of cell/ activity state of chromatin
22
Q

How does DNA methylation occur?

A
  • DNMT enzymes methylate
  • CpG sequences are targets for cytosine methylation
  • about 60-70% of gene promoters have CpG islands
23
Q

How does DNA methylation regulate gene expression?

A
  1. DNMT activity methylates CpG sequences in islands
    > silence gene expression
  2. DNMT activity methylates sequences within gene bodies
    > prevent spurious initiation of transcription
24
Q

What are the consequences of DNA methylation?

A
  • methylated CpG islands prevent transcription complex from loading onto DNA > steric inhibition (impediment for transcription)
  • methylation pattern of DNA affects higher order chromatin structure (via histone modifications)
25
Q

What kind of methylation happens in cancer?

A
  • both global hypomethylation/ selective hypermethylation
  • disruption of methylation patterns > silencing of TSs/ ectopic expression of normal genes
  • ↑ methylation of TS > silenced/ ↓ methylation of silenced genes
26
Q

What are the possible scenarios of CpG methylation/ TF interactions in cancer?

A
  • TF binding interferes with CpG methylation
  • TF only binds if CpG is methylated
  • TF can not bind if CpG is methylated
27
Q

What is interesting about silenced genes?

A
  • more prone to LOH (loss of heterozygosity)/ mutation
28
Q

How do histone posttranslational modifications regulate gene expression?

“epigenetic” histone code

A
  • posttranslational modifications of histone proteins modify chromatin structure/ impact gene expression
  • acetylation/ deacetylation/ methylation of histone proteins interacts with DNA methylation
  • deacetylation of histones converts chromatin to more compact
29
Q

How do microRNAs regulate gene expression?

  • epigenetic silencing of miRs
A
  • miR system = endogenous post-transcriptional mechanism
  • target groups of genes rather than single targets
  • miRs inhibit production of TFs that express tumor-promoting genes
    > loss of miR > overexpression of tumor-promoting genes
  • overexpression of miR inhibits TS production > pro-carcinogenic
30
Q

What is the difference between a driver/ passenger gene?

A

Driver mutation- germline mutations/ transforming somatic mutation
Passenger mutation- accidental/ do not contribute to cancer phenotype

BIOM 4150 Cancer Biology- Final (6 decks)

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