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Genetics Test 2 > Cancer 2 > Flashcards

Cancer 2 Flashcards

1
Q

Cell cycle (proliferation cells) results in

A

Chromosome replication
Cell division
steps-> mitosis + interphase

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2
Q

Cell cycle is similar in what?

A

All Eukaryotes

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3
Q

Loss of control of the cell cycle results in

A

cancer

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4
Q

Cell cycle steps (Somatic cells)

A

S phase: DNA synthesis (chromosome replication, 10h)
G1 phase: phase (gap) between M and S phase (9h)
G2 phase: phase (gap) between S and M phase (4.5h)
M phase: mitosis (0.5h)
o Prophase: chromosome condensation
o Metaphase: chromosome align in center
o Anaphase: chromosomes segregation
o Telophase: chromosome de-condensation
♣ Reformation of nuclear envelope
♣ Remodeling of ER and Golgi
♣ Cytokinesis
G0 phase: resting phase, no cycling (post mitotic cells) cells that do not divide continuously

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5
Q

What regulates the cell cycle

A

Cdk complexes

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6
Q

Heterodimeric protein kinases

A

regulates the cell cycle
Regulatory subunit-> cyclin
Catalytic subunit-> cyclin dependent kinase = Cdk

Cyclin-CDK complex-> Bind their target protein-> phosphorylate -> conformational change

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7
Q

Regulation of the cell cycle

A
  • Premature progression to next phase -> genetic damage

- Checkpoints

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8
Q

Checkpoints

A

DNA damage-> arrest cycle in G1 until repair is completed (no replication until fixed) (restriction point/ point of no return)

Unreplicated DNA-> arrest cycle in S phase

Improper mitotic spindles assembly-> arrest cycle in M phase (used for chromosomal counting/ cytogenetic trick)

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9
Q

Restriction point (late G1)

A

Cells that progress past the restriction point -> committed to enter S phase (even when no growth factors)

  • Must be tightly regulated
  • If cell believes that is has to divide even in the absence of growth factor -> cancer
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10
Q

Loss of checkpoint control

A

Loose p53 (tumor supressor)

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11
Q

p53

A
  • tumor suppressor -> stops cell cycle if DNA is damages-> arrests in cell cycle in G1 or G2 until repair is completed
  • P53 -> unstable transcription factor -> as soon as it is made it is degraded (Damage to the DNA will stabilize p53)
  • > enhances transcription of a cyclin-kinase inhibitor (p21CIP)
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12
Q

What happens to p53 as DNA is repaired

A

it becomes unstable again

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13
Q

extensive DNA damage

A

p53 -> induces apoptosis
aka Radiation therapy -> apoptosis
-Cells w/o p53 are resistant to radiation therapy (why some tumors are responsive to radiation therapy and some are not )

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14
Q

Cells w/o p53

A

replicate damaged DNA -> mutations -> cancer

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15
Q

p53 levels regulated by

A

MDM2 ubiquitin ligase (only for p53)

-puts a ubiquitin molecule on p53-> so that the proteasome recognizes it and degrades it
feedback pathway

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16
Q

p53 degraded by

A
  • the proteasome (protiolitic machinery that degrades everything that has an ubiquitin molecule attached to them)
  • ubiquitin ligase -> Enzyme that attaches ubiquitin
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17
Q

Loss of restriction point control (deff on test)

Cyclin D overexpression

A

(proto-oncogene)

Found in breast cancer

18
Q

Loss of restriction point control (deff on test)

Loss of p16 function

A

(tumor suppressor)

Found in familial melanoma

19
Q

Loss of restriction point control (deff on test)

Loss of Rb function

A

(tumor suppressor)

Retinoblastoma, osteosarcoma

20
Q

restriction point control

Rb function

A

Rb -> binds E2F transcriptional factors-> Rb-E2F complex-> a repressor
(alone E2F is an activator)
-Complex-> prevents transcription of DNA replication enzymes

21
Q

restriction point control

Mitogens

A

Mitogens (growth factors)-> induce expression of G1 Cdk complexes
(mammals -> cyclin D and Cdk4)

Mitogen withdrawal-> accumulation of cyclin kinase inhibitor p16 INK4 -> inhibits Cdk complexes-> arrest cell in G1

22
Q

restriction point control

G1 Cdk complexes

A

G1 Cdk complexes -> phosphorylate Rb (makes Rb-E2F complex dissociated)
- allows for synthesis of DNA replication enzymes -> now process to S phase

23
Q

Oral squamous carcinoma (deff on test)

A
  • p53 inactivation: 50-60%
  • P16 inactivation: 80%
  • Cyclin D amplification: 30-50%
-Common risk factors for oral cancer 
o	Smoking 
o	Tabacco use
o	Betel use  
o	HPV

Hyperplasia-> mild dysplasia -> severe -> early invasion (cancer)

24
Q

Alfred Knudson’s two hit model of carcinogenesis (cancer formation)

A

Model that says you need 2 mutational events to get cancer

  • Sporadic retinoblastoma
  • Hereditary retinoblastoma
25
Sporadic retinoblastoma
* 60% of retinoblastoma cases. * Develops in children with no family history. * Occurs in one eye. * Age of onset is later * Child starts with 2 wild type alleles (RB+/RB+) * Both alleles must mutate to produce disease (RB/RB) * Probability of both mutation occurring in the same cell is low; only one tumor forms one eye
26
Hereditary retinoblastoma
* 40% of retinoblastoma cases. * Onset typically is earlier age of onset than sporadic cases. * Multiple tumors involving both eyes * Child starts with heterozygous alleles (RB/RB+) * Only one mutation is required to produce disease (RB/RB) * Mutations resulting in Loss of heterozygosity (LOH) (becoming homozygous) are more probable in rapidly dividing cells, and multiple tumors occur both eyes and earlier age of onset
27
Loss of heterozygosity
-chromosomal missegregation (30%)(nondisjunction) or -mitotic recombination (30%)
28
Colon cancer
~70 % are sporadic with no genetic history ~25 % with family history w/o known genetic defect ~1 % Familial adenomatous polyposis (FAP) ~2-4 % Hereditary nonpolyposis colon cancer (HNPCC, Lynch syndrome)
29
2 pathways can initiate colon cancer
- 85 % APC inactivation (tumor suppressor gene) | - 15 % MMR inactivation (mutator gene)
30
Familial adenomatous polyposis (FAP) (little bumbs in colon) APC inactivation (tumor suppressor gene)
* 300-1000 polyps by age 30 small noncancerous growths * 100% risk of colon cancer by age 40 because you have so many of them your risk of them progressing to cancer is higher • High risk of developing polyps Average risk of progression to colon cancer • Loss-of-function mutations in the APC gene (Adenomatous Polyposis of the Colon) o APC gene = tumor suppressor gene • APC is part of an ubiquitin ligase complex which marks Beta catenin (activator of gene transcription) for degradation (WNt signally pathway) o No APC -> more Beta catenin-> stimulate expression of genes required for cell proliferation (cancer)
31
Overexpression of COX-2
generating prostaglandins (Inhibited by aspirin and ibuprofen-> protect from colon cancers and other cancers -> but bleeding risk > cancer risk) -FAP -> risk of bleeding is less than the risk of cancer-> but not utilized as a cancer preventing method
32
Hereditary nonpolyposis colon cancer (HNPCC, Lynch syndrome) MMR inactivation (mutator gene)
* 50-80 % lifetime risk of colon cancer * 40-60 % endometrial cc; 15% stomach; 10% ovarian * Average risk of developing polyps ( very low compared to FAP) * high risk of progression to colon cancer * DNA Mismatch Repair (MMR) gene mutations KRAS mutations APC usually normal β-catenin mutations
33
DNA Mismatch Repair (MMR) mutation -> sporadic colon cancer
MLH1 promoter methylation (biallelic) BRAF mutation (protooncogene) o MSH2 gene mutations – 40-60 % o MLH1 gene mutations – 25-30 %
34
Multi-hit model of colorectal cancer
• For colon cancer to occur after APC inactivation-> multiple genetic changes • Accumulation along a pathway of different mutations High risk of developing cancer • DCC-> loose chromosome 18q • Overexpression of COX-2-> generating prostaglandins FAP the risk of bleeding is less than the risk of cancer
35
Widespread alterations in short, repeated DNA sequences
microsatellite instability (replication errors)
36
Most cases of CRC associated with MSI
- not inherited (familial) - arise through sporadic methylation-induced silencing of MLH1 ->CIMP signature -> resulting in methylation of many gene promoters-> MMR activity fails and MSI ensues
37
BRAF mutations
observed in most sporadic colorectal tumors, but do not occur in tumors of patients with Lynch syndrome
38
mutational signature of sporadic tumors
includes CIMP and MSI
39
Colorectal tumors that arise in patients with Lynch syndrome
mutations in KRAS
40
2 molecular pathways to the development of CRC (colorectal cancer) with MSI (microstaletie instability)
20%–25% of colorectal tumors with MSI arise in individuals with Lynch syndrome-> - 1.) germline mutation in one of the MMR genes (rapid accumulation of somatic mutations) - 2.) second hit to the wild-type copy (inherited from the unaffected parent) via LOH, methylation, or point mutation

Genetics Test 2 (2 decks)

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