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Genetics Test 2 > Cancer 2 > Flashcards

Cancer 2 Flashcards

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Biology 101 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
Q

Sporadic retinoblastoma

A
  • 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
Q

Hereditary retinoblastoma

A
  • 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
Q

Loss of heterozygosity

A

-chromosomal missegregation (30%)(nondisjunction)
or
-mitotic recombination (30%)

28
Q

Colon cancer

A

~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
Q

2 pathways can initiate colon cancer

A
  • 85 % APC inactivation (tumor suppressor gene)

- 15 % MMR inactivation (mutator gene)

30
Q

Familial adenomatous polyposis (FAP) (little bumbs in colon)

APC inactivation (tumor suppressor gene)

A
  • 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
Q

Overexpression of COX-2

A

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
Q

Hereditary nonpolyposis colon cancer (HNPCC, Lynch syndrome)

MMR inactivation (mutator gene)

A
  • 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
Q

DNA Mismatch Repair (MMR) mutation -> sporadic colon cancer

A

MLH1 promoter methylation (biallelic)
BRAF mutation (protooncogene)
o MSH2 gene mutations – 40-60 %
o MLH1 gene mutations – 25-30 %

34
Q

Multi-hit model of colorectal cancer

A

• 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
Q

Widespread alterations in short, repeated DNA sequences

A

microsatellite instability (replication errors)

36
Q

Most cases of CRC associated with MSI

A
  • 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
Q

BRAF mutations

A

observed in most sporadic colorectal tumors, but do not occur in tumors of patients with Lynch syndrome

38
Q

mutational signature of sporadic tumors

A

includes CIMP and MSI

39
Q

Colorectal tumors that arise in patients with Lynch syndrome

A

mutations in KRAS

40
Q

2 molecular pathways to the development of CRC (colorectal cancer) with MSI (microstaletie instability)

A

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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