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CMOD-Block 2 Path > Neoplasia 2 > Flashcards

Neoplasia 2 Flashcards

1
Q

What regulators act to promote the G1 to S transition?

A

Cyclin-D/CDK4
Cyclin-D/CDK6
Cyclin-E/CDK2

*These phosphorylate Rb which then releases EL2 to allow for the G1 to S transition

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2
Q

What regulators act during S phase?

A

Cyclin-A/CDK2

Cyclin-A/CDK1

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3
Q

What regulators act during the G2 to M transition?

A

Cyclin B/CDK1

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4
Q

What 3 CDK inhibitors act through G1, S and G2 phase?

- what cyclins can these act on?

A

p21, p27, p57

These Three can act on any cyclin including Cyclin-D/CDK4 and CylcinD/CDK6

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5
Q

What inhibitors compose the INK4 group of inhibitors?

- what can they act on?

A

INK4 = p16, p15, p18, p19

  • These can act on Cyclin-D/CDK4 and Cyclin-D/CDK6 only
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6
Q

What do CDKs do?

- what happens to them after they do this (in a normal cell)?

A

CDKs phosphorylate Cyclins

- In a normal cell they are degraded rapidly after they complete their round of phosphorylation

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7
Q

Differentiate oncogenes and proto-oncogenes.

A

Proto-oncogenes - are STRICTLY regulated by internal and external cellular signals

Oncogenes - Defective - BRICK on the Gas Pedal

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8
Q

Why do we assume some cancers are familial even if hard genetic facts linking two familial cases is hard to find?
- what are 4 of these cancer types?

A

We see characteristics that don’t usually happen in people with acquired cancers like:

  • Early Age of Onset
  • Two or more relatives of index case
  • Mutliple bilateral tumors

Cancer Types:

  • Colon
  • Breast
  • Brain
  • Ovarian
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9
Q

What lies at the heart of any cancer?

A

Non-Lethal Genetic Damage

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10
Q

What type of mutation is typically the in a proto-oncogenes becoming oncogenes?

  • are these typically more or less active?
  • what is the job or a proto-oncogene?
A

Point Mutations

  • Over activity in the protein is typically the result

Normal Function:
- In “on” state these work to promote cell proliferation and differentiation

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11
Q

what are two proto-oncogenes that commonly get mutated in cancer?
- what are these?

A

Ras - G-protein with intrinsic GTPase activity

EGFR - tyrosine

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12
Q

What types of Cancer are typically associated with Ras Mutations?

A 
Ras: 
Pancreatic (90%) 
Colon (50%) 
Thyroid (50%) 
Lung (30%) 
Ovarian (15%) 
Bladder (6%) and other
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13
Q

What General classification of cancer typically results from EGFR mutations?
- in what way is EGFR changed so that cell growth is up-regulated?

A

Squamous Cell Carcinoma

EGFR:
- GETS OVEREXPRESSED and thus MORE TYROSINE KINASE SIGNALING CAN OCCUR

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14
Q

What is the significance of APC?

- what does a loss of APC lead to?

A
  • Inherited loss of APC leads to per-cancerous Polyps on the colon (FAMILIAL ADENOMATUS POYPSIS)

What does it do?
APC is an intermediate in the WNT pathway that regulates the Degradation of ß-catenin which can activate transcription for proteins like CYCLIN D1 and c-MYC that control the C1 to S PHASE OF THE CELL CYCLE

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15
Q

T or F: loss of a Tumor Suppressor gene can promote cancerous transformation of a cell.

A

True, (still recessive at cellular level but you’re much closer to getting to cancer)

**This is known as haploinsuffciency

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16
Q

What is the job of the RB gene?

A

Tumor Supressor Gene - PREVENTS EXCESSIVE CELL GROWTH BY INHIBITING THE CELL CYCLE UNTIL CELL IS READY TO DIVIDE

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17
Q

What virus is thought to bind RB protein so that cell proliferation will be promoted?

A

HPV

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18
Q

What kind of tumor would you be most likely to find a chromosomal deletion?

A

Solid Tumor

19
Q

Loss of 17p results in the loss of what gene?

A

TP53

20
Q

When loss of heterozygosity occurs, what happens to the genetic variants that were pairing with the deleted region?

A

They will now be detected as Homozygous

21
Q

Retinoblastoma is associated with the loss of what chromosome?

A

13q14

22
Q

You take a picture of a child and in one you see red eye and in the other you get a white reflex. What is this indicative of?

A

Retinoblastoma

23
Q

What cell line gives rise to Retinoblastoma?

A

Undifferentiated Neuroectodermal Cells that are precursors of retinal neuroepithelium

24
Q

What are you looking for histologically in retinoblastoma?

A
  1. True (Flexner-Wintersteiner) Rosette Formation

2. Presence of Apoptotic Cells in Between Viable Cells

25
Q

Outside of Retinoblasma what are Flexner-Wintersteiner rosettes a sign of?

A

Neuroectodermal Differentiation

26
Q

How does p53 prevent cancer formation? (3 main ways)

A
  1. Promotes Apoptosis
  2. Ensures Genomic Stability
  3. Inhibits Angiogenesis
27
Q

What types of genes are considered guardians and which are considered governors. Give examples of each.

A

Both guardians and governors are Tumor Suppressor Genes

Governors :

  • RB
  • Cell growth gene that are always turned off unless activated by some other protein
  • these guys try to prevent abnormal activity

Gaudians:

  • TP53
  • If abnormal activity does occur, these guys kick in to try to control things
28
Q
  • *What are the protein is encoded by the TP53 gene and what does this protein do under normal conditions?
  • BE SPECIFIC
A

p53 is encoded by TP53

p53 detects DNA damage and can do 1 of 2 things:
1. G1/S CELL CYCLE ARREST via CDKN1/p21 - gives time for DNA damage repair

  1. APOPTOSIS - mediated by Bcl-2 DOWNREGULATION, and BAX UPREGULATION
29
Q

What regulatory protein of p53 may be upregulated in cancer causing decreased p53 activity?
- how does it do this?

A

MDM2 binds to p53 and targets it for degradation

  • Low p53 results in low guardian surveillance on the G1/S transition and uncontrolled growth of the cell may occur
30
Q

Inherited loss of p53 results in what disease?

- what is the outcome of this loss?

A

Li-Fraumeni Sydrome

  • Patients are ~25x as likely to develope any type of cancer
31
Q

What 2 viruses make proteins that bind to p53 to inhibit its function?

A

EBV and HPV

32
Q

What is Her-2, and what type of mutation or other changes allow it to play a role in oncogenesis?

  • what cancers are closely linked to Her-2 mutations?
  • what chromosome does this gene sit on?
A

Her-2 = Receptor Tyrosine Kinase, Chromosome 17

  • Disease state results from Amplification of Expression of these protein
  • Breast and Ovarian Cancer is linked to this
33
Q

What are the 3 most common types of non-random structural abnormalities seen in cancer cells?

A
  1. Balanced Translocations
  2. Deletions
  3. Cytogenetic Manifestations of Gene Amplification

**Note these do not lead to the crazy aneuploid phenotypes you sometimes think about when you think about cancer

34
Q

What diseases result from balanced translocations in the Heavy Chain gene for B cells?

  • Genes Involved?
  • Chromosomes involved?
  • Outcome of these mutations on the Cell Cycle?
A
  1. Burkitt Lymphoma t(8, 14) - c-MYC gene (8) exchanges with the Heavy chain gene (14), and still gets the same amount of expression so c-MYC gets way over expressed
    - PROMOTION OF CELL GROWTH
  2. Follicular B cell Lymphoma t(14, 18) - Bcl-2 gene (18) exchanges with the Heavy Chain genes (14) and you get overexpression of Bcl-2
    - PREVENTION OF CELL DEATH (slower growing cancer)
35
Q

What kind of balanced translocation causes Philadelphia chromosome formation?

  • genes involved?
  • gene product?
  • what disease is caused by this?
A

t(9,22) results in the formation of the small BCR-ABL Philadelphia Chromosome

  • Genes product = FUSION PROTEIN that is a constantly active ABL
  • COMMON MYELOID LEUKEMIA is caused by this
36
Q

What chromosomal process(es) typically lie(s) behind gene overexpression?

A

The Development of:
Homogeneously Staining Regions - extended segments of the gene lead to over transcription

Double Minutes - extrachromosomal bits of DNA

37
Q

What genes are often located on Double minutes?

A
  • Amplified Oncogenes

- Genes involved in Drug Resistance

38
Q

What Disease is NMYC important in?

- **MYC upregulation typically leads to programmed cell death so how can it cause cancer?

A

Neuroblastoma

  • programmed cell death appears to be blocked by Bcl-2 in these cancers so MYC apoptosis is prevented
39
Q

How does an NMYC mutation change the prognosis of a neuroblastoma?

A

Cancer with NMYC mutation is much more aggresive and usually fatal

40
Q

What role does epigenetics play in oncogenesis?

A

Methylation and Demethylation of different parts of the genome may cause upward and downward regulation of oncogenes or tumor suppressor genes

41
Q

What genes are often found to be epigenitically silenced, ultimately leading to cancer?
- associated cancer?

A

APC - Familial Adenocarcinoma Polypsis
MLH1 - Colon Cancer
BRCA1 - Breast cancer

42
Q

Is Bcl-2 considered an Oncogene?

- why or why not?

A

Yes, its an oncogene because it INHIBITS cell death

**Oncogenes either promote cell growth or inhibit cell death

43
Q

What does overexpression of Her-2/neu cause?

A

Stimulates Cell division

44
Q

What are the 4 Oncogenes we MUST KNOW?

A

Her-2/neu
MYC
Ras
Bcl-2

CMOD-Block 2 Path (22 decks)

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