Neoplasia 2

Question 1

What regulators act to promote the G1 to S transition?

Answer 1

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

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

Question 2

What regulators act during S phase?

Answer 2

Cyclin-A/CDK2

Cyclin-A/CDK1

Question 3

What regulators act during the G2 to M transition?

Answer 3

Cyclin B/CDK1

Question 4

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

- what cyclins can these act on?

Answer 4

p21, p27, p57

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

Question 5

What inhibitors compose the INK4 group of inhibitors?

- what can they act on?

Answer 5

INK4 = p16, p15, p18, p19

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

Question 6

What do CDKs do?

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

Answer 6

CDKs phosphorylate Cyclins

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

Question 7

Differentiate oncogenes and proto-oncogenes.

Answer 7

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

Oncogenes - Defective - BRICK on the Gas Pedal

Question 8

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?

Answer 8

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

Question 9

What lies at the heart of any cancer?

Answer 9

Non-Lethal Genetic Damage

Question 10

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?

Answer 10

Point Mutations

• Over activity in the protein is typically the result

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

Question 11

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

Answer 11

Ras - G-protein with intrinsic GTPase activity

EGFR - tyrosine

Question 12

What types of Cancer are typically associated with Ras Mutations?

Answer 12

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

Question 13

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

Answer 13

Squamous Cell Carcinoma

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

Question 14

What is the significance of APC?

- what does a loss of APC lead to?

Answer 14

• 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

Question 15

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

Answer 15

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

**This is known as haploinsuffciency

Question 16

What is the job of the RB gene?

Answer 16

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

Question 17

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

Answer 17

HPV

Question 18

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

Answer 18

Solid Tumor

Question 19

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

Answer 19

TP53

Question 20

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

Answer 20

They will now be detected as Homozygous

Question 21

Retinoblastoma is associated with the loss of what chromosome?

Answer 21

13q14

Question 22

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?

Answer 22

Retinoblastoma

Question 23

What cell line gives rise to Retinoblastoma?

Answer 23

Undifferentiated Neuroectodermal Cells that are precursors of retinal neuroepithelium

Question 24

What are you looking for histologically in retinoblastoma?

Answer 24

1. True (Flexner-Wintersteiner) Rosette Formation

2. Presence of Apoptotic Cells in Between Viable Cells

Question 25

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

Answer 25

Neuroectodermal Differentiation

Question 26

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

Answer 26

1. Promotes Apoptosis 2. Ensures Genomic Stability 3. Inhibits Angiogenesis

Question 27

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

Answer 27

**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

Question 28

* *What are the protein is encoded by the TP53 gene and what does this protein do under normal conditions? - BE SPECIFIC

Answer 28

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

Question 29

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

Answer 29

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

Question 30

Inherited loss of p53 results in what disease? | - what is the outcome of this loss?

Answer 30

Li-Fraumeni Sydrome - Patients are ~25x as likely to develope any type of cancer

Question 31

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

Answer 31

EBV and HPV

Question 32

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?

Answer 32

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

Question 33

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

Answer 33

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

Question 34

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?

Answer 34

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)

Question 35

What kind of balanced translocation causes Philadelphia chromosome formation? - genes involved? - gene product? - what disease is caused by this?

Answer 35

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

Question 36

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

Answer 36

The Development of: Homogeneously Staining Regions - extended segments of the gene lead to over transcription Double Minutes - extrachromosomal bits of DNA

Question 37

What genes are often located on Double minutes?

Answer 37

- Amplified Oncogenes | - Genes involved in Drug Resistance

Question 38

What Disease is NMYC important in? | - **MYC upregulation typically leads to programmed cell death so how can it cause cancer?

Answer 38

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

Question 39

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

Answer 39

Cancer with NMYC mutation is much more aggresive and usually fatal

Question 40

What role does epigenetics play in oncogenesis?

Answer 40

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

Question 41

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

Answer 41

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

Question 42

Is Bcl-2 considered an Oncogene? | - why or why not?

Answer 42

Yes, its an oncogene because it INHIBITS cell death **Oncogenes either promote cell growth or inhibit cell death

Question 43

What does overexpression of Her-2/neu cause?

Answer 43

Stimulates Cell division

Question 44

What are the 4 Oncogenes we MUST KNOW?

Answer 44

Her-2/neu MYC Ras Bcl-2