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BMR 607 Test 1 > Neoplasia > Flashcards

Neoplasia Flashcards

1
Q

“Driver Mutation”

A

Mutation that contributes to the development of the malignant phenotype.

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2
Q

What are two ways in which healthy cells respond to Growth Signals?

A
  • Induction and activation of transcription factors and epigenetic alterations that initiate and sustain DNA transcription
  • Promote entry and progression of the fell into the cell cycle.
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3
Q

Define Protooncogenes?

A

Promote normal growth and differentiation (code for proteins that trigger cell division/cell cycle progression).

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4
Q

Protooncogenes can be converted into what?

and how?

A
  • Oncogenes
  • Genetic alterations, usually only allele needs muted to add growth promoting effect.
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5
Q

Oncogenes have what growth promoting effect?

A

Dominant acting/gain of function

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6
Q

What are Oncoproteins and how are they produced?

A
  • Devoid of regulatory elements
  • Their production in the transformed cell does not depend on growth factors or other external signals
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7
Q

What is common to all proto-oncogenes?

A

All participate in some way in signaling pathways that drive proliferation.

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8
Q

What do Oncoproteins give to cells?

A

Renders the cells with self-sufficiency in growth.

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9
Q

Growth Factors:

FGF3, FGF4 (Fibroblast growth factor)

Mode of activation?

Associated tumors?

A

Overexpression

Stomach, Breast, Bladder

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10
Q

Growth Factors:

PDGF (platelet derived growth factor)

Mode of activation?

Associated tumors?

A

Overexpression

Astrocytoma

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11
Q

Growth Factors:

TGFa (Transforming growth factor)

Mode of activation?

Associated tumors?

A

Overexpression

Sarcomas, Astrocytoma

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12
Q

Growth Factors:

ERB1 (Epidermal growth factor receptor)

Pathway involved?

Mode of activation?

Associated tumors?

A
  • Receptor Tyrosine Kinase
  • Mutation
  • Non-small cell carcinoma of lung (NSCLC), Glioblastoma
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13
Q

Growth Factors:

ERB2 (HER/neu)

Pathway involved?

Mode of activation?

Associated tumors?

A
  • Receptor Tyrosine Kinase
  • Amplification
  • Breast, Ovary, lung
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14
Q

Growth Factors:

RET (Receptor for Neurotrophic Factor)

Pathway involved?

Mode of activation?

Associated tumors?

A
  • Receptor Tyrosine Kinase
  • Point Mutation
  • Multiple Endocrine neoplasia (MEN 2A and 2B)
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15
Q

Growth Factors:

ALK

Pathway involved?

Mode of activation?

Associated tumors?

A
  • Receptor Tyrosine Kinase
  • EML4-ALK fusion on chromosome 5
  • Lung Adenocarcinoma (NSCLC)
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16
Q

How does the point mutation of ERB1 work?

A

Mutation of the Epidermal growth factor (EGF) receptor can make it active even in the absence of EGF, and consequently oncogenic.

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17
Q

Ras (H-,K-,N- subtype) functions as a?

A

Molecular switch

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18
Q

What stimulates the dissociation of GDP and the subsequent uptake of GTP from the cytosol, thereby activating Ras.

A

Ras-GEFs - Ras Guanine nucleotide exchange factors.

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19
Q

What do Ras-GEFs - Ras Guanine nucleotide exchange factors do?

A

Stimulates the dissociation of GDP and the subsequent uptake of GTP from the cytosol, thereby activating Ras.

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20
Q

What do Ras-GAPs do?

A

Increase the rate of hydrolysis of bound GTP by Ras, thereby inactivating Ras.

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21
Q

What occurs with Hyperactive mutant forms of Ras?

A
  • They are resistant to GAP-mediated GTPase stimulation and are locked permanently in the GTP-bound active state.
    • This promotes the development of cancer.
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22
Q

What is the most common abnormality of dominant oncogenes in human cancers?

Percentage?

A

Point mutations of RAS family genes

~30% of all tumors

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23
Q

Percentage of pancreatic adenocarcinomas that contain RAS mutations?

A

~90%

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24
Q

Percentage of colon, endometrial, and thyroid cancers that contain RAS mutations?

A

50%

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25
**100% of hairy cell leukemias, and \>60% of melanomas** caused by?
**BRAF mutations**
26
What is BRAF?
Serine/Threonine protein kinase that activates downstream kinases of the MAPK cascade.
27
**~30% of breast cancers** have a mutation involving the a-isoform of ?
PIK3 catalytic subunit
28
What is the associated tumor with the proto-oncogene **ABL-**non-receptor tyrosine kinase.
**Chronic myelogenous leukemia**, acute lymphoblastic leukemia.
29
What is the associated tumor with the proto-oncogene **JAK2.**
**Myeloproliferative disorders,** acute lymphoblastic lymphoblastic leukemia.
30
Nonreceptor Tyrosine Kinase oncogoenes?
**ABL** NOTCH1 **JAK2**
31
Describe the BCR-ABL Fusion mutation?
ABL gene is translocated from its normal location on chromosome 9 to chromosome 22 (the **Philadelphia chromosome 22)** where it fuses with the BCR gene.
32
What is detected in **\>90% patients with CML and up to 20% patients with ALL**?
BCR-ABL Fusion Protein
33
Involves C-myc Pathway
Burkitt Lymphoma
34
Involves N-myc pathway?
Neuroblastoma
35
Involves L-myc Pathway
Small cell lung carcinoma
36
Burkitt Lymphoma is associated with what translocation in 75% of casses and commonly with what infection?
t(8;14) EBV infection
37
In adults, EBV occurs in association with what?
HIV infection
38
What sensor for DNA damage blocks progression from G1 to S phase?
p53
39
What Balance of growth promoters/inhibitors regulate G1/S-Cdk?
Rb
40
What controls control cell-cycle progression
Cyclin-dependent kinase (Cdk)
41
What are the two classes of mutations that affect the G1/S checkpoint?
**Gain-of-function** **Loss-of-function**
42
G1/S checkpoints Gain-of-function example
* **D cyclin genes and CDK4** * **Melanomas, glioblastomas,** sarcomas.
43
G1/S checkpoints Loss-of-function means what?
* Mutations in genes that inhibit G1/S progression. * **Technically tumor suppressor**
44
What Loss-of-Function mutation is found in 25% of melanoma-prone families
Germline mutations of p16 (CDKN2A)
45
What Loss-of-function mutation is seen in 75% of pancreatic carcinomas?
Somatically acquired deletion or inactivation of p16
46
The two most important tumor suppressor genes, RB and TP53, both encode?
Proteins that inhibit G1/S progression
47
Explain Knudson's Two-Hit Hypothesis?
* First hit: Children inherit one **defective copy of RB** and one normal copy in the germline. * Second Hit: **Spontaneous somatic mutation** that causes the normal RB allele in retinoblasts to form a retinoblastoma. * **In sporadic cases both normal RB alleles must undergo somatic mutation in the same retinoblast.**
48
What is the locus on RB in which the two mutations (hit) are required to produce retinoblastoma?
**Locus 13q14**
49
Patients with mutated retinoblastoma alleles are at risk for developing what other tumors?
**Osteosarcoma, carcinomas of breast, colon, lung.**
50
Phosphorylation of RB is what?
Molecular on-off switch for cell cycle.
51
Describe RB in Cell Cycle?
* **Hypophosphorylated** RB binds to a protein complex including **E2F** * **E2F remains in cytoplasm** * Stimulation by growth factors - **Increase cyclins D and E** * **Active E2F** * **Growth inhibitors activate CDK inhibitors** * Mutated RB **fails to block E2F** * **Gain of function mutation of cyclins D and E mimic loss of Rb**
51
Describe RB in Cell Cycle?
* **Hypophosphorylated** RB binds to a protein complex including **E2F** * **E2F remains in cytoplasm** * Stimulation by growth factors - **Increase cyclins D and E** * **Active E2F** * **Growth inhibitors activate CDK inhibitors** * Mutated RB **fails to block E2F** * **Gain of function mutation of cyclins D and E mimic loss of Rb**
52
What mutation is found in \>50% of cancers (mostly somatic)?
**Mutations in TP53**
53
What causes **Li-Fraumeni Syndrome?**
**Inherited germline mutations of p53**
54
What does APC normally do?
* In complex with B-cantenin and destroys the B-Cantenin. * When stimulated by WNT it deactivates this and allows B-cantenin to bind to TCF and begins activating genes involved in cell cycle.
55
What mutation is associated with familial adenomatous polyposis, and what type of disorder is this?
* **Germline loss-of-function mutation involving the APC locus on chromosome 5q21.** * **Autosomal dominant**
56
For **an adenoma to arise** what must occur?
**Both copies of APC must be lost.**
57
70% to 80% of nonfamilial colorectal carcinomas and sporadic adenomas also show acquired defects where?
Involving both APC genes.
58
What is present in approximately 20% of hepatocellular carcinomas?
Gain-of-function mutations in B-catenin
59
Defective functions of BRCA1 and BRCA2 cause what?
**Non-homologous end-joining**
60
**Defective BRCA1** causes what?
**Familial breast and ovarian carcinoma, and carcinomas of male breast (BRCA1)**
61
**Lynch Syndrome** (formally **HNPCC)** details?
* Defects in genes involved in DNA mismatch repair **(MSH2 and MLH1)** * **Microsatellite instability (MSI).** * Short, repeated DNA sequences (1-6 base pairs)
62
In Knudson's two hit hypothesis how does the second hit occur?
**Somatically**
63
2 Ways in which Cell death is evaded?
* Deregulation of potent **oncoproteins (MYC)** * normally a signal that triggers apoptosis. * **Intrinsic pathway is most frequently disabled in cancer**
64
In over 85% of follicular B-cell lymphomas?
* **The BCL-2 gene is overexpressed due to a (14;18) translocation**
65
Describe the mitochondrial pathway mutations?
* **Cytochrome C** is used in unhealthy cells to initiate suicide * tightly controlled by **BCL2 family** of proteins * **Pro-apoptotic proteins** promote **leakage of cytochrome C.** * **p53 and BCL2 have functionally opposing effects on apoptosis.**
66
3 major mutations affecting evasion of cell death?
* **Loss of p53** * **Amplification of MDM2** * **Over-expression of BCL2**
67
Describe the Warburg effect?
**Mutations in PI3/Akt/mTOR** up-regulate glucose transporters and glycolytic enzymes
68
What normally prevents the Warburg effect?
**PTEN suppress this pathway in healthy cells.**

BMR 607 Test 1 (7 decks)

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