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BMR 607 Final > 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
Q

100% of hairy cell leukemias, and >60% of melanomas caused by?

A

BRAF mutations

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26
Q

What is BRAF?

A

Serine/Threonine protein kinase that activates downstream kinases of the MAPK cascade.

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27
Q

~30% of breast cancers have a mutation involving the a-isoform of ?

A

PIK3 catalytic subunit

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28
Q

What is the associated tumor with the proto-oncogene ABL-non-receptor tyrosine kinase.

A

Chronic myelogenous leukemia, acute lymphoblastic leukemia.

29
Q

What is the associated tumor with the proto-oncogene JAK2.

A

Myeloproliferative disorders, acute lymphoblastic lymphoblastic leukemia.

30
Q

Nonreceptor Tyrosine Kinase oncogoenes?

A

ABL

NOTCH1

JAK2

31
Q

Describe the BCR-ABL Fusion mutation?

A

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
Q

What is detected in >90% patients with CML and up to 20% patients with ALL?

A

BCR-ABL Fusion Protein

33
Q

Involves C-myc Pathway

A

Burkitt Lymphoma

34
Q

Involves N-myc pathway?

A

Neuroblastoma

35
Q

Involves L-myc Pathway

A

Small cell lung carcinoma

36
Q

Burkitt Lymphoma is associated with what translocation in 75% of casses and commonly with what infection?

A

t(8;14)

EBV infection

37
Q

In adults, EBV occurs in association with what?

A

HIV infection

38
Q

What sensor for DNA damage blocks progression from G1 to S phase?

A

p53

39
Q

What Balance of growth promoters/inhibitors regulate G1/S-Cdk?

A

Rb

40
Q

What controls control cell-cycle progression

A

Cyclin-dependent kinase (Cdk)

41
Q

What are the two classes of mutations that affect the G1/S checkpoint?

A

Gain-of-function

Loss-of-function

42
Q

G1/S checkpoints

Gain-of-function example

A
  • D cyclin genes and CDK4
    • Melanomas, glioblastomas, sarcomas.
43
Q

G1/S checkpoints

Loss-of-function means what?

A
  • Mutations in genes that inhibit G1/S progression.
    • Technically tumor suppressor
44
Q

What Loss-of-Function mutation is found in 25% of melanoma-prone families

A

Germline mutations of p16 (CDKN2A)

45
Q

What Loss-of-function mutation is seen in 75% of pancreatic carcinomas?

A

Somatically acquired deletion or inactivation of p16

46
Q

The two most important tumor suppressor genes, RB and TP53, both encode?

A

Proteins that inhibit G1/S progression

47
Q

Explain Knudson’s Two-Hit Hypothesis?

A
  • 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
Q

What is the locus on RB in which the two mutations (hit) are required to produce retinoblastoma?

A

Locus 13q14

49
Q

Patients with mutated retinoblastoma alleles are at risk for developing what other tumors?

A

Osteosarcoma, carcinomas of breast, colon, lung.

50
Q

Phosphorylation of RB is what?

A

Molecular on-off switch for cell cycle.

51
Q

Describe RB in Cell Cycle?

A
  • 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
Q

What mutation is found in >50% of cancers (mostly somatic)?

A

Mutations in TP53

53
Q

What causes Li-Fraumeni Syndrome?

A

Inherited germline mutations of p53

54
Q

What does APC normally do?

A
  • 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
Q

What mutation is associated with familial adenomatous polyposis, and what type of disorder is this?

A
  • Germline loss-of-function mutation involving the APC locus on chromosome 5q21.
  • Autosomal dominant
56
Q

For an adenoma to arise what must occur?

A

Both copies of APC must be lost.

57
Q

70% to 80% of nonfamilial colorectal carcinomas and sporadic adenomas also show acquired defects where?

A

Involving both APC genes.

58
Q

What is present in approximately 20% of hepatocellular carcinomas?

A

Gain-of-function mutations in B-catenin

59
Q

Defective functions of BRCA1 and BRCA2 cause what?

A

Non-homologous end-joining

60
Q

Defective BRCA1 causes what?

A

Familial breast and ovarian carcinoma, and carcinomas of male breast (BRCA1)

61
Q

Lynch Syndrome (formally HNPCC) details?

A
  • Defects in genes involved in DNA mismatch repair (MSH2 and MLH1)
  • Microsatellite instability (MSI).
    • Short, repeated DNA sequences (1-6 base pairs)
62
Q

In Knudson’s two hit hypothesis how does the second hit occur?

A

Somatically

63
Q

2 Ways in which Cell death is evaded?

A
  • Deregulation of potent oncoproteins (MYC)
    • normally a signal that triggers apoptosis.
  • Intrinsic pathway is most frequently disabled in cancer
64
Q

In over 85% of follicular B-cell lymphomas?

A
  • The BCL-2 gene is overexpressed due to a (14;18) translocation
65
Q

Describe the mitochondrial pathway mutations?

A
  • 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
Q

3 major mutations affecting evasion of cell death?

A
  • Loss of p53
  • Amplification of MDM2
  • Over-expression of BCL2
67
Q

Describe the Warburg effect?

A

Mutations in PI3/Akt/mTOR up-regulate glucose transporters and glycolytic enzymes

68
Q

What normally prevents the Warburg effect?

A

PTEN suppress this pathway in healthy cells.

69
Q

Describe RB in Cell Cycle?

A
  • 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

BMR 607 Final (10 decks)

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