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Neoplasia > Lec 2 - Molecular Basis of Cancer > Flashcards

Lec 2 - Molecular Basis of Cancer Flashcards

AUCOM

1
Q

change in morphological appearance of a cell is due to ______ change

A

Molecular

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2
Q

Each cancer must result from accumulations of ________

A

multiple mutations

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3
Q

Morphological appearance means

A

phenotype

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4
Q

Molecular change means

A

genotype

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5
Q

change in genotype results in ______

A

change in phenotype

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6
Q

Morphologic appearance: Normal epithelium
Molecular change:

A

Loss/mutation in APC locus on chromosome 5q

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7
Q

Morphologic appearance: hyperproliferative epithelium
Molecular change:

A

loss of DNA methylation

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8
Q

Morphologic appearance: early adenoma
Molecular change:

A

mutation of RAS gene on chromosome 12q

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9
Q

Morphologic appearance: intermediate adenoma
Molecular change:

A

loss of TSG on chromosome 18p

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10
Q

Morphologic appearance: late adenoma
Molecular change:

A

loss of RAS gene on chromosome 17q

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11
Q

Molecular change: mutation/loss in APC locus on c/5q
Morphologic appearance:

A

normal epithelium

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12
Q

Molecular change: loss of DNA methylation
Morphologic appearance:

A

hyperproliferative epithelium

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13
Q

Molecular change: mutation of RAS on c/12p
Morphologic appearance:

A

early adenoma

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14
Q

Molecular change: loss of TSG on c/18q
Morphologic appearance:

A

intermediate adenoma

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15
Q

Molecular change: loss of RAS gene on c/17p
Morphologic appearance:

A

late adenoma

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16
Q

irreversible alteration of DNA

A

mutation

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17
Q

cause of mutation

A

inherited in germ line, or
acquired (radiation, chemicals, virus, etc..)

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18
Q

are most malignant tumors monoclonal or polyclonal

A

monoclonal

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19
Q

result from transformation of a single cells

A

monoclonal

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20
Q

What are the molecular basis of cancer?

A
  1. Mutation
  2. involvement of cell replication and death regulatory genes
  3. tumors result from clonal expansion of a single precursor cell
  4. Progression of tumor cells inducing mew features (heterogenous)
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21
Q

Normal regulatory genes involved in cell replication & death

A
  1. Growth promoting genes (encode GF, GFR, proteins of cell cycle)
  2. Tumor suppressor genes
  3. Genes regulating apoptosis
  4. Genes of DNA repair enzyme (Repair mutations before progression)
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22
Q

______ are cancer inducing genes derived from cellular genes called protooncogenes.

A

Oncogenes

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23
Q

he mutant alleles of protooncogenes are called ______

A

oncogenes

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24
Q

_______ are dominant because mutation of a single allele can lead to cellular transformation

A

oncogenes

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25
Q

Protooncogene: PDGF
oncogene:

A

SIS

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26
Q

Protooncogene: EGF-R
oncogene:

A

ERB-B2

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27
Q

Protooncogene: Tyrosine kinase
oncogene:

A

ABL
(Signal transduction)

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28
Q

Protooncogene: transcription activator
oncogene:

A

MYC
(DNA binding protein)

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29
Q

Methods of gene activation

A

1-Point mutation
2-Chromosomal translocation.
3-Gene amplification.
4-Gene deletion

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30
Q

gene activation results in

A

change in structure or quantity of gene product (change in functional proteins)

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31
Q

give examples of 2 tumors produced by gene activation via Chromosomal Translocation

A

Burkitt lymphoma and
Chronic myelogenous leukemia.

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32
Q

Explain the chromosomal translocation & associated oncogenes in chronic myelogenous leukemia

A

Chromosomal Translocation in Chronic Myelogenous Leukemia (CML):
Chronic myelogenous leukemia is often characterized by a specific chromosomal translocation known as the Philadelphia chromosome. Parts of chromosome 9 and chromosome 22 exchange places, resulting in the formation of the Philadelphia (Ph) chromosome.

Associated Oncogene:
The key oncogene involved in the Philadelphia chromosome is called BCR-ABL1. This fusion gene is created when a portion of the ABL gene from chromosome 9 fuses with a portion of the BCR gene on chromosome 22. The BCR-ABL1 gene produces a protein with abnormal tyrosine kinase activity, leading to uncontrolled cell growth and the development of chronic myelogenous leukemia.

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33
Q

Explain the chromosomal translocation & associated oncogenes in Burkitt Lymphoma

A

Chromosomal Translocation in Burkitt Lymphoma:
Burkitt lymphoma is often characterized by a specific chromosomal translocation known as t(8;14). This means that a portion of chromosome 8 breaks off and attaches itself to chromosome 14. This translocation leads to the activation of oncogenes.
Associated Oncogenes:
The translocation involves the MYC oncogene, which is normally located on chromosome 8. When it fuses with the immunoglobulin heavy chain gene (IGH) on chromosome 14 due to the translocation, it results in the overexpression of MYC. This overexpression is a key factor in the rapid and uncontrolled division of B cells, leading to the development of Burkitt lymphoma.

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34
Q

Give an example of a tumor produced by gene activation via Gene Amplification

A

Neuroblastoma

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35
Q

Gene involved in Burkkit’s Lymphoma

A

MYC gene

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36
Q

Gene involved in chronic myeloid lymphoma

A

BCR-ABL1 gene

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37
Q

Explain gene amplification of N-MYC gene in Neuroblastoma

A

N-MYC present normally on 2p, becomes amplified & seen either as extra chromosomal double minutes or as a chromosomally integrated homogenous staining region (HSR)

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38
Q

What are the changes necessary for malignant phenotype?

A

SIA-GRAM

  1. Self-sufficiency in growth signals (Oncogenes).
  2. Insensitivity to growth inhibitory signals (Suppressors).
  3. Evasion of apoptosis (programmed cell death :i.e. immortality of neoplastic cells)
  4. Genetic instability (Accumulation of mutation Enabler of malignancy), due to defect in DNA repair.
  5. Limitless replication potential (Telomeres determine the life of individual cell) i.e overcoming cellular senescence, due to telomerase expression .
  6. Development of Sustained angiogenesis.
  7. Ability to invade & metastasize (new features acquired during new mutations ).
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39
Q

Genes that promote autonomous cell growth in cancer cells in absence of normal promoting signals. They are usually dominant genes

A

Oncogenes

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40
Q

Oncogenes are classified by

A

site of action

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41
Q

Oncogenes include:

A
  1. growth factors
  2. growth factor receptors
  3. signal transducing proteins
  4. nuclear transcription factors
  5. cell cycle proteins (cyclins and CDKs)
  6. antiapoptotic proteins
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42
Q

Cancer cells acquire growth self-sufficiency by:

A
  1. Ability to synthesize the same growth factors to which they are responsive to (autocrine)
  2. Overexpression of growth factor genes
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43
Q

what are the 2 ways mutant receptor proteins work?

A

A)) Continuous mitogenic signals to cells, even in the absence of GF in environment.
B)) Normal but overexpressed receptors that are hypersensitive to GF. (amplifications)

44
Q

Epidermal GF receptor families:

A
  1. ERBB1 in 80% of sq. CA lung
  2. ERBB2 ( HER 2 ) in 25-30% of breast & ovarian carcinoma
45
Q

ERBB1 is expressed in

A

80% of sq. CA lung

46
Q

ERBB2 ( HER 2 ) is expressed in

A

25-30% of breast & ovarian carcinomas

47
Q

overexpression growth factor receptor leads to

A

constitutive tyrosine kinase activity (mitogenic signals)
cells become hypersensitive with a small amount of GF

48
Q

Breast carcinoma responds to

A

Herceptin therapy (Anti Her-r antibodies)

49
Q

RAS action

A

Active RAS activates down-stream regulators of proliferation (kinase mitogenic cascade) which flood the nucleus with signals for cell proliferation.

50
Q

________ in RAS are present in +30% of all cancers, specially pancreatic & GIT cancer

A

Point mutations

51
Q

A proto-oncogene that has tyrosine kinase activity and is located in cytoplasm and effect on nucleus where it promotes apoptosis of cells that suffer DNA damage .

A

ABL

52
Q

action of ABL

A

Proliferation + Absent Apoptosis.

53
Q

Gleevec - imanitib mesylate is a drug that inhibits:

A

ABL-BCR Kinase

54
Q

ABL-BCR Kinase is inhibited by (drug)

A

Gleevec - imantinib mesylate

55
Q

gene mutated in: Burkitt’s lymphoma

A

C-MYC

56
Q

gene mutated in: neuroblastoma

A

N-MYC

57
Q

gene mutated in: CA of breast, lung, colon

A

L-MYC

58
Q

CDKs at G1 > S phase checkpoint

A

CDK4 & CDK6

59
Q

Activity of CDK/Cyclin is regulated by

A

CKD inhibitors

60
Q

Overexpression of cyclin D in:

A

breast, liver, & esophageal cancers

61
Q

Amplification of CDK4 gene in:

A

melanoma, sarcomas, glioblastoma

62
Q

P16: Inhibits Rb phosphorylation by______ leading to ______

A

blocking Cyclin D-CDK4 complex.
inhibition of cell growth

63
Q

P14ARF : Activate P53 pathway by ______ leading to _______

A

inhibiting MDM2.
increased apoptosis

64
Q

P16 & P14 are silenced/activated in many malignancies?

A

silenced

65
Q

Growth inhibitory pathway is achieved by:

A

Rbgene
PT 53
TGF-beta
APC

66
Q

TGF-beta function

A

Block GF signals

67
Q

Rb gene regulates

A

cell cycle

68
Q

P53 Regulate

A

cycle & apoptosis:

69
Q

APC function

A

regulates beta-catenin

70
Q

_______ gene is mutated in colon carcinoma

A

APC

71
Q

_________ genes are recessive genes which may be lost in familial or sporadic cases or may become mutated

A

Cancer/tumor suppressor genes

72
Q

_______is cytoplasmic protein that regulates intracellular level of beta-catenin and it exerts an antiproliferative effect

A

APC gene

73
Q

a transcription activation factor (TcF) of growth promoting genes ( CyclinD1, MYC).

A

beta-catenin

74
Q

Function of Rb gene

A

prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, Rb is phosphorylated to pRb, leading to the inactivation of the activity of Rb.

75
Q

Normally, Rb phosphorylation allows cells to enter into the cell cycle. Rb role is regulating what part of the cell cycle?

A

G1&raquo_space; S check point of cell cycle.

76
Q

T/F
Rb exists in active nonphosphorylated & inactive phosphorylated forms.

A

True

77
Q

An autosomal recessive hereditary disease. May be sporadic.

A

Retinoblastoma

78
Q

how many alleles are required to be mutant for retinoblastoma to occur?

A

two alleles in 13q14 (recessive)

79
Q

mutant alleles are required for retinoblastoma to form

A

two alleles in 13q14

80
Q

Loss of normal cell cycle control is central to malignant transformation & at least one of the following is mutated in most human cancers :

A
  • Cyclin D
  • CDK 2, CDK 4, CDK 6
  • CDK inhibitors
  • RB
81
Q

T/F
Many virus (HPV) bind to the hypo-phosphorylated Rb. This leads to diminished cell proliferation.

A

False
hypo-phosphorylated Rb = Active Rb. If a virus binds to it, Rb becomes inactive and proliferation increases.

82
Q

_______ is a tumor suppressor gene , play important role as guardian of the genome

A

PT53

83
Q

normal half life of P53

A

normally present in low levels with short half life ( 20 minutes )

84
Q

in stressed, healthy cells, the half life of P53 increases or decreases?

A

In stressed, healthy cells, P53 undergo post transcreptional modefication that release it from MDM2 and increase half life

85
Q

what happens to P53 in stressful situations in healthy cells?

A

In stressed, healthy cells, P53 undergoes post transcreptional modefication that release it from MDM2 and increase half life

86
Q

T/F?
Non functioning mutants of PT53 have a long half life & accumulate in cell

A

True

87
Q

PT 53 effects

A

it has an antiproliferative effect & regulates apoptosis.

88
Q

Acquired mutation of P53 leads to

A

many cancers : e.g. colon, breast, lung , leukemia etc…

89
Q

Inherited mutation of P53 leads to

A

cancers like Li -Fraumeni S. sarcoma, leukemia, breast & brain, etc…

90
Q

P21(=CDK inhibitor) function

A

Arrest cell at G1

91
Q

GADD45 gene function

A

DNA repair

92
Q

BAX gene function

A

apoptosis

93
Q

BAX,
BCL-2,
BCL-x,
BAD

A

Apoptosis Genes

94
Q

BCL-2 function

A

prevents apoptosis

95
Q

how is BCL-2 (antiapoptotic gene) activated?

A

Activated by translocation (18:14 )
leads to low grade B cell Lymphoma .

96
Q

DNA Repair Genes include

A
  1. Nucleotide excision repair genes
  2. DNA Mismatch repair genes
97
Q

genes that repair damage caused by U-V light. Defect in the genes that encode certain enzymes involved in DNA synthesis

A

Nucleotide excision repair genes

98
Q

genes that repair errors in pairing of nucleotides during cell division . e.g. G+T instead of A+T

A

DNA Mismatch repair genes

99
Q

These genes are not oncogenic but allow mutation in other genes in normal cell cycle

A

Hereditary Nonpolyposis Colonic CA.) (HNPCC).

100
Q

important in repairing breaks in DNA but are rarely inactivated in sporadic cases.

A

BRCA1 , BRCA2

101
Q

BRCA-1 repairs DNA in

A

In familial breast cancer & ovarian CA

102
Q

BRCA-2 repairs DNA in

A

in breast CA in both sexes,
prostate, ovary, pancreas, stomach CA

103
Q

what’s ‘senescence’?

A

After a certain number of divisions, the chromosomes can become damaged to the point that the cells can’t divide anymore — a state called senescence.

104
Q

Cancer cells often avoid senescence or cell death by _______

A

by maintaining their telomeres despite repeated cell divisions, via telomerase enzyme.

105
Q

how can cancer cells maintain their telomeres despite repeated cell divisions?

A

This is possible because the cancer cells activate an enzyme called telomerase, which adds genetic units onto the telomeres to prevent them from shortening.
As a result, cancer cells essentially become immortal.

Neoplasia (2 decks)

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