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MOD > Chapter 7 Part 3 > Flashcards

Chapter 7 Part 3 Flashcards

1
Q

What is the stepwise acquisition of mutations that lead to the development of cancer?

A
  1. Initial carcinogen induced mutation
  2. mutation affecting genomic integrity
  3. additional driver mutations, acquisition of cancer hallmarks
  4. Additional mutations and emergence of subclones
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2
Q

Eight fundamental changes in cell physiology considered hallmarks of CA

A
  1. self-sufficiency in growth signals
  2. Insensitivity to growth-inhibitory signals
  3. altered cell metabolism
  4. Evasion of apoptosis
  5. Limitless replicative potential
  6. sustained angiogenesis
  7. ability to invade and metastasize
  8. ability to evade host immune response
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3
Q

What is a proto-oncogene?

A

growth promoter, involved in normal cell division and growth

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4
Q

What is an oncogene?

A

cancer-causing gene, promote autonomous growth

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5
Q

What allelic mutations are needed to promote neoplasia?

A

Conversion of one of two alleles from proto-oncogene to an oncogene, or loss of both tumor suppressor alleles

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6
Q

What is an oncoprotein?

A

resembles normal product of proto-oncogenes but contains mutations that inactivate internal regulatory elements

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7
Q

Mode of action of growth factor oncogene

A

Growth factors can acquire the ability to synthesize their own growth factors and cause autocrine stimulation

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8
Q

Mode of action of growth factor receptor oncogene

A

constiutive, growth-factor independent tyrosine kinase activity

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9
Q

EGFR1 gene product and associated CA

A

epidermal growth factor receptor, lung adenocarcinoma

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10
Q

EGFR2 gene product and associated CA

A

HER2 tyrosine kinase, amplified in breast carcinoma

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11
Q

ALK proto-oncogene activation and associated CA

A

translocation or fusion with EML4, associated with lymphomas and adenocarcinomas of the lung

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12
Q

Function of RAS proteins

A

signal transduction from RTKs to MAPK/PI3K pathways

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13
Q

Common point mutation result of RAS proteins

A

decreased GTPase activity resulting in constitutive pro-growth signals

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14
Q

Cancers associated with RAS protein mutations

A

colon, lung, pancreatic, bladder, kidney, melanomas, hematologic, pituitary, etc.

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15
Q

Result of activating BRAF mutation

A

downstream kinase and transcription factor activation

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16
Q

Mode of activation of BRAF and associated CAs

A

point mutation, melanomas, leukemias, colon carcinoma

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17
Q

ABL tyrosine kinase mode of activation and associated CA

A

translocation of gene from C9 to C22 - BCR-ALK gene product, acute lymphoblastic leukemias and chronic myelogenous leukemia

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18
Q

Main actions of MYC

A

activates genes involved in cell growth – protein synthesis, cell cycle progression; upregulates telomerase, reprogram somatic cells to stem cells

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19
Q

MYC mechanism of activation in tumor and associated CA

A

translocation, Burkitt lymphoma

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20
Q

CA associated with constiutive Wnt signaling

A

colon carcinoma

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21
Q

CA associated with constiutive HH signaling

A

meduloblastoma

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22
Q

Mechanism of activation in tumor of cyclin and associated CA

A

Translocation - mantle cell lymphoma and multiple myeloma

Amplification - breast and esophageal CA

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23
Q

Mechanism of activation in tumor of CDKs and associated CA

A

amplification or pt mutation, glioblastoma, melanoma, sarcoma

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24
Q

Main function of RB

A

tumor suppressor protein that binds E2F transcription factors in hypophosphorylated state to prevent G1/S transition

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25
Q

Main function of p53

A

tumor suppressor, acts through p21 to cause cell cycle arrest, causes apoptosis

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26
Q

Proto-Oncogene mutations result in…

A

excessive increase in one or more normal functions encoded in gene

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27
Q

tumor-suppressor mutations result in…

A

lack of growth inhibition, requires both alleles to be damages

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28
Q

mutations in genes that regulate apoptosis result in…

A

less death, enhanced survival

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29
Q

mutations in DNA-repair genes result in…

A

impaired ability to recognize and repair nonlethal genetic damage, can result in genetic instability

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30
Q

APC function

A

inhibit WNT signaling

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31
Q

APC familial syndromes and CAs

A

familial colonic polyps and carcinomas, carcinomas of stomach, colon, pancreas; melanoma

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32
Q

NF1 function

A

inhibit RAS/MAPK signaling

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33
Q

NF2 function

A

cytoskeletal stability

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34
Q

NF1 familial syndromes and CAs

A

neurofibromatosis type 1; neuroblastoma, juvenile myeloid lukemia

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35
Q

NF2 familial syndromes and CAs

A

Neurofibromatosis type 2; schwannoma, meningioma

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36
Q

PTCH function

A

inhibitor of HH

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37
Q

PTCH familial syndromes and CAs

A

Gorlin syndrome; basal cell carcinoma, medulloblastoma

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38
Q

VHL function

A

inhibitor of hypoxia induced transcription factors

39
Q

VHL familial syndromes and CAs

A

Von Hippel Lindau syndrome; renal cell carcinomas

40
Q

CDH1 function

A

cell adhesion, inhibition of cell motility

41
Q

CDH1 familial syndromes and CAs

A

familial gastric CA; gastric carcinoma, lobular breast carcinokma

42
Q

BRCA1 / BRCA 2 function

A

repair ds DNA breaks

43
Q

BRCA1/2 familial syndromes and CAs

A

familial breast and ovarian carcinoma, carcinomas of male breast, chronic lymphocytic leukemia; sporadic CA development rare

44
Q

MSH function

A

DNA mismatch repair

45
Q

MSH familial syndromes and CAs

A

hereditary nonpolyposis colon carcinoma; colonic and endometrial carcinoma

46
Q

WT1 function

A

transcription factor

47
Q

WT1 familial syndrome and CAs

A

familial wilms tumor; wilms tumor, certain leukemias

48
Q

What mutations are required to produce retinoblastoma?

A

two hits involving both RB alleles at 13q14

49
Q

Function of PD-1

A

checkpoint protein on T cells that prevent T cells from attacking other cells in the body by binding to PD-L1

50
Q

Mabs for PD-1

A

block binding of PD-1 to PD-L1 to bosst immune response to CA cells

51
Q

CTLA4 function

A

downregulate immune response, upregulated on T cells after activation

52
Q

Problem with CTLA4 Mab

A

serious and life-threatening side effects

53
Q

PDE4 function

A

degrades cAMP in immune cells, prevents anti-inflammatory effects - psoriatic lesion development

54
Q

Epigenome

A

factors other than DNA sequence that regulate gene expression

55
Q

Methylation of DNA

A

causes changes in DNA structure and thus causes activation or silencing of genes

56
Q

Histone acetylation

A

causes changes in chromatin regulatory complexes activating or silencing genes

57
Q

miRNAs

A

function to modulate translation of mRNAs into their proteins, posttranscriptional silencing of gene expression

58
Q

long noncoding RNA

A

modulate gene expression by binding to chromatin, restricting RNA polymerase access to coding genes

59
Q

Warburg effect

A

increased lactose production in the presence of glucose via the glycolytic pathway, demonstrates “glucose hunger” of tumors

60
Q

Is Warburg metabolism cancer specific?

A

No, it also occurs in growing cells (embryonic)

61
Q

What does Warburg metabolism provide for a cell that oxidative phosphorylation does not?

A

metabolic intermediates needed for synthesis of cellular components

62
Q

Role of PI3K/AKT in Warburg effect

A

upregulates glucose transports, glycolytic enzymes, shunts intermediates

63
Q

Role of RTK activity in Warburg effect

A

upregulate enzymatic activity leading to a build up of glycolytic intermediates

64
Q

Role of MYC activity in Warburg effect

A

upregulation of glutaminase and glycolytic enzymes

65
Q

How can apoptosis be initiated?

A

intrinsic or extrinsic pathways

66
Q

Which pathway of apoptosis is more commonly mutated in lesions?

A

intrinsic

67
Q

What anti-apoptotic gene is most commonly overexpressed in B-cell lymphoma and why?

A

BCL2 due to a 14;18 translocation

68
Q

How do cancer stem cells arise?

A

through transformation of a normal stem cell or acquired genetic lesions

69
Q

What two lesions are commonly acquired in cancer cells that convey limitless replicative potential?

A

inactivated senescence signals and reactivated telomerase

70
Q

Why is angiogenesis important?

A

required for growth of tumors

71
Q

What triggers angiogenesis?

A

hypoxia via HIF-1a and VEGF

72
Q

Actions of p53 for angiogenesis

A

induces synthesis of angiogenesis inhibitor thrombospondin-1

73
Q

Actions of RAS, MYK, MAPK in angiogenesis

A

upregulate VEGF to stimulate angiogenesis

74
Q

VEGF treatment

A

inhibitors can be used to prolong the clinical course but are not curative

75
Q

What cells recognize tumor ags?

A

CD8 T cells

76
Q

Classes of tumor antigens

A

products of mutated proto-oncogenes, tumor suppressor genes, overexpressed proteins, tumor ags produced by oncogenic viruses, oncofetal antigens, altered glycolipids and glycoproteins and cell-specific differentiation antigens

77
Q

What types of cancer are immunocompromised pts at an increased risk for?

A

oncogenic DNA viruses

78
Q

how may tumors avoid the immune system?

A

reduced expression of histocompatabilty antigens, immunosuppression expression, selective outgrowth of antigen-negative variants

79
Q

HNPCC syndrome

A

hereditary nonpolyposis colon cancer; defects in mismatch repair systems leading to carcinomas of colon

80
Q

xeroderma pigmentosum

A

defect in nt excision repair, increased risk for skin cancer due to inability to repair pyrimidine dimers

81
Q

Defects in homologous recombination DNA repair system constitute what disorders?

A

Bloom syndrome, ataxia-telangiectasia, fanconi anemia

82
Q

DNA damage in B and T lymphocyte tumors

A

occurs due to presence of products that induce genetic instability (RAG1, RAG2, AID)

83
Q

CA enabling effects of inflammatory cells

A

release of factors that promote proliferation, removal of growth suppressors, enhanced resistance to cell death (anoikis), inducing angiogenesis, activating invasion and metastasis, evading immune destruction

84
Q

oncogenic mutations

A

point mutations, chromosomal abnormalities, translocations, deletions, amplifications

85
Q

How do balanced translocations contribute to carcinogenesis?

A

overexpression of oncogenes or fusion protein generation with altered signaling capacity

86
Q

How do deletions contribute to carcinogenesis?

A

loss of tumor suppressor gene function, activation of proto-oncogenes

87
Q

How do amplifications cause carcinogenesis?

A

increased expression and function of oncogenes

88
Q

chromothrypsis

A

shattered chromosome reassembled in haphazard way

89
Q

Translocation of CML

A

9;22

90
Q

Translocation of AML

A

8;21 or 15;17

91
Q

Translocation of burkitt lymphoma

A

8;14

92
Q

Translocation of Mantle cell lymphoma

A

11;14

93
Q

Translocation of follicular lymphoma

A

14;18

94
Q

All-trans retinoic acid in acute promyelocytic leukemia

A

used to activate gene transcription to activate PMNs, PML+RARa translocation normally prevents gene expression with normal RA but ATRA allows for transcription

MOD (34 decks)

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