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ESA 2- Mechanisms of Disease > Neoplasms 3 > Flashcards

Neoplasms 3 Flashcards

1
Q

What accounts for cancer risk?

A

A combination of intrinsic host factors and extrinsic factors

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2
Q

Give 3 examples of intrinsic host factors that can account for cancer risk

A

Hereditary
Age
Gender (especially hormonal)

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3
Q

What are extrinsic factors for cancer risk related to?

A

The environment and behaviour

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4
Q

What is much of the increased cancer incidence over the last century due to?

A

Prolonged life span

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5
Q

What are the five leading behavioural and dietary risks for cancer?

A 
High body mass index
Low fruit and vegetable intake 
Lack of physical activity 
Tobacco use 
Alcohol use
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6
Q

What % of cancer deaths are due to the 5 leading behavioural and dietary risks?

A

30%

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7
Q

What is tobacco smoke alone associated with?

A

Approx. 1/4 of all cancer deaths

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8
Q

Where does most of the evidence about cancer risk come from?

A

Epidemiological and animal studies

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9
Q

How much of a populations cancer risk do extrinsic factors account for?

A

About 85%

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10
Q

What categories to extrinsic carcinogens fall into?

A

Chemicals
Radiation
Infections

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11
Q

Give an example of a industrial carcinogen

A

2-napthylamine

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12
Q

Where is 2-napthylamine used?

A

In the dye manufacturing industry

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13
Q

What do malignant neoplasms caused by 2-napthylamine show?

A

There is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset
The risk of cancer depends on carcinogen dosage
There is sometimes organ specificity for particular carcinogens

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14
Q

What does 2-napthylamine cause?

A

Bladder carcinoma

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15
Q

What does the dependance on dosage of carcinogens mean?

A

Industrial carcinogens and tobacco smoke are especially important

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16
Q

Give 3 examples of industrial carcinogens

A

Asbestos
Coal tars
Vinyl chloride

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17
Q

What is tobacco smoke associated with?

A

Bronchial carcinoma

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18
Q

What does chemical carcinogenesis involve?

A

Initiation and promotion

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19
Q

What do animal experiments show?

A

The sequence in which carcinogens are administrated is critical

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20
Q

What is important about the sequence in which carcinogens are administrated?

A

Some chemical carcinogens, called initiators, must be given first, followed by a second class of carcinogens, called promoters

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21
Q

What does the Ames test show?

A

Initiators are mutagens, while promoters cause prolonged proliferation in target tissues

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22
Q

What does promoter induced proliferation in target tissues culminate in?

A

Monoclonal expansion of mutant cells

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23
Q

How does a mutant monoclonal collection of cells eventually become fully malignant?

A

Through a process called progression

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24
Q

How can mutagenic chemical carcinogens be classified?

A 
Polycyclic aromatic hydrocarbons 
Aromatic amines 
N-nitroso compounds 
Alkylating agents 
Diverse natural products
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25
Q

Give an example of a natural initiator

A

Aflatoxin

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26
Q

What is true of some of the mutagenic chemical carcinogens?

A

They are pro-carcinogens

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27
Q

What are pro-carcinogens?

A

They are only converted to carcinogens by P450 enzymes in the liver

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28
Q

What are carcinogens that act as both initiators and promoters called?

A

Complete carcinogens

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29
Q

What is radiation?

A

Any type of energy travelling through space

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30
Q

Is radiation mutagenic?

A

Some forms are

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31
Q

How far can ultraviolet (UV) light penetrate?

A

No deeper than the skin

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32
Q

What does ionising radiation do?

A

Strips electrons from atoms

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33
Q

What can produce ionising radiation?

A

X-rays

Nuclear radiation arising from radioactive elements

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34
Q

What does nuclear radiation comprise of?

A

Alpha particles, beta particles, and gamma rays

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35
Q

How can radiation cause damage?

A

It can damage DNA directly, or cause indirect damage by generating free radicals

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36
Q

What is the most important type of radiation?

A

UV

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37
Q

Why is UV radiation the most important type of radiation?

A

Because we are exposed daily from sunlight, leading to an increased skin cancer risk

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38
Q

What is the main exposure to ionising radiation for most people?

A

Natural background radiation from radon, which seeps from the earths crust

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39
Q

What does ionising radiation do in the body?

A

Damages DNA bases and causes single and double strand DNA breaks

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40
Q

How can infections act to cause cancer?

A

Some directly affect genes that control cell growth
Others do so indirectly by causing chronic tissue injury, where the resulting regenerating acts either as a promoter for any pre-existing mutations, or elses causes new mutations from DNA replication errors

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41
Q

What is Human Papilloma Virus (HPV) strongly linked to?

A

Cervical carcinoma

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42
Q

What kind of carcinogen is the HPV virus?

A

Direct

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43
Q

How does HPV act as a carcinogen?

A

It expresses the E6 and E7 proteins that inhibit p53 and pRB protein function respectively, both of which are important in cell proliferation

44
Q

What kind of carcinogens are Hep B and C viruses?

A

Indirect

45
Q

How do Hep B and C act as carcinogens?

A

They cause chronic liver cell injury and regeneration

46
Q

Can bacteria and parasites lead to neoplasms?

A

Yes, indirectly

47
Q

Give an example of a bacteria that can cause neoplasms?

A

Helicobacter pylori

48
Q

How does helicobacter pylori cause neoplasms?

A

It can cause chronic gastric inflammation, increasing the risk of gastric carcinomas

49
Q

Give an example of a parasitic cause of neoplasms

A

Parasitic flukes

50
Q

How do parasitic flukes cause neoplasms?

A

They cause inflammation to the bile ducts and bladder mucosa, increasing the risk for cholangio- and bladder carcinomas respectively

51
Q

How does Human Immunodeficiency Virus (HIV) increase the risk of neoplasms?

A

It acts indirectly by lowering immunity, and allowing other potentially carcinogenic infections to occur

52
Q

What pattern of inheritance is seen with retinoblastoma?

A

Dominant

53
Q

Does retinoblastoma occur sporadically, or just in families?

A

Yes

54
Q

How was the differences between tumours occurring in families and those occurring in the general population explained?

A

Knudson postulated a ‘two hit hypothesis’

55
Q

What is the two hit hypothesis?

A

For familial cancers, the first hit was delivered through the germline, and affected all the cells in the body. The second hit was a somatic mutation.
In the case of retinoblastoma, this was in one of the 10million+ retinal cells already carrying the first hit
In contrast, sporadic retinoblastoma has no germline mutation, and so requires both hits to be somatic mutations and to occur in the same cell.

56
Q

When do initiation and promotion lead to neoplasms?

A

When they affect proto-oncogenes and tumour suppressor genes

57
Q

What are tumour suppressor genes?

A

Genes that inhibit neoplastic growth

58
Q

Why do tumour suppressor genes need two hits?

A

Because both alleles must be inactivated

59
Q

What are oncogenes?

A

Genes that enhance neoplastic growth that are abnormally activated versions of normal genes called proto-oncogenes

60
Q

Do proto-oncogenes need two hits to convert them to oncogenes?

A

No, only one allele of each proto-oncogene needs to activated to favour neoplastic growth

61
Q

What was the first human oncogene to be discovered?

A

RAS

62
Q

In what proportion of malignant neoplasms is RAS mutated in?

A

Approx 1/3

63
Q

What does the RAS proto-oncogene encode?

A

A small G protein that relays the signals into the cell that eventually pushes the cell past the cell cycle restriction point

64
Q

What does mutant RAS do?

A

Encodes a protein thats always active, ultimately producing a constant signal to pass through the cell cycle’s restriction point

65
Q

What does the RB gene do?

A

Restrains cell proliferation by inhibiting passage through the restriction point

66
Q

What does inactivation of both RB alleles allow?

A

Unrestrained passage through the restriction point

67
Q

What does the action of RB and RAS show?

A

How one component of growth control, the restriction point, can be deregulated either by an activated oncogene or inactivated TS gene

68
Q

What can proto-oncogenes encode for?

A 
Growth factors 
Growth factor receptors 
Plasma membrane signal transducers 
Intracellular kinases 
Transcription factors 
Cell cycle regulators 
Apoptosis regulators
69
Q

Give an example of a growth factor

A

PDGF

70
Q

Give an example of a growth factor receptor

A

HER2

71
Q

Give an example of a plasma membrane signal transducer

A

RAS

72
Q

Give an example of an intracellular kinase

A

BRAF

73
Q

Give an example of a transcription factor

A

MYC

74
Q

Give an example of a cell cycle regulator

A

CYCLIN D1

75
Q

Give an example of an apoptosis regulator

A

BCL2

76
Q

What do tumour suppressor genes encode for?

A

Proteins in the same pathways, but with anti-growth effects

77
Q

Give an example of a tumour suppressor gene?

A

TP53

78
Q

What do some inherited cancer syndromes have?

A

Germline mutations that cause malignant neoplasms indirectly by affecting DNA repair

79
Q

What inheritance pattern does xeroderma pigmentosum (XP) show?

A

Autosomal recessive

80
Q

What is XP due to?

A

Mutations in one of the 7 genes that affect DNA nucleotide excision repair (NER)

81
Q

What are patients with XP sensitive to?

A

UV damage

82
Q

What is the result of patients with XP being sensitive to UV damage?

A

They develop skin cancer at a young age

83
Q

What inheritance pattern does hereditary non-polyposis colon cancer (HNPCC) show?

A

Autosomal dominant

84
Q

What is HNPCC syndrome associated with?

A

Colon carcinoma

85
Q

What happens in HNPCC syndrome?

A

The germline mutation affects one of several DNA mismatch repair genes

86
Q

What is familial breast carcinoma associated with?

A

Either BRCA1 and BRCA2 genes, which are important for repairing double strand DNA breaks

87
Q

Can the mutations found in hereditary cancers be found in sporadic malignant neoplasms?

A

Yes

88
Q

What stage of mitosis can be abnormal in malignant cells?

A

Chromosomal segregation during mitosis

89
Q

What do the alterations found in hereditary neoplasms account for?

A

The accelerated mutation rate found in the malignant neoplasms that is known as genetic instability

90
Q

What do genes that maintain genetic stability belong to?

A

A class of tumour suppressor genes called caretaker genes

91
Q

What do most malignant tumours require?

A

Alterations affecting a combination of multiple TS genes and proto-oncogenes

92
Q

What is the need for most malignant tumours to have alterations affecting a combination of TS genes and proto-oncogenes illustrated by?

A

Colon carcinoma

93
Q

What does colon carcinoma usually start as?

A

A colonic adenoma, from which arises a carcinoma

94
Q

What is the the conversion of adenoma to carcinoma known as?

A

The adenoma-carcinoma sequence

95
Q

What is shown to happen during the adenoma-carcinoma sequence?

A

Mutations accumulate

96
Q

How has it been shown that mutations accumulate during the adenoma-carcinoma sequence?

A

Analysis of early adenomas, later adenomas, primary carcinomas and metastatic carcinomas

97
Q

What is the time frame for the adenoma-carcinoma sequence?

A

Typically decades

98
Q

What does the adenoma-carcinoma sequence illustrate?

A

A general principle of step-wise accumulation of mutations in malignant neoplasms

99
Q

What is the steady accumulation of multiple mutations called?

A

Cancer progression

100
Q

How does cancer evolve?

A

By initiation and promotion, and then finally by progression

101
Q

What is the exact number of mutations required for a fully evolved malignant neoplasm?

A

Unknown, but thought to be approx. 10 or less

102
Q

What is it now believed that a fully evolved malignant neoplasm exhibits?

A

6 hallmarks of cancer, plus one enabling feature

103
Q

What are the six hallmarks of cancer?

A

Self-sufficiency in growth signals
Resistance to growth stop signals
No limit on the number of times a cell can divide (cell immortilisation)
Sustained ability to induce new blood vessels (angiogenesis)
Resistance to apoptosis
The ability to invade and produce metastases

104
Q

What kind of neoplasms are the hallmarks related to?

A

Hallmarks 1 to 5 are primarily about increased growth, and therefore likely to be relevant to both benign and malignant neoplasms
Hallmark 6 is exclusively relevant to malignant neoplasms

105
Q

What is genetic instability regarded as?

A

An enabling characteristic

106
Q

What is the model of cancer pathogenesis?

A

First, somatic cells are exposed to environmental carcinogens that are either initiators or promoters, culminating in a monoclonal population of mutant cells
By chance, some of these clones harbour mutations affecting a proto-oncogene or tumour suppressor gene, which protein transcripts play crucial roles in cell signalling pathways affecting ‘hallmark’ changes.
During progression the cells acquire further activated oncogenes, or inactivated tumour suppressor genes, including the ones that cause genetic instability
This eventually results, after many years or even decades, in a population of cells that has acquired a set of mutations that produce all of the ‘hallmarks of cancer’

107
Q

What % of cancers have inherited mutations in the germline present?

A

5%

ESA 2- Mechanisms of Disease (11 decks)

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