Neoplasms 3 Flashcards Preview

ESA 2- Mechanisms of Disease > Neoplasms 3 > Flashcards

Flashcards in Neoplasms 3 Deck (107):
1

What accounts for cancer risk?

A combination of intrinsic host factors and extrinsic factors

2

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

Hereditary
Age
Gender (especially hormonal)

3

What are extrinsic factors for cancer risk related to?

The environment and behaviour

4

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

Prolonged life span

5

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

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

6

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

30%

7

What is tobacco smoke alone associated with?

Approx. 1/4 of all cancer deaths

8

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

Epidemiological and animal studies

9

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

About 85%

10

What categories to extrinsic carcinogens fall into?

Chemicals
Radiation
Infections

11

Give an example of a industrial carcinogen

2-napthylamine

12

Where is 2-napthylamine used?

In the dye manufacturing industry

13

What do malignant neoplasms caused by 2-napthylamine show?

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

14

What does 2-napthylamine cause?

Bladder carcinoma

15

What does the dependance on dosage of carcinogens mean?

Industrial carcinogens and tobacco smoke are especially important

16

Give 3 examples of industrial carcinogens

Asbestos
Coal tars
Vinyl chloride

17

What is tobacco smoke associated with?

Bronchial carcinoma

18

What does chemical carcinogenesis involve?

Initiation and promotion

19

What do animal experiments show?

The sequence in which carcinogens are administrated is critical

20

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

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

21

What does the Ames test show?

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

22

What does promoter induced proliferation in target tissues culminate in?

Monoclonal expansion of mutant cells

23

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

Through a process called progression

24

How can mutagenic chemical carcinogens be classified?

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

25

Give an example of a natural initiator

Aflatoxin

26

What is true of some of the mutagenic chemical carcinogens?

They are pro-carcinogens

27

What are pro-carcinogens?

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

28

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

Complete carcinogens

29

What is radiation?

Any type of energy travelling through space

30

Is radiation mutagenic?

Some forms are

31

How far can ultraviolet (UV) light penetrate?

No deeper than the skin

32

What does ionising radiation do?

Strips electrons from atoms

33

What can produce ionising radiation?

X-rays
Nuclear radiation arising from radioactive elements

34

What does nuclear radiation comprise of?

Alpha particles, beta particles, and gamma rays

35

How can radiation cause damage?

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

36

What is the most important type of radiation?

UV

37

Why is UV radiation the most important type of radiation?

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

38

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

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

39

What does ionising radiation do in the body?

Damages DNA bases and causes single and double strand DNA breaks

40

How can infections act to cause cancer?

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

41

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

Cervical carcinoma

42

What kind of carcinogen is the HPV virus?

Direct

43

How does HPV act as a carcinogen?

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

44

What kind of carcinogens are Hep B and C viruses?

Indirect

45

How do Hep B and C act as carcinogens?

They cause chronic liver cell injury and regeneration

46

Can bacteria and parasites lead to neoplasms?

Yes, indirectly

47

Give an example of a bacteria that can cause neoplasms?

Helicobacter pylori

48

How does helicobacter pylori cause neoplasms?

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

49

Give an example of a parasitic cause of neoplasms

Parasitic flukes

50

How do parasitic flukes cause neoplasms?

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

51

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

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

52

What pattern of inheritance is seen with retinoblastoma?

Dominant

53

Does retinoblastoma occur sporadically, or just in families?

Yes

54

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

Knudson postulated a 'two hit hypothesis'

55

What is the two hit hypothesis?

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

When do initiation and promotion lead to neoplasms?

When they affect proto-oncogenes and tumour suppressor genes

57

What are tumour suppressor genes?

Genes that inhibit neoplastic growth

58

Why do tumour suppressor genes need two hits?

Because both alleles must be inactivated

59

What are oncogenes?

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

60

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

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

61

What was the first human oncogene to be discovered?

RAS

62

In what proportion of malignant neoplasms is RAS mutated in?

Approx 1/3

63

What does the RAS proto-oncogene encode?

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

64

What does mutant RAS do?

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

65

What does the RB gene do?

Restrains cell proliferation by inhibiting passage through the restriction point

66

What does inactivation of both RB alleles allow?

Unrestrained passage through the restriction point

67

What does the action of RB and RAS show?

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

68

What can proto-oncogenes encode for?

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

69

Give an example of a growth factor

PDGF

70

Give an example of a growth factor receptor

HER2

71

Give an example of a plasma membrane signal transducer

RAS

72

Give an example of an intracellular kinase

BRAF

73

Give an example of a transcription factor

MYC

74

Give an example of a cell cycle regulator

CYCLIN D1

75

Give an example of an apoptosis regulator

BCL2

76

What do tumour suppressor genes encode for?

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

77

Give an example of a tumour suppressor gene?

TP53

78

What do some inherited cancer syndromes have?

Germline mutations that cause malignant neoplasms indirectly by affecting DNA repair

79

What inheritance pattern does xeroderma pigmentosum (XP) show?

Autosomal recessive

80

What is XP due to?

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

81

What are patients with XP sensitive to?

UV damage

82

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

They develop skin cancer at a young age

83

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

Autosomal dominant

84

What is HNPCC syndrome associated with?

Colon carcinoma

85

What happens in HNPCC syndrome?

The germline mutation affects one of several DNA mismatch repair genes

86

What is familial breast carcinoma associated with?

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

87

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

Yes

88

What stage of mitosis can be abnormal in malignant cells?

Chromosomal segregation during mitosis

89

What do the alterations found in hereditary neoplasms account for?

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

90

What do genes that maintain genetic stability belong to?

A class of tumour suppressor genes called caretaker genes

91

What do most malignant tumours require?

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

92

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

Colon carcinoma

93

What does colon carcinoma usually start as?

A colonic adenoma, from which arises a carcinoma

94

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

The adenoma-carcinoma sequence

95

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

Mutations accumulate

96

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

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

97

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

Typically decades

98

What does the adenoma-carcinoma sequence illustrate?

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

99

What is the steady accumulation of multiple mutations called?

Cancer progression

100

How does cancer evolve?

By initiation and promotion, and then finally by progression

101

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

Unknown, but thought to be approx. 10 or less

102

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

6 hallmarks of cancer, plus one enabling feature

103

What are the six hallmarks of cancer?

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

What kind of neoplasms are the hallmarks related to?

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

What is genetic instability regarded as?

An enabling characteristic

106

What is the model of cancer pathogenesis?

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

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

5%