MoD Session 10 Flashcards Preview

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Flashcards in MoD Session 10 Deck (141):
1

What are the extrinsic factors that increase cancer risk?

Environment
Lifestyle

2

What are the 5 leading behavioural and dietary risks in developing cancer?

High BMI
Low fruit and veg intake
Lack of physical activity
Tobacco use
Alcohol use

3

Which leading behavioural and dietary factors act synergistically to increase cancer risk?

Tobacco and alcohol use

4

When adjusted for age, what does the incidence of cancer compared to that in the 1900s show?

It hasn't changed much, individual risk has increased due to extrinsic factors

5

Why does increasing dietary intake of fruit and veg reduce the risk of cancer?

Decreases GI transit time
Fibre absorbs carcinogens and removes them
Rich in antioxidants

6

What are the three main categories of extrinsic factors that increase cancer risk?

Infections
Radiation
Chemicals

7

What did 2-napthylamine, an industrial carcinogen, show about neoplasia?

Long delay
Depends on dosage
Organ specificity

8

What does the organ specificity of a carcinogen depend on?

Where it comes into contact with

9

Give three examples of industrial carcinogens.

Vinyl chloride
Coal tars
Asbestos

10

What type of cancer is vinyl chloride associated with?

Liver

11

What explains the lag time between carcinogen exposure and development of neoplasia?

Need for high level of promoter exposure over a long period of time in combination with an initiator to form a monoclonal population

12

Describe the Ames test when it shows a mutagen is an initiator.

Rat liver, salmonella which requires histamine and possible mutagen--> media w/minimal histidine --> incubate --> high number of revertants

13

What is an initiator?

A mutagen

14

What do promoters do on neoplasia?

Cause prolonged proliferation

15

What are pro-carcinogens?

Chemicals converted by P450 to become carcinogens

16

What is a complete carcinogen?

A chemical which is both an initiator and a promoter

17

How does cigarette smoke act as a complete carcinogen?

Initiator = 2-napthylamine
Promoter = hot water

18

What classes can initiators be sorted into?

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

19

How do alkylating agents cause DNA damage?

Disrupts covalent bonds on DNA

20

Give two examples of natural carcinogens.

Aflatoxin
Asbestos

21

How can N-nitroso compounds be formed?

In industry
Smoked food
Produced in stomach

22

How far does UV radiation penetrate?

No deeper than the skin

23

How does ionising radiation such as X-Ray and nuclear radiation cause DNA damage?

Strips electrons from atoms

24

What are the three types of direct damage caused by ionising radiation?

Alter bases
Single/double strand breaks

25

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

Radon released from rocks

26

How does radiation cause indirect DNA damage?

Free radical production

27

How can carcinogenic infections cause cancer?

Directly affect genes that control cell growth
Indirectly carcinogenic
Reduced immunity

28

How does HPV cause cervical cancer?

Expresses E6 which inhibits p53
Expresses E7 which inhibits pRB
No apoptosis and no cell-cycle breaks

29

How does EBV behave as an indirect carcinogen?

Chronic liver inflammation --> free radicals

30

How do Hep B and C act as indirect carcinogens?

Cause regeneration

31

How does Helicobacter pylori cause cancer?

Indirectly carcinogenic causing gastric inflammation

32

How do parasitic flukes cause cancer?

Lay eggs in bile ducts and bladder mucosa --> metaplasia and inflammation

33

What viral infection leads to Kaposi's sarcoma?

Human herpes virus 8

34

How does reducing immunity cause cancer?

Allows other potentially carcinogenic infections to occur

35

How many hits are needed for germline mutations to occur?

2

36

How does the pathogenesis of inherited familial cancers differ to that of sporadic cancers?

Familial - 1st hit in germline, only need one somatic hit
Sporadic - 2 somatic hits needed

37

How do the graphs of unilateral (sporadic) and bilateral (inherited) cancer v.s. time differ?

Bilateral - straight line
Unilateral - curve

38

What are oncogenes?

Abnormally activated proto-oncogenes

39

How many alleles must be activated for an oncogene to be turned on?

1

40

How does a RAS mutation cause cell cycle entry?

G-protein activated --> cyclin D --> CDK

41

How does mutant RAS cause a constant cell cycle?

It is always active so allows cells past the cell cycle restriction point

42

What proto-oncogene mutation is common in colorectal cancer and melanoma?

RAS

43

What is the function of tumour suppressor genes?

Inhibit neoplasticism growth

44

How many alleles must be inactivated in tumour suppressor gene mutation?

2

45

What allows unrestrained passage of cells through the restriction point?

Inactivation of both RB alleles

46

Give examples of some proto-oncogenes.

BRAF
BCL2
RAS
HER2
Cyclin D1
PDGF
MYC

47

What is BLC2?

An apoptosis regulator

48

What is BRAF?

Intracellular kinase

49

What is MYC?

Transcription factor

50

What are the three methods of DNA repair which are mutated in carcinoma?

Nucleotide excision
Mismatch repair
Double strand DNA breaks

51

What causes Xeroderma Pigmentosum?

Autosomal recessive mutation of 1 of 7 genes affecting nucleotide excision repair

52

What does Xeroderma Pigmentosum cause?

Early onset skin cancer from UV exposure

53

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

Autosomal dominant

54

What does mismatch repair mutation cause?

Microsatellite instability

55

What are the intrinsic factors that increase cancer risk?

Age
Sex
Heredity

56

How do BRAC1 and BRAC2 cause familial breast carcinoma?

Causes double strand DNA break which causes chromosomal instability

57

What does nucleotide excision mutation cause?

Nucleotide instability

58

What is genetic instability?

Alterations accounting for accelerated mutation rate

59

What is genetic instability counteracted by?

'Caretaker' tumour suppressor genes

60

Do mutations to DNA repair have to be inherited?

No, seen in sporadic cases

61

What normal cellular replication process can be abnormal in malignant cells?

Chromosome segregation

62

How does the adenoma-carcinoma sequence progress?

Normal epithelium --> early adenomal dysplastic crypt --> intermediate adenoma --> late adenoma --> carcinoma --> metastasis

63

What is progression in malignant neoplasm?

Alterations of multiple TS genes and proto-oncogenes which involves genetic instability

64

How many mutations are needed for malignant neoplasm to establish?

65

What are the 6 hallmark cellular behaviours from cancer mutations?

Self-sufficiency in growth signals
Resistance to growth stop signals
Cell immortalisation
Sustained angiogenesis ability
Resistance to apoptosis
Ability to invade and metastasise

66

What is the one enabling feature seen with the 6 hallmarks of cellular behaviours in cancer mutations?

Genetic instability

67

Which cellular behavioural hallmark is only seen in malignant neoplasm?

Ability to invade and metastasise

68

What does HER2 gene amplification in breast cancer cause?

Self-sufficiency in growth signals

69

What does CDKN2A gene deletion in melanoma cause?

Resistance to growth stop signals

70

What do most cancers do to overcome cell senescence?

Activate telomerase genes

71

What does VEGF activation, which occurs in many cancers, allow?

Sustained angiogenesis ability

72

What does BLC2 gene transcription in lymphoma do?

Cause resistance to apoptosis

73

In gastric cancer, what allows for invasion and metastasis?

E-Catherine mutation

74

How does a neoplasm become more genetically heterogenous?

More mutations are acquired as proto-oncogenes and TSG interact to affect hallmarks of cancer

75

Give a brief overview of the progression of cancer.

Somatic cells exposed to environmental carcinogens --> monoclonal population forms --> progression over many years/decades --> hallmarks of cancer

76

What increase in risk does having a sibling with a given cancer cause?

2-3 fold

77

What are cancer family syndromes?

Patients are afflicted by several types of cancer and often develop more than one type

78

How can secondary cancers be caused by therapy for primary cancer?

X-Rays and antineoplastic drugs are powerful carcinogens

79

What can be considered as a phenotype that predisposes to melanoma?

Fair complexion

80

What phenotype predisposes dye-stuff workers to bladder cancer?

Poor acetylator

81

What inborn differences can be considered as a cancer phenotype?

Enzymes that inactivate or detoxify carcinogens

82

What is usually the first sign of cancer in retinoblastoma?

Abnormal reflection in pupil (child does not complain of poor eyesight) - leukokoria = cat's eye reflex

83

How does retinoblastoma usually progress?

Develops from outer layer of retina --> grows backwards into eye

84

When do hereditary and sporadic retinoblastoma usually appear?

Hereditary - children, often bilateral
Sporadic - adults, usually unilateral

85

How do two successive mutations cause retinoblastoma?

1st mutation affects one locus on one chromosome
2nd affects same locus on the other allele

86

What happens to the RB1 genes in a normal, healthy individual?

Occasional cell inactivates one of its two good RB1 genes but won't cause a tumour

87

Why does the occasional cell inactivation of an RB1 copy in people with hereditary retinoblastoma cause a tumour to develop?

They only have one good copy

88

When is the first mutation in hereditary retinoblastoma present?

In the sperm or ovum before fertilisation

89

When is a likely time for the only functioning RB1 gene in a patient with hereditary retinoblastoma to be lost?

Development of the retina when mitoses are occurring

90

Why does retinoblastoma become dominant by pedigree analysis?

It occurs commonly in mutant retinoblastoma carriers

91

What are children with hereditary retinoblastoma at a greater risk of?

Other tumours e.g. Osteosarcoma, risk increased by irradiation which may be used therapeutically

92

How does pRB stop the normal cell cycle?

Encodes a phosphoprotein that binds to DNA which is phosphorylated through the cycle and loses its suppressor function

93

What is the most common genetic change in human cancer?

Mutation in TSG p53

94

What is the pathogenesis of familial polyposis of the colon?

Carriers inherit predisposition to develop polyps of colon in adolescence --> turn into carcinoma at 40 in 80% of patients

95

What is the treatment of familial polyposis?

Early preventative colectomy

96

How are breast and colon cancers thought to occur in adults?

Dominantly inherited syndromes which predispose to these cancers

97

What enzyme is lacking in Xeroderma Pigmentosum?

Endonuclease that repairs UV light DNA damage

98

How can an error during meiosis to form ovum or sperm increase the risk of neoplasia?

Meiotic instability forms root of later mitotic instability

99

How does Down's syndrome affect the risk of developing leukaemia?

Increases by 20 fold

100

What do men with Klinefelter's syndrome have a 2-3 fold increased risk of?

Breast cancer

101

Congenital defects in which system predispose to cancer?

Immune

102

How can karyotyping be used to examine tumour progression?

Increasingly severe karyotypic aberrations are seen with tumour progression

103

What chromosome change is seen in 90% of chronic myelogenous leukaemia cases?

Balanced translocation of Philadelphia chromosome (chromosome 22)

104

What is the usual chromosomal change seen in balanced translocation of the Philadelphia chromosome?

Part of gene on 22 fuses with abI oncogene on chromosome 9

105

What is the result of a balanced Philadelphia translocation?

More powerful than normal tyrosine phosphorylase

106

Where is the Philadelphia chromosome found in chronic myelogenous leukaemia patients?

All myeloid cells - incl. erythrocyte, granulocyte and megakaryocyte

107

What indicates that a clone deriving from a pleuripotent stem cell has overcome the entire bone marrow in CML?

Presence of Philadelphia chromosome in all myeloid cells

108

What is seen with the N-myc gene in neuroblastoma and the neu (Her2) gene in breast cancer?

Gene amplification in association with tumour progression

109

What chromosomal abnormality occurs in many tissues where it may have survival value?

Polyploidy

110

What chromosomal abnormalities become a visible aspect of progression in tumours?

Aneupoidy and polyploidy

111

What precipitates a cascade of increasing chromosomal instability in tumour development?

Destabilising mutation early in tumour development

112

What are chromosomal fragility syndromes?

Rare inborn abnormality of DNA repair

113

Give three examples of chromosomal fragility syndromes.

Fanconi's anaemia
Ataxia telangiectasia
Xeroderma Pigmentosum

114

What are chromosomal fragility syndromes associated with?

An increased risk of tumour development

115

What do many, if not most, cancers develop from?

Precursor lesions

116

Give examples of some known precancerous lesions.

Forms of metaplasia, dysplasia, carcinoma in situ, some benign lesions and sundry lesions

117

How do epithelial and connective tissue metaplasias vary?

Epithelial virtually all precancerous
CT generally safe

118

What does metaplasia imply?

Expression of a different but normal set of genes

119

Give two examples of precancerous metaplasia.

Gastric epithelium in oesophagus - Barrett's epithelium
Abnormal hyperplastic epithelium (leukoplakia) on tongue or exocervix

120

What does dysplasia refer to?

Cellular changes that are too irregular for hyperplasia and not irregular enough for neoplasia

121

What does dysplasia in surface epithelia blend into which is definitely neoplastic?

Carcinoma in situ

122

Describe what is meant by 'carcinoma in situ'.

Covering epithelium replaced by layer of cancer cells
All boundaries respected
Thickness about the same as normal epithelium
Basement membrane intact

123

What changes the diagnosis of in situ carcinoma to invasive?

Epithelial boundary breakdown

124

In carcinoma in situ of the cervix, what does Pap smear show?

Epithelial cells sloughed off failed to mature
Not normal flat, eosinophilia cell with shrivelled pyknotic nucleus
Cells retain structure and basophilia of basal cells

125

What is Bowen's disease?

Carcinoma in situ of epidermis which appears reddened, scaly and crusty

126

Why is carcinoma in situ of the exocervix better visualised after swabbing with iodine?

Normal squamous cells have glycogen and stain brown
Carcinoma cells don't produce glycogen so remain unstained

127

How does the peak age for cervix carcinoma in situ and carcinoma compare?

In situ - 30 y.o.
Carcinoma - 45 y.o.

128

How does the time taken for progression in cervix carcinoma compare to that in bladder, stomach and lung.

Cervix - 15 years
Bladder - 5 years
Stomach and lung -

129

What can happen to both dysplasia and carcinoma in situ of the cervix?

Unpredictably persist, regress or progress to invasive cancer

130

Is it possible to tell what the course of either dysplasia or carcinoma in situ of the cervix will be?

Nope

131

Why can a sarcoma in situ not exist?

Lack the boundary of a basement membrane to serve as a definition of invasiveness

132

Give examples of benign growths which given enough time can progress to carcinoma.

GI polyps
Paipllomas of the larynx
Large congenital naevi
Pigmented moles
V. occasionally: leiomyomas of the uterus and fibroadenomas of breast

133

Why can ongoing chronic inflammation be a precursor to cancer?

Likely to be secondary due to sustained cell proliferation from constant epithelial damage and regeneration

134

How long does chronic inflammation have to persist in liver cirrhosis to cause carcinoma?

Decades

135

Why does decades of chronic inflammation in cirrhosis lead to hepatocellular carcinoma?

Has a strong inflammatory response

136

Which two types of chronic gastritis can prelude gastric carcinoma?

Autoimmune or bacterial

137

Which chronic inflammatory disease carries a heavy risk of colon cancer?

Ulcerative colitis

138

How does asbestos lead to carcinoma?

Causes chronic inflammation
Absorbs carcinogens onto fibre surface

139

Which type of asbestos is more dangerous?

Blue - sharp spikes get stuck in peripheral lungs where they cannot be wafted out by mucociliary escalator

140

What is asbestos?

Naturally occurring silicate fibre of which there is a whispy white type and sharper blue type

141

What is the most common condition associated with asbestos exposure which is benign and doesn't usually cause a problem?

Pleural plaques