Causes of cancer

Question 1

What are the 5 ways of identifying human carcinogens?

Answer 1

1) Geographical variation in risk - studies in migrant populations
2) Occupational exposure
3) Accidental exposure
4) Big epidemiological surveys
5) Laboratory experiments

Question 2

What are the categories of carcinogens? 6

Answer 2

1) Chemicals eg. PAHs, nitrosamines
2) Infectious agents eg. HPV, H pylori
3) Radiation eg. UV light, radon
4) Minerals eg. asbestos, heavy metals
5) Physiological eg. oestrogen, androgens
6) Chronic inflammation - free radicals and growth factors

Question 3

Aflatoxin targets what tissue?

Answer 3

Liver

Question 4

Alcohol targets what 4 tissues?

Answer 4

Pharynx, larynx, oesophagus, liver

Question 5

Asbestos targets what tissue?

Answer 5

Lung pleura

Question 6

X-rays target what tissue?

Answer 6

Bone marrow (leukaemia)

Question 7

UV light targets what tissue?

Answer 7

Skin

Question 8

Oestrogen targets what tissue?

Answer 8

Breast

Question 9

Tobacco smoke targets what 6 tissues?

Answer 9

Mouth, lung, oesophagus, pancreas, kidney, bladder etc.

Question 10

HBV targets what tissue?

Answer 10

liver

Question 11

HPV targets which tissue?

Answer 11

Cervix

Question 12

What is meant by the term carcinogen?

Answer 12

Any agent that significantly increases the risk of developing cancer

Question 13

What is the difference between initiator, promotor and complete carcinogens?

Answer 13

Initiators are genotoxic i.e. can chemical modify or damage DNA
Promotors are non genetic and induce proliferation and DNA replication
Complete carcinogens can do both

Question 14

Name a complete carcinogen?

Answer 14

UV light

Question 15

What 2 things does mutation indiction (initiation) require?

Answer 15

Chemical modification of DNA
Replication of modified DNA and mis-incorporation by DNA polymerase - requires 2 rounds of replication for a mutations to be fixed

Question 16

The presence of what in the DNA exacerbates the tendency of polymerase to make mistakes?

Answer 16

Chemical modifications - miscoding or non-coding adducts or lesions

Question 17

In which 2 ways do promotor carcinogens contribute to carcinogenesis?

Answer 17

1) They can stimulate the 2 rounds of DNA replication required for mutation fixation
2) Secondly they can stimulate clonal expansion of mutated cells, which enables the accumulation of further mutations

Question 18

Why is clonal expansion of a cell with 1 mutation so important in carcinogenesis?

Answer 18

To form a malignant cell need 2-8 specific mutations, very hard for a cell to acquire these without significant clonal expansion

Question 19

Give 2 examples of endogenous mutagens?

Answer 19

1) Oxygen radicals

2) Lipid metabolism byproducts

Question 20

Describe the process of initiation, promotion and progression using a mouse model skin tumour?

Answer 20

1) Genotoxic initiating agent damages DNA
2) Promoting agent fixes the damage as a mutation and converts normal calls into mutant initiated cell
3) Promoting agent stimulates clonal expansion of initiated cells to produce papillomas
4) Further rounds of mutations and clonal expansion allows papilloma to progress to carcinoma

Question 21

Give the 7 common genetic abnormalities?

Answer 21

1) Base pair substitution
2) Frameshift
3) Deletion
4) Gene amplification (having up to a hundred copies of a gene it would normally only have 2 copies of)
5) Chromosomal translocation
6) Chromosomal inversion
7) Aneuploidy

Question 22

What is meant by a TSG?

Answer 22

Tumour suppressor gene

Question 23

What is the most common TSG inactivation event?

Answer 23

Abberant methylation of gene promotor

Question 24

What is meant by CpG islands and what role do they have in TSG inactivation?

Answer 24

Approximately 70% of genes have CpG islands associated with their promoter sequence, CpG methylation is only effective in shutting down the expression of a gene if it occurs within the promotor sequence of the gene - this is how TSGs are inactivated

Question 25

Give 4 mutations that occur in oncogenes?

Answer 25

1) Base pair substitutions 2) Amplification 3) Translocation eg. proto-oncogene moved to an area where the genes are more frequently expressed thus ends up expressed more frequently to 4) Inversions

Question 26

What do mutations in oncogenes lead to?

Answer 26

A gain of function

Question 27

What do mutations in TSGs lead to?

Answer 27

Loss of function

Question 28

Give 7 types of mutation which can occur in TSGs?

Answer 28

1) Base pair substitutions 2) Frameshifts 3) Deletions 4) Insertions 5) Chromosomal rearrangements 6) Chromosome loss 7) Promoter methylation

Question 29

What is meant by a direct activating carcinogen? Give 4 examples.

Answer 29

Interact directly with DNA: 1) Oxygen radicals 2) Nitrosamines 3) UV light 4) Ionising radiation

Question 30

What is meant by a procarcinogen?

Answer 30

Carcinogens which require enzymatic (metabolic) activation before they react with DNA, though not yet carcinogenic they are often toxic and its the enzymes that normally function in the detoxification and excretion of toxic chemicals which are normally implicated in their activation

Question 31

How can the process of metabolic activation of procarcinogens present a genetic influence on the formation of a malignant tumour?

Answer 31

Enzymes involved in activation of procarcinogens are normally those involved in excretion and detoxification. People who have enzymes which activate a particular chemical more efficiently are more likely to get cancer as are those which excrete the activated chemical less efficiently

Question 32

Name 2 procarcinogens?

Answer 32

1) Aromatic amines | 2) Polycyclic aromatic hydrocarbons (PAHs)

Question 33

Which enzymes are involved in the conversion of Benzopyrene to BDPE and thus the activation of benzopyrene a procarcinogen?

Answer 33

P450 mixed function oxidases and epoxide hydrolase

Question 34

How does BDPE damage DNA and how is Benzopyrene produced?

Answer 34

Benzopyrene is generated through the combustion of most organic material such as meat, tobacco and fuel BDPE forms a DNA adduct

Question 35

Mutational defects in mismatch repair enzymes gives a predisposition to what disease?

Answer 35

Hereditary non polyposis colorectal cancer, also known as Lynch syndrome

Question 36

Mutational defects in recombinational repair proteins gives a predisposition to what disease?

Answer 36

Ataxia telangiectasia

Question 37

Mutational defects in nucleotide-excision repair proteins gives a pre-disposition to what disease?

Answer 37

Xeroderma pigmentosum

Question 38

Genetic polymorphisms in genes encoding which 3 types of enzyme involved in the process from carinogen exposure to cancer may confer greater or lesser susceptibility to the effects of carcinogenic exposure?

Answer 38

1) Metabolic activation enzymes 2) Detoxification/ Excretion enzymes 3) DNA repair eznymes

Question 39

Give 5 of the bodies defences against cancer?

Answer 39

1) Dietary antioxidants 2) Detoxification mechanisms 3) DNA repair enzymes 4) Apoptotic response to unrepaired genetic damage 5) Immune response to infection and abnormal cells

Question 40

How many carcinogens have been identified in tobacco smoke?

Answer 40

19

Question 41

Give 5 carcinogens which have been found in tobacco smoke?

Answer 41

1) Polycyclic aromatic hydrocarbons eg. benzopyrene, require metabolic activation 2) Acrolein - acrid smell, potent direct-actin mutagen 3) Nitrosamines - formed during curing of leaves 4) Radioactive lead and polonium 5) Heavy metals - cadmium, chromium

Question 42

In combination with promotion by alcohol tobacco smoke leads to what increased risk for head and neck cancer?

Answer 42

100 fold increased risk

Question 43

Alcohol is linked to what 7 cancers?

Answer 43

1) Oral 2) Oesophageal 3) Bowel 4) Liver 5) Pharynx 6) Larynx 7) Breast

Question 44

Alcohol is converted into what substance which can cause DNA damage?

Answer 44

Acetaldehyde

Question 45

Alcohol increases the levels of which 2 hormones?

Answer 45

oestrogen and testosterone

Question 46

How does alcohol affect the cells of the upper GI system?

Answer 46

Increases uptake of carcinogenic chemicals into cells within the upper GI system

Question 47

How can alcohol affect surface epithelium what does this lead to?

Answer 47

Can kill surface epithelium leading to unscheduled proliferation - increases chance of mutation

Question 48

Alcohol reduces levels of what chemical needed for accurate DNA replication?

Answer 48

Reduces levels of folate

Question 49

All of the strongest risk factors for breast cancer are associated with what?

Answer 49

Increased exposure to oestrogen which can both stimulate cell division and induce DNA damage

Question 50

Give 7 breast cancer risk factors?

Answer 50

1) HRT 2) Oral contraception 3) Alcohol consumption 4) Age of 1st pregnancy >30 years 5) Early menarche 6) Later menopause 7) Post-menopausal obesity

Question 51

Why does chronic inflammation play an important role in cancer?

Answer 51

The inflammatory response results in a double hit: 1) DNA damage from release of free radicals by immune cells - initiation 2) Growth factor induced cell division to repair tissue damage - promotion

Question 52

What proportion of cancer deaths are attributable to environmental or behavioural factors ie preventable causes?

Answer 52

>50%

Question 53

What role can diet play in cancer incidence?

Answer 53

In some cases diet leads to exposure to carcinogens eg. red meat, burnt food, heavy metals and in some its the absence of protective factors which can lead to the increased cancer incidence eg. fibre and antioxidants.