Environmental basis of cancer

Question 1

What is a complete carcinogen?

Answer 1

A carcinogen that is capable of causing cancer by itself/ can cause cancer at any stage. eg radiation

Question 2

What is a cancer initiator?

Answer 2

A substance that causes the initial changes or mutation in DNA of cells that can lead to cancer. Otherwise known as a very very dilute dose of a complete carcinogen.

Question 3

What is a cancer promoter?

Answer 3

A substance that targets proteins/enzymes/receptors to amplify the effect of initiator carcinogens.

Question 4

Approx when were complete carcinogens identified and in what setting?

Answer 4

A Dr called Percival Potts identified in 1775 that boys who work in the chimney sweeping developed high rates of squamous cell carcinoma. It was then found that in soot there was a lot of PAH’s (polycyclic aromatic hydrocarbons). PAH’s are a complete carcinogen.

Question 5

What must happen in order for an initiator carcinogen to form cancer?

Answer 5

Initiator and promoter must synergise to produce a tumour. Multiple doses of a promoter carcinogen must be given following the initiator exposure.

Question 6

What happens if there are many months between when the initiator is given and then the promoter doses?

Answer 6

The cancer will still develop - this shows that the initiator effect on cells in irreversible. (this seems to be true as we know that the initiator carcinogens make changes to the DNA)

Question 7

What happens if there are many months between each promoter dose following the initial initiator dose?

Answer 7

The cancer will not develop - this shows that the promoter effect is reversible/temporary. (this seems to be true as we know that the promoters act on the signaling/proteins in the cells and do not actually make permanent changes to the DNA sequence). Promoters are ineffective is dosage is too widely spread.

Question 8

UV radiation is an example of a physical carcinogen, what are the two types of UV radiation?

Answer 8

UVA and UVB

Question 9

What relative wavelengths are UVA and UVB and what effect does this radiation have on cells?

Answer 9

UVB is a complete carcinogen

• it is responsible for sunburn
• it causes changes in the DNA of cells
• it has the shorter wavelength (290-320)

UVA is a weak complete carcinogen and is a good promoter

• it is not responsible for sunburn
• it dosent cause changes in the DNA but instead produces reactive oxygen species
• it has the longer wavelength (320-400)

Question 10

What gene is often mutated in cancers caused by sunlight exposure? What is the mutation in this gene?

Answer 10

p53 (a tumour suppressor gene)

Point mutation/transtition from C to T
Double mutation from CC to TT

Question 11

Describe what happens to cause the CC to TT mutation during DNA replication when UVB light damages a skin cell.

Answer 11

• When UVB light hits a skin cell, it causes a cross link to form between adjacent C bases in the p53 gene. This is otherwise known as “cyclobutane dimers”
• Hopefully there is DNA repair genes that can repair this damage but if not then when this cell goes through DNA replication, the replication can proceed only when the error prone DNA polymerase n adds two A bases opposite the C dimer
• This forms the template strand and so the replicated DNA will then have two T bases where there was intitially meant to be two C bases. Hence the C to T mutation.

Question 12

What is an actinic keratosis?

Answer 12

A rough/dry/scaly patch on the skin that contains sun damaged cells. These cells generally have the C-T or CC-TT mutations in the p53 gene and are pre-cancerous cells.

Question 13

What normally happens to skin cells exposed to too much UVB light?

Answer 13

The UVB light damages the DNA in the cell and this damage leads to increased expression of the p53 gene. Expression of the p53 gene results in apoptosis of the damaged cell which is visible as peeling sunburn.

Question 14

What happens when the UV light damages the p53 gene DNA as opposed to other segments of DNA?

Answer 14

When the p53 gene is damaged it results in a heterozygous p53 gene (one normal functional allele and one mutated non functioning allele). The p53 is still able to carry out its apoptotic role but not as well as it should.

These p53 heterozygotes tend to survive better than the wild type cells (two normal alleles) and so with subsequent rounds of DNA replication. This results in the formation of keratosis (when we get older) which are patches of dry/scaly skin that are probably patches of p53 heterozygotes.

Question 15

What happens when you get big doses of UV light on actinic keratosis/ skin that has previously had damage?

Answer 15

Some of the p53 heterozygote cells may be damage and the one remaining normal allele may be mutated producing a p53 knockout (no functioning p53).

This means there is a loss of control of DNA replication/ the cell cycle/ DNA repair and so it is likely that the actinic keratosis will proliferate and turn into a malignant mass eg a squamous cell carcinoma

Question 16

Will bad sun damage as a kid still effect you as an adult?

Answer 16

Yes - the damage you get in childhood probably means you have initiated cells in your skin (p53 heterozygotes) so every time you expose youself to UV light you can potentially cause outgrowth of the p53 clone.

Question 17

How many known carcinogens are there in tobacco?

Answer 17

60

Question 18

What is the most studied cancer causing agent?

Answer 18

Tobacco

Question 19

What is the most common carcinogen found in tobacco and can you find this carcinogen in anything else apart from tobacco? What is the second common carcinogen in tobacco?

Answer 19

PAH’s (polycyclic aromatic hydrocarbons)

Yes if you burn any kind of plant product (any form of smoking eg weed), you will deliver PAH’s to the body.

NNK (nicotine derivative)

Question 20

What mutation does PAH cause and what mutation does NNK cause?

Answer 20

PAH = a G to T mutation
NNK = a G to A mutation

Question 21

Explain the mechanism of the G to A mutation caused by NNK.

Answer 21

When you light up and smoke a plant material, it forms NNK. NNK is toxic and so your body tried to detoxify it and remove it from the body by making it soluble and by adding an OH group (hydroxylating it).

However when the OH is added it tends to break down and liberate methyldiazohydroxide which then binds to the oxygen of Guanine (base G).

This forms 60MeG which when undergoing DNA replication wrongly base pairs with T to then produce DNA with an A base. Hence the G to A mutation.

Question 22

What mutations are common in people who get lung cancer from smokey indoor fires compared to those who get lung cancer from smoking cigarettes?

Answer 22

Smokey indoor fire =
exposed to lots of PAH’s so G to T mutation

Smoking cigarettes =
exposed to lots of nicotine derivatives so G to A mutations

Question 23

What are two receptors on cancer cells that bind NNK which may induce cell division/proliferation, suppress apoptosis and contribute to addiction etc

Answer 23

BAR = beta-adrenergic receptor

nAChR’s = nicotinic acetylcholine receptors

Question 24

In poor countries, what is often responsible for a mutation in the p53 gene that leads to hepatocellular carcinoma? And what mutation does this cause?

Answer 24

A fungal metabolite (aflatoxin B1) in poorly stored food (eg peanuts, rice, corn).

A mutation on codon 249 which causes a point mutation/substitution of G to T (AGG to AGT). This mutation gives the cell a growth advantage in the prescence of a promoter which leads to outgrowth of the mutant clone.

Question 25

The mutated genes caused by aflotoxin B1 fungus have a growth advantage but only when in the prescence of a promoter. What other virus synergises with aflotoxin B1 to produce hepatocellular carcinoma? How does HBV act as a promoter and what is the role of the protein X it produces?

Answer 25

Chronic Hepatitis B virus.

HBV acts as a promoter by causing cell death (induces necrosis) which results in inflammation and cell undergoing rapid regenerative proliferation in order to repair themselves.

Often this regeneration happens so fast that the cells do not have time to repair the mutation caused by aflotoxin B1 and so there is proliferation of the initiated/mutated cells.

HBV also produces protein X which inhibits DNA repair, binds to and inhibits the action of the p53 gene and also indirectly activates the Ras protein which induces proliferation.

Question 26

What is the most important endogenous carcinogen?

Answer 26

Chronic inflammation - it causes damaged cells from mutation and then cytokines result in altered cell signalling and proliferation.