Dermatology Photocarcinogenesis

Question 1

what are oncogenes?

Answer 1

an overactive form of a gene that +vely regulates cell division. Oncogenes are proto-oncogenes which have mutated so that they are never turned off.

Question 2

what is the general process of carcinogenesis?

Answer 2

a series of genetic mutations occur in successive generations (process called clonal evolution), eventually - a cell accumulates enough mutations to become cancerous

Question 3

which populations are at risk of skin cancer?

Answer 3

UV radiation exposure (e.g. holidays, childhood sunburn, outdoor occupation, living abroad)
Genetics (fair skin type, oculocutaneous albinism, naevoid basal cell carcinoma syndrome, xeroderma pigmentosum, dystrophic variant of epidermolysis bullosa)
Age
Chemical exposure (coal tar, soot, shale oils, arsenic, petroleum products)
Immune suppression

Question 4

what are the effects of UVA?

Answer 4

photoageing

pigmentation

Question 5

what are the effects of UVB?

Answer 5

photoageing
pigmentation
sunburn

Question 6

what are the effects of UVC?

Answer 6

none - it is blocked by ozone layer

Question 7

what blocks UVA?

Answer 7

sunscreens

Question 8

what blocks UVB?

Answer 8

sunscreens

window glass

Question 9

what blocks UVC?

Answer 9

window glass

ozone layer

Question 10

how does UVA cause skin cancer?

Answer 10

causes INDIRECT OXIDATIVE damage.

UVA penetrates more deeply into the skin than UVB

Question 11

how does UVB cause skin cancer?

Answer 11

causes DIRECT DNA damage.

1000x more damaging than UVA when sun is directly overhead.

Question 12

which populations are at risk of skin cancer?

Answer 12

UV radiation exposure (e.g. holidays, childhood sunburn, outdoor occupation, living abroad)
Genetics (fair skin type, albinism, xeroderma pigmentosum, dystrophic variant of epidermolysis bullosa)
Age 
Chemical exposure (coal tar, soot, shale oils, arsenic, petroleum products)
Immune suppression (autoimmune conditions such as UC or Crohn's disease, immunosuppressants such as azathioprine/ ciclosporin/ adalimumab, organ transplant recipients)

Question 13

what is an example of a tumour suppressor?

Answer 13

p53. Normally, p53 is activated by damaged DNA, and stops cells passing on damaged DNA. BUT when mutated, p53 cannot bind DNA, and so mutations are passed on.

Question 14

sunburn can cause immunosuppression. True/ False?

Answer 14

True

Sunburn decreases skin surface immunity locally - this may play a role in developing skin cancer.

Question 15

Pyrimidine dimer formation is a type of DNA damage. What is it?

Answer 15

Pyrimidine dimers are formed from thymine or cytosine bases in DNA via photochemical reactions. UV light induces the cross-linking. These lesions alter DNA structure. May be repaired, but unrepaired dimers are mutagenic.

Question 16

sunburn can cause immunosuppression. True/ False?

Answer 16

True
Sunburn decreases skin surface immunity locally - this may play a role in developing skin cancer.
There is depletion of Langerhans cells and reduced ability to present antigens. There is generation of UV induced Treg cells with immune suppressive activity. There is secretion of anti-inflammatory cytokines e.g. IL-10 by macrophages and keratinocytes.

Question 17

what are the 2 major types of UVB induced DNA lesions?

Answer 17

-cyclobutane pyrimidine dimers (CPDs)
- pyrimidine-pyrimidine (6-4) photo-products
Both are formed by covalent bonding between adjacent pyrimidines on the same DNA strand
If these products are not repaired - they can eventually become cancers.

Question 18

how are CPDs and 6-4PPs (which are both UVB induced DNA lesions) repaired?

Answer 18

they are removed by nucleotide excision repair (NER):
recognition of damaged DNA, cleavage of damage on either side, DNA polymerase fills in the gap using the undamaged strand as a template, DNA ligase seals the ends.

Question 19

what is an example of a genetic disease in which there is defective repair mechanism?

Answer 19

xeroderma pigmentosum (this is why these people have such a high skin cancer risk)

Question 20

what is the UVA induced DNA lesion called?

Answer 20

8-oxo-deoxyguanosine.
UVA causes indirect DNA damage via oxidation of DNA bases, especially deoxyguanosine to form 8-oxo-deoxyguanosine. This is a problem because:
8-oxo-dG can mispair. If not removed, 8-oxo-dG can cause mispairing of DNA and lead to mutations which can cause cancer

Question 21

how is 8-oxo-deoxyguansine (which is a UVA induced DNA lesion) repaired?

Answer 21

repaired by base excision repair (BER):

• recognition of chemically altered base causing helix distortion
• cleavage
• gap filled by DNA polymerase

Question 22

what are some common mutations in melanomas?

Answer 22

mutations in Ras, Raf, MAPK signalling pathways

>50% melanomas have an activating Braf mutation

Question 23

what are some common mutations in melanomas?

Answer 23

mutations in Ras, Raf, MAPK signalling pathways

>50% melanomas have an activating Braf mutation

Question 24

what are the 2 gene families that have been linked to familial melanomas?

Answer 24

CDKN2A

CDK4