Photocarcinogenesis

Question 1

Define cancer

Answer 1

An accumalation of abnormal cells that muiltiply through cell division and spread to other parts of the body by invasion and/or distant metastases via the blood and lymphatic system.

Question 2

Describe the disease process of cancer.

Answer 2

Cancers originate from a single cell. This cell will have mutated to give it a selective (growth) advantage. A series of mutations accumulate in successive generations in a process called clonal evolution. Eventually a cell accumulates enough mutations to become cancerous.

Question 3

Hallmarks of cancer

Answer 3

Resisting cell death
Sustaining proliferative signalling
Inducing angiogenesis
Evade growth suppressors 
Activate invasion and metastasis
Enable replicative immortality.

Question 4

Upcoming hallmarks of cancer

Answer 4

Deregulating cellular energetics- must be able to regenerate metabolism e.g. upregulate glycolysis
Avoid immune destruction- by hiding or changing the immune response
Genome instability- promote tumorogenesis (the production of tumours). Enhances its growthability e.g. draws cells that can produce growth factors

Question 5

Oncogene

Answer 5

Increase cell division- mutated form of the protooncogene.

Question 6

Tumour supressor

Answer 6

Suppress tumour growth

Question 7

Risk factors for skin cancer

Answer 7

UV radiation, old age, muiltiple benign naevi, genetics, chemical exposure

Question 8

Chronic long term UV radiation indicates which sorts of cancer

Answer 8

Squamous cell carcinoma

Question 9

Intense intermittent and recreational UV exposure

Answer 9

Melanoma

BCC

Question 10

Burning UV exposure

Answer 10

Melanoma

BCC

Question 11

Artificial UV exposure

Answer 11

SCC
BCC
Melanoma

Question 12

How is genetics related to skin cancer risk

Answer 12

Skin complexion inherited- types can be from 1-6
Also genetic pre-dispositions such as:
Albinism- Reduced or complete lack of pigment in the skin
Xeroderma Pigmentosum- XP associated genes associated with DNA repair.

Question 13

How is immune suppression related to increased risk of cancer.

Answer 13

In transplant patients- immunosuppression is needed for the organs to be accepted. Means the immune system isn’t as equipped to deal with cancerous cell growth.
Autoimmune conditions
UC- 23% likelier to get malignant melanomas
Crohns disease- 80% likelier to get malignant melanomas

Question 14

What does UVA do?

Answer 14

Causes indirect oxidative damage to DNA, however penetrates more deeply into the skin than UVB.

Question 15

What does UVB do?

Answer 15

Directly causes DNA damage.

Question 16

What types of UVB induced DNA lesions are there?

Answer 16

Cyclobutane pyrimidine dimers (CPD’s)
Pyrimidine-pyrimidine (6-4) photo producers

Both are formed by covalent bonding between adjacent pyrimidines on DNA strands.

Question 17

How are UVB induced lesions repaired?

Answer 17

CPD’s and 6,-4 PP’s are relatively stable structures and are removed by nucleotide excision repair.

Question 18

Nucleotide Excision repair

Answer 18

Recognition of damaged DNA
Cleavage of the damaged DNA on either side of the photo product
DNA polymerase fills in the gap, using the undamaged DNA strand as a template
DNA ligase seals it up.

Question 19

Error prone DNA repair

Answer 19

Unrepaired UV induced photoproducts interfere with base pairing during DNA replication, leading to mutations.
In most cases, polymerase inserts the correct bases. However if polymerase is error prone it may not correctly give the structure of the lesion and insert the wrong base pair.

Question 20

Indirect UV damage to DNA

Answer 20

UVA causes indirect DNA damage via oxidation of DNA bases especially deoxyguanosine to form 8-oxo deoxyguanosine.
8-oxo dG can mispair with deoxyguanosine rather than forming a normal base pair with deoxycytosine,

Question 21

How are oxidised bases repaired?

Answer 21

Base excision repair

Question 22

Describe base excision repair

Answer 22

Recognition of chemically altered base causing slight helix distortion.
Cleavage of the altered base from the deoxyribose by DNA glycosylase
Base free deoxyribose cleaved away by endonclease
Single nucleotide gap filled by DNA polymerase B
DNA ligase seals the end

Question 23

UV induced immunosupression

Answer 23

Depletion of langerhans cells in the skin and reduced ability to present antigens
Generation of UV induced regulatory T cells with immune supressive activity
Secretion of anti-inflammatory cytokines.

Question 24

Basal cell carcinoma mutations

Answer 24

Mutations in the PTCH1 are associated with BCC

Question 25

Melanoma mutations

Answer 25

Mutations into the Ras/Raf/ MAPK signalling pathways are common in melanoma.

Question 26

Melanoma drugs

Answer 26

Dastinab and Imatinib- target C-Kit- prevent cell growth
Vemurafenib and Dabrafenib- target B-Raf- prevent cell growth
Trametinib- target MEK- prevent cell growth
Ipimumab- CTLA-4 on T cells- T cell activation to enable tumour cell killing.
Pembrolizumab- PD-1 on T cells t666