Photocarcinogenesis

Question 1

What is carcinogenesis?

Answer 1

The process whereby a normal cell becomes malignant

Question 2

What is cancer?

Answer 2

An accumulation of abnormal cells that multiply through uncontrolled cell division and spread to other parts of the body via direct invasion or metastases

Question 3

Which two gene changes are required for cancer to form?

Answer 3

Gain of function of oncogenes (proto-oncogenes) and loss of function of tumour suppressor genes

Question 4

How do proto-oncogenes form? Give some examples of oncogenes

Answer 4

Mutation or copy gain. Cyclins, RAS, MYC

Question 5

How do tumour suppressor genes mutate? Give some examples of tumour suppressor genes

Answer 5

Mutation or loss of heterozygosity. CDKI, p53, retinoblastoma (Rb)

Question 6

Describe the process of cancer formation

Answer 6

Single normal cell > genetic mutation > accumulation of genetic mutations (clonal evolution) > cancerous growth

Question 7

What is the difference between monoclonal and polyclonal tumours?

Answer 7

Monoclonal - tumour consists of one type of mutated cell Polyclonal - tumour consists of many types of mutated cell (due to multiple, parallel clonal expansions)

Question 8

What are the hallmarks of cancer?

Answer 8

Sustained proliferation, evasion of growth suppressors, activating invasion & metastases, replicative immortality, inducing angiogenesis, resisting cell death

Question 9

Mutations cause cancer, which factors increase mutation rate?

Answer 9

Natural accumulation of DNA damage with age, carcinogens (UV, smoking), inherited defects

Question 10

In terms of the earths UV light, which type is most destructive?

Answer 10

UVB (causes burning)

Question 11

Which types of UV light does sunscreen protect against?

Answer 11

UVB & UVA

Question 12

Which types of UV light are responsible for skin cancer and ageing?

Answer 12

UVB & UVA

Question 13

How do UVB and UVA cause DNA damage, respectively?

Answer 13

UVA - indirect DNA damage, more prevalent (penetrates more deeply into the skin) UVB - direct DNA damage when sun is directly overhead,, more damaging

Question 14

What is the typical type of mutation caused by UV light? How is this corrected?

Answer 14

Pyrimidine dimer. Nucleotide excision repair

Question 15

What are the different types of DNA mutation?

Answer 15

Pictured

Question 16

How do UV induced mutations occur?

Answer 16

UV causes the formation of photoproducts > accumulation of photoproducts causes mutation, genetic instability & cancer

Question 17

What are the types of DNA repair?

Answer 17

Nucleotide excision repair, base excision repair, double strand break repair & mismatch repair

Question 18

Mutations in genes involved in DNA repair causes what? Mutations in genes involved in cell devision causes what?

Answer 18

A mutator phenotype (cells acquired further mutations more rapidly). Chromosome instability (accumulation of chromosomal abnormalities)

Question 19

How do UVB and UVA cause DNA damage respectively?

Answer 19

UVB - generation of photoproducts (C-T, CC-TT) UVA - induces guanine oxidation products in DNA (oxidative damage)

Question 20

What is UV induced immunosuppression?

Answer 20

Dendritic cells lose ability to present antigen > T cells switch from helper to suppressor (regulatory T cells) > keratinocytes & dendritic cells secrete immunosuppressive cytokines

Question 21

Is UV radiation a mutagenic or immunosuppressive carcinogen? How do these effects occur?

Answer 21

Mutagenic & immunosuppressive. -DNA damage (photoproducts) > activation of signal transduction pathways > inflammation/oxidative stress (AK) > acquires hallmarks of cancer

Question 22

What are the risk factors for skin cancer?

Answer 22

Sunlight (latitude, childhood sunburn, intense & intermittent exposure), genetics, chemicals, age, immunosuppression, HPV, skin type, phototoxic/sensitising drugs

Question 23

Tanning is a reaction to sun damage. T/F

Answer 23

True

Question 24

What is the difference between type 1 skin and other skin types?

Answer 24

Possess pheomelanin instead of eumelanin which absorbs light less effectively

Question 25

What are the chronic skin changes due to photodamage?

Answer 25

UVB - sunburn & solar lentigo UVA - solar ageing

Question 26

Freckles mean you cannot tan and must protect your skin from the sun. T/F

Answer 26

True

Question 27

Which mutation causes Gorlin's syndrome?

Answer 27

Germline mutation in PTCH gene (causing hedgehog signalling)

Question 28

BCC tend to be homogenous tumours. T/F

Answer 28

True

Question 29

Hedgehog inhibitors and BRAF inhibitors are useful for which types of cancer?

Answer 29

HI - BCC BRAFI - melanoma

Question 30

The mutation of which gene is common in NMSC?

Answer 30

p53

Question 31

As cancers become more invasive they acquire more and more mutations. T/F

Answer 31

True

Question 32

Give examples of some phototoxic drugs/classes

Answer 32

Voriconazole (antifungal), thiazide diuretics, NSAIDs, anti-TNF, azathioprine

Question 33

Immunosuppressed individuals have a particularly high risk of developing which type of skin cancer?

Answer 33

SSC

Question 34

Which factors contribute to the development of transplant associated SSC?

Answer 34

Drugs, UV radiation, viruses and genetics

Question 35

How does azathioprine increase skin cancer risk?

Answer 35

When metabolised produces 6-TG \> 6-TG is incorporated into the DNA of replicating cells \> 6-TG acts as a UVA chromophore \> induces DNA lesions

Question 36

Cutaneous HPV infection contributes to the development of SSC in which ways?

Answer 36

inhibition of apoptosis, delay of DNA repair, promotion of keratinocyte invasion

Question 37

How can skin cancer be prevented?

Answer 37

Surveillance & monitoring of transplant/immunosuppressed patients, treatment of premalignancy, behavioural, sunscreen, minimisation of immunosuppression (mTORi), retinoid use

Question 38

How can premalignancy be treated?

Answer 38

Cryotherapy, Surgery, Topicals, Photodynamic therapy