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Dermatology > Skin Photocarcinogenesis > Flashcards

Skin Photocarcinogenesis Flashcards

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Dermatology Board Prep flashcards
1
Q

What is the definition of cancer?

A

An accumulation of abnormal cells that multiply through uncontrolled cell division and spread to other parts of the body by invasion and/or distant metastasis via the blood or lymphatic system

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2
Q

What do cancers originate from?

A

A single cell

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3
Q

What contributes to the emergence of a cancer cell, and what does it involve?

A

Genetic mutations (e.g changes to the normal base sequence of DNA); involves multi-step gene damage

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4
Q

What is clonal evolution?

A

The process of a cancer cell accumulating a series of mutations in successive generations (each generation is a clonal expansion)

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5
Q

What is the end result of clonal evolution?

A

The cell has enough mutations to be cancerous

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6
Q

What does dynamic clonal diversification result in?

A

Multiple parallel clonal expansions

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7
Q

What is field cancerisation?

A

Large areas of cells at tissue surface/within an organ are affected by a carcinogenic alteration

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8
Q

What are the original hallmarks of cancer?

A 
Resisting cell death
Sustaining proliferative signalling
Evading growth suppressors
Activating invasion and metastases
Enabling replicative immortality
Inducing angiogenesis
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9
Q

What are the additional capabilities that facilitate cancer?

A

Deregulating cellular energetics
Genome instability and mutation
Tumour-protecting inflammation
Avoiding immune destruction

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10
Q

What is an oncogene?

A

Over-active form of a gene that positively regulates cell division which drives tumour formation when activity/copy number is increased (e.g Ras, Raf)

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11
Q

What is a proto-oncogene?

A

Normal, not yet activated form of an oncogene

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12
Q

What is a tumour suppressor?

A

Inactive/non-functioning form of a gene that negatively regulates cell division and prevents the formation of a tumour when functioning normally (e.g Rb, Tp53)

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13
Q

How does normal Ras function, and how does this differ in oncogenic Ras?

A

Normal Ras will cause cell division once it has been activated by GTP after growth factors have been bound; oncogenic Ras is always activated (even in the absence of growth factors) which causes uncontrolled cell division

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14
Q

How does normal p53 function?

A

Activated when there is DNA damage and halts the cell cycle at G1 checkpoint before activating DNA repair and triggering apoptosis, meaning cells don’t pass on damaged DNA

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15
Q

What happens when p53 is non-functioning?

A

It doesn’t halt cell cycle progression so the DNA remains unchanged and mutations are passed on

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16
Q

What can cause p53 mutations?

A

Induced by the sun - mutant p53 in 14% of all sun-exposed epidermal cells

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17
Q

What are some skin cancer risk factors?

A

UV radiation, genetics, age, chemical exposure, immune suppression

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18
Q

What can indicate sun sensitivity?

A

Pale skin, poor tanning, easy burning

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19
Q

What factors make up sun exposure?

A

Dose and pattern, latitude, sunburn in childhood, intense intermittent expose vs chronic life long UV exposure

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20
Q

What dictates skin type?

A

The amount and type of melanin in the skin

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21
Q

What are the different skin types?

A 
Type 1 = always burns, never tans
Type 2 = usually burns, can tan
Type 3 = can burn, usually tans
Type 4 = always tans, never burns 
Type 5 = brown skin
Type 6 = black skin
22
Q

What kind of sun-exposure is squamous cell carcinoma associated with?

A

Life-time cumulative UV-exposure (outdoor workers), >90% occur on head/neck/hands/forearms

23
Q

What kind of sun-exposure is associated with melanomas and basal cell carcinomas?

A

Intermittent burning episodes of exposure, sunbed use

24
Q

When does most sun damage occur?

A

Up to 80% of sun damage occurs during the first 18 years of life, childhood sunburn increases melanoma risk 4x

25
Q

What chemicals increase the risk of skin cancers?

A

Coal tar, soot, creosote, petroleum products, shale oils, arsenic

26
Q

What are some autoimmune conditions that increase risk of skin cancer?

A

Ulcerative colitis (23% increased risk of melanoma), Crohn’s (80% increased risk of melanoma)

27
Q

What are some immunosuppressants that increase the risk of skin cancer?

A

Azathioprine, cyclosporine, adalminub

28
Q

What are some features of UVB radiation?

A

Wavelengths between 290-320nm, causes direct skin damage, 1000x more damaging than UVA when sun overhead

29
Q

What are some features of UVA radiation?

A

Wavelengths between 320-400nm, causes indirect oxidative damage, penetrates deeper than UVB

30
Q

What are the two main types of UVB induced lesions?

A

Cyclobutane-pyrimidine dimers (CPD-3x more common), pyrimidine-pyrimidone (6-4) photo products (6-4PP)

31
Q

How are CPDs and 6-4PPs formed when induced by UVB?

A

Covalent bonding between adjacent pyrimidines on the same DNA strand

32
Q

What are the signature UVB mutations?

A

C-T or CC-TT

33
Q

How are CPDs and 6-4PPs removed?

A

Relatively stable so removed by nucleotide excision repair (NER):
Recognition and cleavage of damaged DNA on either side of the photoproduct
DNA polymerase fills the gap, using the undamaged strand as a template
DNA ligase seals the ends

34
Q

How can errors arise during DNA repair?

A

Polymerase is error prone so may not “guess” the structure of the lesion and insert the wrong thing

35
Q

How does UVA cause damage to the DNA?

A

Causes indirect damage via oxidation of DNA bases, especially deoxyguanosine to form 8-oxodeoxyguanosine

36
Q

How does 8-oxodeoxyguanosine act abnormally?

A

It can mispair with deoxyadenosine rather than forming normal base pair with deoxycytosine

37
Q

What mutations can occur if 8-oxodeoxyguanosine isn’t removed?

A

GC-AT point mutations

38
Q

How are 8-oxodeoxyguanosine lesions repaired?

A

By base excision repair:
Recognition of altered base causing helix distortion
Cleavage of altered base from deoxyribose by DNA glycosylase
Base free deoxyribose cleaved away by endonuclease
Single nucleotide gap filled by DNA polymerase beta
DNA ligase seals the ends

39
Q

How can UV damage induce immunosuppression?

A

Depletion of Langerhans cells in the skin and reduced ability to recognise antigens
Generation of UV induced regulatory T cells with immune suppressive activity
Secretion of anti-inflammatory mediators

40
Q

Mutations in what gene are associated with basal cell carcinomas?

A

PTCH1 (human homologue of the Drosophilia gene patched - key component of the hedgehog signalling pathway)

41
Q

How does hedgehog signalling work?

A

Activates the transcription factors Gli 1/2 leading to induction of cell proliferation genes and angiogenesis activation

42
Q

How does vismodegib work?

A

Binds to Smoothened to block hedgehog signalling and prevent cell cycle activation and angiogenesis

43
Q

What are the familial melanoma genes?

A

CDKN2A, CDK4

44
Q

What does unmutated CDKN2A do?

A

Encodes p16INK4 and p14ARF, prevents cells from replicating when they contain damaged DNA (mutations in p16 allows cell division in the presence of damaged DNA)

45
Q

How does unmutated CDK4 function?

A

Permits cell cycle progression by phosphorylation of Rb (activating mutations accelerate the cell cycle)

46
Q

What is a side effect of vemurafenib?

A

Patients become immune after a few months (does improve survival though)

47
Q

What do vemurafenib and dabrafenib target?

A

B-Raf (50% of melanomas have activating B-Raf mutation)

48
Q

What does trametunib target?

A

MEK

49
Q

Where do familial melanoma mutations commonly occur?

A

In the Ras, Rf and MAPK signalling pathways

50
Q

What are the benefits of iplimumab and ant-PDL/PDL1 inhibitors?

A

They show durable responses in patients, especially in combination

51
Q

What are some phototoxic drugs?

A

Voriconazole (antifungal), thiazide diuretics, NSAIDs, anti-TNF, azathioprine (sensitises skin to UVA)

Dermatology (31 decks)

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