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Dermatology week 3 > Intro to photocarcinogenesis > Flashcards

Intro to photocarcinogenesis Flashcards

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Dermatology Board Prep flashcards
1
Q

Define what cancer is

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 and lymphatic system

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2
Q

What does the emergence of a cancer cell involve ?

A
  • Cancer cells originate from a single cell
  • Genetic mutations contribute to the emergence of cancer cell
  • There is then a series of mutations which accumulate in successive generations in a process known as colonal evolution
  • Eventually a cell accumulates enough mutations to become cancerous
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3
Q

The emergence of cancer follows linear clonal succession rather than Dynamic clonal diversification - T/F?

A

False

The emergence of cancer follows dynamic clonal diversification rather than linear clonal succession

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4
Q

What are the 6 main hallmarks of cancer ?

A
  1. Sustaining proliferative signalling
  2. Evading growth surppressors
  3. Activating invasion and metastases
  4. Enabling replicative immortality
  5. Inducing angiogenesis
  6. Resisting cell death
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5
Q

Define what a proto-oncogene is and what they do

A

They are normal genes which stimulate cell proliferation, promote survival (anti-apoptotic) and/or overcome cell senescence

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6
Q

What does a proto-oncogene become when it becomes mutated ?

A

An oncogene

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7
Q

What are oncogenes and what do they do ?

A

An over-active form of a gene that positively regulates cell division. Drives tumour formation when activity or copy number is increased e.g. Ras, Raf, growth factor receptors

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8
Q

What are tumour suppressors and what do they do ?

A
  • They control the cell cycle (cell cycle arrest) and signal cell senescence or programmed cell death (apoptosis).
  • Prevents the formation of a tumour when functioning normally (brake) e.g. Rb, TP53
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9
Q

Describe what cell senesence is, what it is triggered/regulated by & what is needed to be done in realtion to this for cancer development ?

A
  • This is an irreversible arrest of cell proliferation, is a major barrier to the development of many cancers.
  • Triggers for senescence include telomer shortening (replicative senescence) and oncogenic stress (overactivation of proliferation)
  • Two important regulators of cell senescence are the p53 pathway and the p16-RB pathway
  • To overcome senescence cancers cells usually must activate telomerase as well as block p53/p16-RB pathways
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10
Q

Appreciate the pic explaining the idea of oncogenic signalling

A
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11
Q

Appreciate the pic explaining the inactivation of a tumour suppressor - specifically p53

A
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12
Q

What are the 2 main conditions mentioned that are linked with a genetic predisposition for developing skin cancer ?

A

Albinism and Xeroderma pigmentosum (XP- genes are involved in the repair of damaged DNA) XP has a 2000 fold risk of developing skin cancer before age 20

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13
Q

What are some of the causes of immune suppression which increases the risk of skin cancer ?

A

Autoimmune conditions:

  • UC and chrons both increase the risk of malignant melanomas

Immunosuppressants:

  • e.g. azathioprine, cyclosporine, adalimumab

Organ transplant recipients

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14
Q

How does UVB damage the skin ?

A

Causes direct DNA damage - 1000x’s more damaging than UVA

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15
Q

How does UVA damage the skin ?

A

Causes indirect oxidative damage - penetrates more deeply than UVB

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16
Q

Bar specifically the mechanisms and skin damage of UVA and UVB what is the other way in which UV radiation also plays a role in the development of skin cancer ?

A

UV induced immunosuppression

17
Q

What is the characteristic type of DNA damage caused by UV radiation ?

A

Pyrimidine dimers:

They are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions. Ultraviolet light induces the formation of covalent linkages by reactions localized on the C=C double bonds.

18
Q

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

A
  • Cyclobutane pyrimidine dimers (CPDs)
  • Pyrimidine–pyrimidone (6–4) photo-products
19
Q

How are UVB induced DNA lesions formed ?

A

Both are formed by covalent bonding between adjacent pyrimidines on the same DNA strand

20
Q

Recall which bases in DNA are classified as purines and which are classified as pyrimidines

A
  • Purines - A&G
  • Pyrimidines - T,C&U
21
Q

How is UVB induced lesions repaired ?

A

By nucleotide excision repair (NER):

  1. Recognition of the damaged DNA
  2. Cleavage of the damaged DNA on either side of the photoproduct
  3. DNA polymerase fills in the gap, using the undamaged strand as a template
  4. DNA ligase seals the ends
22
Q

What is meant by error prone DNA repair ? (hint to do with DNA polymerase)

A
  • In most cases, polymerase will insert the correct bases (A-A)
  • Beacuse polymerase is error prone, it may not correctly “guess” the structure of the lesion and instead insert G-G opposite the thymidine dimer
23
Q

Describe what happens during Indirect DNA damage by UVA

A
  • UVA causes indirect DNA damage via oxidation of DNA bases, especially deoxyguanosine to form 8-oxo-deoxyguanosine:
  • 8-oxo-dG can mispair with deoxyadenosine rather than forming a normal base pair with deoxycytosine.
  • If 8-oxo-dG is not removed, when DNA is replicated, dA rather than dC can be incorporated causing GC → AT point mutations
24
Q

How are 8-oxo-dG lesions (UVA induced lesions) repaired ?

A

Mainly repaired by base excision repair (BER)

  1. Recognition of the chemically altered base causing slight helix distortion
  2. Cleavage of the altered base from the deoxyribose by DNA glycosylase
  3. Base-free deoxyribose cleaved away by endonuclease
  4. Single nucleotide gap filled by DNA polymerase β
  5. DNA ligase seals the ends
25
Q

Appreciate the summary of UVB and UVA induced DNA lesions

A

UVB leads to direct DNA damage:

  • cyclobutane pyrimidine dimers (CPDs)
  • pyrimidine–pyrimidone (6–4) photo-products
  • Repaired by nucleotide excision repair
  • TT → CC UV signature mutation

UVA causes indirect DNA damage:

  • Oxidation of deoxyguanosine forming 8-oxo-deoxyguanosine
  • Repaired by base excision repair
  • C → A point mutation

Mutations in genes involved in DNA repair or maintaining chromosomal integrity will accelerate tumorigenesis

26
Q

More specifically how does UV induced DNA damage cause immunosppression ?

A
  • Depletion of Langerhans cells in the skin and reduced ability to present antigens
  • Generation of UV induced regulatory T (Treg) cells with immune suppressive activity
  • Secretion of anti-inflammatory cytokines e.g. IL-10 by macrophages and keratinocytes
27
Q

Mutations in what are associated with BCC development ?

A

PTCH1

28
Q

What is a targeted BCC drug and how does it work ?

A

Vismodegib - binds to Smoothened to block hedgehog signalling and prevent cell cycle activation and angiogenesis

29
Q

What pathway is PTCH1 involved in ?

A

The hedgehog signalling pathway - Hedgehog signalling activates the transcription factors Gli1/2, leading to induction of cell proliferation genes (cyclins D/E), and angiogenesis activators. Hence Vismodegib used in BCC’s

30
Q

What is the mutation which >50% of melanomas have ?

A

B-RAF mutation

31
Q

What are the two genes that have been linked to familial melanoma and what do they do ?

A

The two genes - CDKN2A & CDK4:

  • CDKN2A encodes two proteins, p16INK4a and p14ARF
  • CDKN2A prevents cells from replicating when they contain damaged DNA by activating the G1/S
  • Inactivating mutations in p16 permits cell division in the presence of unrepaired DNA
  • CDK4 = cyclin dependent kinase 4
  • CDK4 permits cell cycle progression by phosphorylation of retinoblastoma protein (Rb)
  • Activating mutations in CDK4 accelerates the cell cycle
32
Q

What are the 2 drugs which target the mutated form of B-Raf?

A

Vemurafenib and Dabrafenib

33
Q

What drug targets MEK ?

A

Tramatenib

34
Q

Resistance to B-Raf inhibitors is rapid (~6-7 months) so these are now approved for use in combination with Trametinib - T/F?

A

True

35
Q

Appreciate the table of targeted melanoma drugs

A

Dermatology week 3 (14 decks)

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