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Year 2 Clinical > Introduction to Photocarcinogenesis > Flashcards

Introduction to Photocarcinogenesis Flashcards

1
Q

What is cancer?

A

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

Progression of genetic damage in cancer development?

A

Cancers originate from a single cell and gather genetic mutations (give it a growth advantage)

A series of mutations accumulate in successive generation in a process called CLONAL EXPANSION

Eventually, enough mutations result in a cancerous cell

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3
Q

Mutations in relation to morphology?

A

A single mutation can make the difference between skin being morphologically normal or abnormal (hyperplastic, dysplastic or neoplastic)

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4
Q

Why are tumour populations not homogenous?

A

Cancer cells are genetically unstable and so there are MULTIPLE PARALLEL CLONAL EXPANSIONS (branched, not linear, expansion), so tumour populations are HETEROGENOUS

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5
Q

Hallmarks of cancer?

A

Sustaining proliferative signalling

Resisting cell death - cancer cells reactivate telomerase, allowing them to replication beyond their normal lifespan

Inducing angiogenesis - for sustenance

Evading growth suppressors

Achieving invasion and metastases

Enabling replicative immortality

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6
Q

Enabling characteristics of cancer cells?

A

Genome instability and mutation

Tumour promoting inflammation - use growth factors provided by recruited cells as sustenance

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7
Q

Emerging hallmarks of cancer cells?

A

Deregulating cellular energetics

Avoiding immune destruction

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8
Q

Difference between proto-oncogenes and oncogenes?

A

Proto-oncogene - normal, not yet mutated, form of an oncogene

Oncogene - 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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9
Q

What is a tumour suppressor gene?

A

Inactive or non-functional form of a gene that negatively regulates cell division, e.g: p53, Retinoblastoma gene; when functioning normally, prevents the formation of a tumour

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10
Q

How does normal Ras signalling work?

A

When growth factor is present:

  1. Growth factor binds to the receptor and Ras is switched on, when it binds GTP
  2. Raf drives cell division and proliferation

When no growth factor is present:

  1. Growth factor receptor is unoccupied, Ras binds GDP and is off; there is no division or proliferation
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11
Q

How does oncogenic Ras signalling work?

A

Even when there is no growth factor present:

  1. Mutant Ras is always on and binds GTP
  2. There is cell division and proliferation
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12
Q

How does the functional p53 tumour suppressor gene work?

A
  1. DNA damage activates p53, which binds DNA
  2. Cdk and G/S cyclin are inhibited by Cdk inhibitor and the cell cycle progression is halted
  3. Cell halts at the G1 checkpoint
  4. DNA repair is activated
  5. Apoptosis is triggered, if repair is impossible

Net effect: CELLS DO NOT PASS ON DAMAGED DNA

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13
Q

How does the non-functional tumour suppressor gene work?

A
  1. DNA damage occurs but p53 cannot binds DNA
  2. Cdk and G/S cyclin are not inhibited by Cdk inhibitor and thus none of the previous normal effects occur

Net effect: DAMAGED DNA (mutations) PASSED ON

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14
Q

Types of skin cancers?

A

Malignant melanoma - most serious form

Non-melanoma (NMSC) - most skin cancer:
Basal Cell Carcinoma (BCC)
Squamous Cell Carcinoma (SCC)

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15
Q

Skin cancer risk factors?

A

UV radiation

Genetic risk factors

Age

Chemical exposure

Immune suppression

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16
Q

Examples of how the dose and pattern of sunlight exposure are important in determining the type of skin cancer?

A

ADD TABLE

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17
Q

How does skin type affect skin cancer risk?

A

Fitzpatrick type I-VI

Fair-skinned with light-coloured hair and eye - more likely to burn rather than tan

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18
Q

Genetic conditions that increase risk of skin cancer?

A

Albinism - no melanin produced so there is no UV protection

Xeroderma pigmentosum

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19
Q

Describe xeroderma pigmentosum

A

XP-assoc. genes are involved in repair of DNA damage; 2000-fold increase in skin cancer risk before the age of 20

20
Q

Examples of chemicals that increase the risk of skin cancer?

A

Coal tar pitch

Soot

Creosote (wood preservative)

Petroleum products, e.g: mineral oil or motor oil

Shale oils

Arsenic

21
Q

Examples of autoimmune conditions that increase of malignant melanoma?

A

Ulcerative colitis

Crohn’s disease - increases risk more than UC

22
Q

Examples of immunosuppressants?

A

Azathioprine, cyclosporine, adalimumab

23
Q

How does organ transplant increase the risk of skin cancer?

A

Non-melanoma (~30x) skin cancer risk is massively increased, esp. SCC

Malignant melanoma risk is more than doubled

24
Q

Types of UV radiation?

A

UVA and UVB - involved with sunburn, ageing and skin cancer
UVA causes INDIRECT oxidative damage and penetrates the skin more deeply
UVB causes DIRECT DNA damage

UVC - shortest wavelength

25
Q

Types of DNA damage?

A

Altered or missing base

Incorrect base

PYRIMIDINE DIMER (UV SIGNATURE)

Insertion/deletion

Strand break

Cross-linking

26
Q

2 major types of UVB induced DNA lesions?

A

Cyclobutane pyrimidine dimers (CPDs)

Pyrimidine-pyrimidone (6-4) photo-products

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

27
Q

How can UVB induced DNA lesions be repaired?

A

CPDs and 6-4 PPs are relatively stable and are removed by NUCLEOTIDE EXCISION REPAIR (NER)

28
Q

Steps of NER?

A
  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
29
Q

How does error prone DNA repair cause mutations?

A

Unrepaired UB-induced photoproducts interfere with base pairing during DNA replication, leading to mutations

In most cases, polymerase inserts the correct bases (A-A); however, because polymerase is error prone, it may not correctly “guess” the lesion structure and may insert G-G opposite the thymidine dimer

30
Q

Describe indirect DNA damage by UVA

A

Causes indirect DNA damage via oxidation of DNA bases, esp. deoxyguanosine to form 8-oxo-deoxyguanosine

31
Q

How does 8-oxo-deoxyguanosine cause mutations?

A

Can MISPAIR with deoxyadenosine, rather than forming a normal base pair with deoxycytosine

If 8-oxo-deoxyguanosine is not removed, when the DNA is replicated,deoxyaadenosine is incorporated, causing GC to AT point mutations

32
Q

Method by which 8-oxo-deoxyguanosine lesions be repaired?

A

Oxidised bases are mainly repaired by BASE EXCISION REPAIR (BER)

33
Q

Steps of BER?

A
  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
34
Q

Summary of UVB induced DNA damage?

A

UVB leads to DIRECT DNA damage:

Cyclobutane pyrimidine dimers (CPDs) OR pyrimidine–pyrimidone (6–4) photo-products

Repaired by nucleotide excision repair (NER)

TT → CC UV signature mutation

35
Q

Summary of UVA induced DNA damage?

A

UVA causes indirect DNA damage:

Oxidation of deoxyguanosine forming 8-oxo-deoxyguanosine

Repaired by base excision repair (BER)

C → A point mutation

36
Q

How does UV induced DNA damage cause immunosuppression?

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

37
Q

Important mutations in BCC development?

A

In PTCH1, which is a key component of the Hedgehog signalling pathway

This should normally activate certain transcription factors, leading to induction of cell proliferation gene and angiogenesis activators

38
Q

Which drug used in BCC treatment exploits Hedgehog signalling?

A

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

39
Q

Important mutations in malignant melanoma development?

A

Mutations in Ras/Raf/MAPK signalling pathways are common in melanomas:
Over half of melanomas have an activating B-Raf mutation

40
Q

Which drugs target mutated form of B-raf?

A

Vemurafenib and Dabrafenib

41
Q

Which drugs target MEK?

A

Tramatenib

42
Q

Which two genes have been linked to familial melanoma?

A

CDKN2A - encodes two proteins (p16 and p14) and prevents cells from replicating when they contain damaged DNA, by activating G1/S

CDK4 (cyclin-dependent kinase 4) - permits cell cycle progression by phosphorylation of Retinoblastoma protein

43
Q

What do mutations do in familial melanoma?

A

Inactivating mutations in p16 permit cell division in the presence of unrepaired DNA

Activating mutations in CDK4 accelerated the cell cycle

44
Q

Name of drugs, their targets and functions?

A

Table 2

45
Q

How are B-raf inhibitors used and why?

A

Used in combo with Trametinib, as resistance to them is rapid (6-7 months)

Year 2 Clinical (119 decks)

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