Week 8 Flashcards
In general, why do melanomas arise?
Due to transformation of the melanocytes.
What are melanocytes and where are they found?
Melanin-producing cells found in the skin, eyes, mucous epithelia and meninges.
What controls the development of the melanocytes ?
The RTK c-KIT and the transcription factor MITF
What types of pigment do the melanocytes produce?
What colour are they?
Eumelanin (black/brown)
Pheomelanin (Red)
Why may prediction and diagnosis of melanomas be tricky?
There are links to benign moles and sun exposure, but no reliable histological precursor.
What % of global cancers are accounted for by melanomas?
1.7%
How have mortality rates due to melanomas varied in the past years?
Mortality rates have fallen by 30% in the last decade.
How has incidence of melanoma changed in the past 30 years?
Increased by 140%
What % of skin cancers are melanomas?
4%
What % of skin cancer deaths are caused by melanomas?
80%
Outline some risk factors for melanoma.
Sun exposure Indoor tanning Immunosuppression Moles Family history
How do the genotoxicity levels and exposure levels of UVA and UVB vary in terms of melanoma?
UVB is more genotoxic per photon than UVA. However, exposure to UVA is 30% higher.
How do UVB levels change throughout the day?
Fluctuate throughout the day
What type of cancer is caused by UVB?
Basal/ squamous cell carcinoma
Describe exposure to UVA
High and constant
What type of cancer does UVA cause?
Melanoma
What components of indoor tanning cause melanomas?
UVA and UVB. Older sunbeds didn’t filter UVA.
How does UVR affect the immune system? And how does this lead to tumour formation/ infiltration?
- Apoptosis of keratinocytes triggers an innate immune response. This drives IFNy release from macrophages. This causes expression of immune evasion genes and enables tumour infiltration.
- There are changes in the population of adaptive immune cells in the skin meaning that there is a reduction in cytotoxic T-cells but an increase in Treg cells which suppress inflammation.
What are the main genes found in families with melanoma?
CDK2NA and CDK4
Does UBV cause direct or indirect damage to the skin?
Direct
How does UBV damage the skin?
It directly damages the skin by producing cyclobutene pyramid dimers and pyrimidine-pyrimidine photoproducts.
These block transcription and translation.
Does UVA cause direct or indirect DNA damage?
Indirect
How does UVA cause skin damage?
UVA causes indirect DNA damage via generation of reactive oxygen species. This lead to SSB/DSBs and 8oxoG.
What can reduce UVA induced damage to skin cells?
Antioxidants
What are nevi?
Benign moles recognised as direct precursors to melanomas.
For people with over 100 moles, what is the level of their increased risk of developing melanoma compared with people who have more than 15 moles?
7 fold increase
What are the advantages of using the ABCDE approach to grade melanoma?
Useful
Saved many lives
What are the disadvantages of using the ABCDE approach to grade melanoma?
Around 60% clinical accuracy
Name some methods for staging primary melanomas.
ABCDE
Clarks
Breslow
TNM
What are the 2 stages of melanoma progression and what happens in each?
Stage 1 = Radial growth phase
Spreading within the epidermis
Stage 2 = Vertical growth phase
Invasion into the deeper dermis
Associated with metastasis
What is the most common type of molecular mutation found in UVR induced melanomas?
C to T deamination
What are the most common gene mutations found in melanomas?
BRAF(V600E)
NRAS
What does the BRAF mutation do that eventually leads to melanoma?
Hyperactivation of the MAPK pathway
What molecular modifications are often found when a person has melanoma?
- Hyperactivation of the MAPK pathway
- Amplification of AKT
- Epigenetic
silencing of PTEN - Amplified MIFT transcription factor causing it to become an oncogene
What does the CDKN2 locus encode for?
2 tumour suppressor proteins:
- P14(ARF) which regulates the P53 checkpoints
- P16(INK4a) which regulates the Rb checkpoints
How does lactate dehydrogenase act as a biomarker for melanoma?
Elevated levels in the blood correlate with poor survival in stage IV melanoma.
Lower levels = response to immunotherapy.
What is the most clinically useful biomarker for melanoma?
Lactate dehydrogenase
What is the most common type of treatment for melanoma?
Targeted therapies.
Specifically BRAF inhibitors - have great efficacy.
What are the issues with targeted therapies used to treat melanomas?
There are issues with intrinsic and acquired resistance.
Paradoxal hyper activation of alternative MAPK pathways is also an issue.
How can resistance of melanomas to therapies be predicted?
Can be predicted by assessing if tumours possess mutations in genes modulating apoptosis, proliferation etc.
E.g. loss of PTEN, activation of cyclin D1
What mutations allow melanomas to be resistant to targeted therapies?
Usually via MEK1-activation mutations or RTK driver P13K activation.
How is immunosuppression linked to melanoma?
Melanoma is more prevalent in immunosuppressed patients
What are CAR-T cells and why are they unsuccessful in solid tumours?
Chimeric antigen receptor T cells.
- Migration to the tumour site via vasculature
- Immunosuppressive TME
- Unsure of what CAR to use
What was the first non-chemotherapeutic agent approved to treat melanoma and what were the issues with it?
High dose interleukin 2
- Limited efficacy
- High toxicity
How do immune checkpoint inhibitors work against melanomas and why are they successful?
T cell activation required T-cell receptor recognition of an antigen of the surface of an antigen presenting cell and a costimulatory interaction between the T cell and APC.
The 2nd costimulatory step can be mediated by either stimulatory or inhibitors ligand pairs known as immune checkpoints.
Outline how CTLA4 works as an immune checkpoint inhibitor against melanoma.
TLA4 is a negative regulator of T cell activation which blocks antibodies when bound to Fc receptor on antigen presenting cells.
This promotes antibody-dependant cellular cytotoxicity.
A-CTLA4 can bind to CTLA4 on the surface of the T regulatory cells and prevent them from counter-regulating the CD28-mediated co-stimulatory pathways that are playing a role in T cell activation.
A-CTLA4 can also promote T cell responses by blocking CTLA4 on the surface of conventional T cells as they undergo activation.
What is the purpose of melanin in the body?
Skin pigmentation
What are some possible results caused by mutations in. the MC1R melanin receptor?
Altered signalling and melanin production.
Some mutations within this receptor mean that no eumelanin is produced. This is often the case in individuals with red hair.
What are the 3 types of UV radiation?
UVA
UVB
UVC
Can UVC penetrate the epidermis?
No, it is blocked by the ozone layer.
Can UVB penetrate the epidermis? If so, where up to ?
Yes, up to the desmosomes
Can UVA penetrate the epidermis and if so, where up to?
UVA can penetrate the whole epidermis, up to the basal lamina.
What is the main difference between the way UVA and UVB cause melanoma.
UVB causes direct DNA damage.
UVA causes indirect DNA damage.
What does each of the categories in the ABDE screening system mean?
A = Symmetry B = Border C = Colour D = Diameter E = Evolving
Which progression stage of melanoma indicates metastasis?
Vertical growth phase - invasion deeper into the dermis which is associated with metastasis.
Outline the effect of a mutation within the P14ARF tumour suppressor protein at the CDKN2A locus.
P14ARF which regulates the P53 checkpoints.
Regulates HDM2 which is a negative regulator of p53
P53 locked into inactive state
Cannot respond properly to DNA damage
DNA damage and genomic instability acrues
This allows melanocyte transformation to develop
What affects the likelihood of an individual to develop resistance to a BRAF inhibitor ?
If PTEN is wild type, it is unlikely that you will develop resistance to the BRAF inhibitor. If it is wiltype, and is therefore mutated, the individual is likely to have resistance to BRAF inhibitors.
How does the antibody drug against PD1 work? (Outline)
Antibody drug to prevent PD1 mediated de-acativation of activated T cells. Also, upregulated the T cell response against the tumour, killing the tumour.
