Melanoma Flashcards
describe melanoma and its risk factors
skin cancer that originates from melanocytes, which are the cells responsible for producing melanin. Melanocytes produce two forms of melanin, eumelanin (black/brown) and pheomelanin (red/yellow)
Risk factors: age, light skin colour, family history, number of moles, weak immune system, uv
what is the relation of UVR and melanomas
about 70% of melanomas are attriubuted to UVR,
the ozone layer absorbs around 77 % of uv radiation-all of uv and 90% of UVB, mostly its uva.
9-15% of uvb reaches melanocytes
50% of uva reaches melanocytes
uvb is more toxic byt uva is more constant
what type of DNA damage does UVB do ?
UVB generates DNA photoproducts including cyclobutane pyrimidine dimers (CPD) and pyrimidine 6-4 pyrimidone photoproducts (6-4PP), which interfere with DNA replication. DNA polymerase incorrectly pairs an adenine to the cytosine within a CPD. In the next round of DNA replication, thymine will pair to the adenine (C to T transition)
what type of DNA damage does UVA do
UVA produces reactive oxygen species (ROS) which can induce single stranded and double stranded DNA damage. ROS can also oxidise guanine to form 8-oxoguanine which binds to adenine (resulting in G to T transversions
what is the realtion between uvr and immunosupression
UVR induces keratinocyte apoptosis, triggering neutrophil and macrophage recruitment – facilitates metastasis and angiogenesis. UVR drives T-cell apoptosis and reduces number of Langerhans cells. UVR also decreases antigen-presenting function of these cells and promotes recruitment of immunosuppressive Treg cells
what are the steps to melanoma progression
- nevi - most common mutation is BRAFV600E which causes hyperactive MAPK signalling and colonal expansion. nervus cells express p16 to induce cell cycle arrest at g1
what is the role of CDKN2A
Mutations or deletions OF GERMALINE in the CDKN2A gene that affect p16^INK4a function result in the loss of this cell cycle checkpoint. This leads to uncontrolled cell division, a key characteristic of cancer. p16 cannot inhibit CDK4-cyclin D mediated phosphorylation of Rb. Rb remains unbounded to E2F transcription factors, allowing them to uncontrollably transcribe genes for S phase
what is the role of CDK4
CDK4 is often overexpressed or amplified
Substitution prevents p16 binding and inhibiting the kinase. CDK4 can freely phosphorylate Rb for S phase progression
what is the role of TERT
is the catalytic component of telomerase to synthesise telomere ends. in melanoma it activates telomerase. This enables melanoma cells to avoid normal cellular aging and continue dividing, contributing to tumor growth and resistance to cell death. TERT activation is often driven by mutations in the ETS transcription factors, particularly GABP. GABP binds to specific DNA regions in the TERT promoter, enhancing its expression. This leads to increased telomerase activity, promoting unlimited cell division and contributing to melanoma progression.
What is the role of shelterin proteins in melanoma
Shelterin remodels telomeres into a ‘t-loop’. Telomeres 3’ end extends beyond the 5’end as a ssDNA. The 3’ overhang then invades into internal telomere sequences to form a ‘d-loop’
what is MIFT
Mutation prevents SUMOylation of MITF – addition of SUMO protein groups. MIF is often overexpressed and contributes to tumor progression by promoting cell survival, migration, and resistance to apoptosis. It activates signaling pathways, such as MAPK and PI3K/Akt, which enhance melanoma cell growth and metastasis. Additionally, MIF can suppress immune responses by inhibiting T-cell activation and promoting an immunosuppressive tumor microenvironment. This helps melanoma evade immune surveillance and enhances its ability to spread. Targeting MIF may offer potential therapeutic strategies to limit melanoma growth and metastasis.
how do u diagnose melanoma
only in epidermis and stages 1a-2a- surgically removed high survival rate
stages 2b-2c with ulceration and w ulceration but bigger than 4mm. stage 3 is treated with surgery where possible and stage 4 is metastasis
what is BRAFV600E inhibitors
BRAFV600E melanomas can be treated with targeted therapeutics vemurafenib or dabrafenib. These drugs inhibit the kinase activity of BRAFV600E. Patients show improved survival but eventually relapse owing to cancer resistance
name 3 ways cells become resistant to brafv600e
altered BRAF signalling: Mutations in NRAS, BRAF or alternative splicing can enhance BRAF dimerization or bypass BRAF, making the tumor resistant to BRAF inhibitors like vemurafenib.
MAPK Pathway Activation: Mutations in MEK or NF1 can reactivate the MAPK pathway independently of BRAF, allowing continued tumor growth even with BRAF inhibition.
Alternative Survival Pathways: Mutations in PI3K and AKT enhance survival signaling, and upregulation RTKs can promote both MAPK and other pathways, supporting melanoma cell survival despite BRAF inhibition.
describe the role of immunotherapy in melanoma
tumour cells are loaded onto MHC molecules by APCs. they present antigens to t-cell recpeotrs leading to t-cell activation. if tumour cells(tc) express PDL1 they can bind to PD1 on T cells and prevent killing.
CTLA4 inhibits T cell function, therefore prevents T cell mediated killing of cancer cells. Anti CTLA4 antibodies neutralises CTLA4, thereby relieving the inhibitory effect on activated T cells
