Rod Dunbar 2 Flashcards
(21 cards)
What are the causes of melanoma?
Sunburn, with skin type affecting the risk and a slight genetic association
What evidence shows that melanoma is not only due to sunburn?
Some melanomas occur in sun-protected in sites
How does skin type effect the risk of melanoma?
There are lower rates in Polynesians, Africans and African americans and higher rates in red heads (melanocortin-1 receptor gene)
What is the slight genetic association for melanoma?
Some families have higher rates due to the inherited mutations (eg CDKN2a) account for 15% of melanoma
While this link is not as strong as the genetic link in other cancers giving important clues about disease origins
What is the best form of melanoma treatment?
Early detection and surgery is the best option where any suspicious pigmented skin lesion should be checked for changes in colour, size, shape as well as bleeding, ulceration and constant itchiness
Early surgery is quick, painless and free of side effects
What are the therapeutic options for late stage melanoma treatment?
Verurafenib (b-raf inhibitors) is a chemotherapeutic option with other kinase inhibitors possible
Immunotherapeutics such as anti-CTLA4 and anti-PD1 are the most effective treatment
What is the melanocyte?
A cell in the epidermis, formed from neural cells which injects pigment granules into skin cells
Have stem cells residing in stem cells
What is the importance of melanocytes being neutrally derived in cancer?
It means they have altered signalling pathways compared to other skin cells and also accounts for their motility
What is Waardenburg/Tietz syndrome?
There are reduced melanocytes in the hair, Iris (causing asymmetric eye colour), ear (sensorineural deafness)
Controlled by key genes like MITF which usually controls melanocyte and melanoblast survival and differentiation
What is piebladism?
Reduced melanocytes in the hair and skin
Regulated by key genes c-Kit and its ligand SCF
These play a role in melanoblast and melanocyte survival, proliferation and homing to the epidermis
What is alpha-MSH gene pathway?
Alpha-melanocyte stimulating hormone is provided from keratinocytes and melanocytes drives pigmentation through binding to the MC1R receptor (which is ‘adapted’ in redheads)
This activates the transcription factor MITF through a signalling cascade allowing it to drive proliferation and survival
What is the SCF pathway in melanocytes?
Stem cell factor binds to its receptor c-Kit to drive proliferation and survival via the ras pathway with beta-catenin helping to drive MITF transcription
Do babies have moles?
Babies don’t have many or any moles and instead have naevi which develop over childhood and increase through adulthood
This shows that melanocytes proliferate in clumps raising the question of are naevi benign tumours
Are naevi benign tumours?
Yes as most of them contain the same raf mutation seen in melanomas
How do Ras mutations play a role in cancer?
The cKit receptor is the growth receptor in melanocytes which leads to ras signalling and cell proliferation
70% of melanomas carry a b-raf mutation with the T1796A mutation accounting for 90% of these with the mutant having 12.5 times the usual kinase activity and explaining the low rate of ras mutations in melanoma
This also lead to the development of verufenib as a major new melanoma drug
How do mutations in the ras pathway in melanoma show the effectiveness of the hananweinburg framework?
There are mutually exclusive mutations in this pathway with the b-raf mutation being the most common, followed N-Ras or c-Kit showing how it is the pathway that needto be altered to allow tumour growth not one particular molecule
What is the role of the Rb pathway in melanoma?
Rb is a molecule that plays a role in cell cycle checkpoints ensuring that cells are free of mutations before they divide
Melanoma is unusual in the fact that Rb is not commonly mutated instead there is a common mutation in p16INK4A which is part of the INK4 family which inhibits cyclin dependent kinase 4 with loss of this gene causing an increase in cyclinD Cdk4 complex increasing cell cycling
How does the p53 pathway play a role in melanoma?
While p53 is mutated in melanoma this does not occur as commonly as in many other cancers
Instead p14ARF which acts to sustain p53 levels through sequestering MDM2 which marks p53 for degradation
P14ARF is commonly lost in melanomas, this is often because it comes from the same gene as p16INKA4 due to RNA splicing
How does e-cadherin play a role in melanoma?
There is a loss of e-cadherin causing decreased adhesion to keratinocytes and an increase in n-cadherin causing an increase in adhesion in fibroblasts there is also a gain in the number of integrins allowing increased adhesion to the extracellular matrix
This induces an epithelial to mesenchymal transition causing the cell to become invasive
What role does the MITF pathway in melanoma?
This gene is often amplified in melanoma and can be upregulated by beta-catenin
This is a transcription factor which is activated by ERK and its therefore enhanced by Ras pathway activation induces many melanocytes including those such as the bcl family which relate to survival
How is Vemurafenib used to treat melanoma?
B-Raf inhibitor for metastatic pathway melanoma
This received lots of media attention due to spectacular clinical trials
However despite halting tumour growth shortly after treatment the therapeutic benefits last only 6-12 months as the tumour will adapt in some way to circumvent the drug
