Photocarcinogenesis Flashcards
how is cancer defined?
accumulated of abnormal cells that multiply through uncontrolled cell division and spread to other parts of the bpdy via blood and lymphatics
how does cancer arise?
multi-step gene damage via clonal evolution
describe the process of clonal evolution
mutation in generation 1 passes to generation 2 cells
1 gen 2 cells might develop a second mutation and pass iton etc until enough mutation have acquired to form a cancerous cell
what is field cancerization?
field of mutated cells
multiple different tumours can arise
what is dynamic clonal diversification?
a single mutation acts as a driver mutation that causes the issues - e.g increased mutation rate
what are the 6 hallmarks of cancer?
evade growth suppressors activating invasion and metastases enabling replicative immortality inducing angiogenesis resisting cell death sustaining proliferative signalling
name 4 emerging and enabling characteristics of cancer
avoiding immune destruction
tumour-promoting inflammation
genome instability and mutation
deregulating cellular energetics
what is an oncogene?
over active form of gene causes increased cell proliferation driving tumour formation
E.g - RAS
what is a proto-oncogene?
normal version of an oncogene that isn’t overactive and causing cancer
what is a tumour suppressor?
inactive or non-functional form of gene causes unregulated cell division
normally functioning gene prevents tumour formation
P53
Rb
how does RAS work?
attached to cell membrane, switched on when growth factor encountered causing cell division and proliferation
oncogene version always switched on even without stimulation
how does P53 work?
switched on if theres DNA damage
binds to DNA causing cell cycle arrest, activation of DNA repair mechanisms or triggers apoptosis
is childhood sunburn more dangerous than adult sunburn?
yes
increases skin cancer risk 4X
why is skin type 1 more at risk
they produce wrong type of melanin
pheomelanin doesn’t protect as much as eumelanin
pheomelanin produces yellowish pigment and freckles
where is SCC usually found?
head, neck, hands, forearms
ageing population as SCCs arise from life-long cumulative UV exposure
what type of exposure is associated with melanoma and BCC?
intermittent burning episodes
sunbeds
when does most sun damage occur?
80% before 18 years old
exposure to what chemicals can increase skin cancer risk?
coal tar soot arsenic shale oils petrol creosote
which causes acute sun damage (tan, burn)?
UVA
which UV is filtered by windows?
UVB
which UV is more damaging?
UVB
as can be directly damage DNA
only really present in summer
how does UVA damage?
causes indirect damage via oxidative damage
causes ageing etc
always present
what is the most common type of damage caused to DNA by sunlight?
pyrimidine dimer
covalent bonding between adjacent pyrimidines on the same DNA strand
what are the 2 types of pyrimidine dimer?
cyclobutene pyrimidine dimers (CPDs - more common)
6,4 photo products (more damaging)
how are CPDs and 6-4PPs removed?
nucleotide excision repair (NER) removes the dimer and polymerase replaces it with the correct bases (but is error prone)
what happens when UV induced photoproducts (CPDs and 6-4PPs) aren’t removed?
interfere with base pairing during DNA replication causing mutations (CC to TT)
how does UVA cause indirect damage?
oxidation of DNA bases forming 8-oxo-deoxyguanosine which can form a base pair with the wrong thing causing a point mutation (C to A)
how are 8-oxo-dG lesions repaired?
oxidised bases repaired by base excision repair (BER)
how does chronic UV exposure affect immune system?
immunosuppressive
causes antigen presenting cells to lose ability to present
causes keratinocytes to secrete immunosuppressive molecules
generation of immune suppressive regulatory T cells
mutation of what gene causes 90% of BCCs?
PTCH
activates hedgehog signalling
what type of cancer does chronic/long term sun exposure cause?
SCC
what type of cancer does intense intermittent/recreational sun exposure cause?
melanoma
BCC
what type of cancer does burning cause?
melanoma
BCC
what type of cancer does artificial UV cause?
SCC
BCC
melanoma
what does hedgehog signalling do?
leads to induction of cell proliferation genes and angiogenesis activators
what is vismodegib?
hedgehog inhibitor
blocks hedgehog signalling and prevents cell cycle activation and angiogenesis
what mutations are common in melanomas?
RAS/Raf/MAPK signalling pathways
what do dasatinib and imatinib inhibit?
c-Kit
what do vemurafenib and dabrafenib inhibit?
B-Raf
what does trametinib inhibit?
MEK
what 2 genes have been linked to familial melanoma?
CDKN2A
CDK4
