Photocarcinogenesis Flashcards
What is carcinogenesis?
The process whereby a normal cell becomes malignant
What is cancer?
An accumulation of abnormal cells that multiply through uncontrolled cell division and spread to other parts of the body via direct invasion or metastases
Which two gene changes are required for cancer to form?
Gain of function of oncogenes (proto-oncogenes) and loss of function of tumour suppressor genes
How do proto-oncogenes form? Give some examples of oncogenes
Mutation or copy gain. Cyclins, RAS, MYC
How do tumour suppressor genes mutate? Give some examples of tumour suppressor genes
Mutation or loss of heterozygosity. CDKI, p53, retinoblastoma (Rb)
Describe the process of cancer formation
Single normal cell > genetic mutation > accumulation of genetic mutations (clonal evolution) > cancerous growth
What is the difference between monoclonal and polyclonal tumours?
Monoclonal - tumour consists of one type of mutated cell Polyclonal - tumour consists of many types of mutated cell (due to multiple, parallel clonal expansions)
What are the hallmarks of cancer?
Sustained proliferation, evasion of growth suppressors, activating invasion & metastases, replicative immortality, inducing angiogenesis, resisting cell death
Mutations cause cancer, which factors increase mutation rate?
Natural accumulation of DNA damage with age, carcinogens (UV, smoking), inherited defects
In terms of the earths UV light, which type is most destructive?
UVB (causes burning)
Which types of UV light does sunscreen protect against?
UVB & UVA
Which types of UV light are responsible for skin cancer and ageing?
UVB & UVA
How do UVB and UVA cause DNA damage, respectively?
UVA - indirect DNA damage, more prevalent (penetrates more deeply into the skin) UVB - direct DNA damage when sun is directly overhead,, more damaging
What is the typical type of mutation caused by UV light? How is this corrected?
Pyrimidine dimer. Nucleotide excision repair
What are the different types of DNA mutation?
Pictured
How do UV induced mutations occur?
UV causes the formation of photoproducts > accumulation of photoproducts causes mutation, genetic instability & cancer
What are the types of DNA repair?
Nucleotide excision repair, base excision repair, double strand break repair & mismatch repair
Mutations in genes involved in DNA repair causes what? Mutations in genes involved in cell devision causes what?
A mutator phenotype (cells acquired further mutations more rapidly). Chromosome instability (accumulation of chromosomal abnormalities)
How do UVB and UVA cause DNA damage respectively?
UVB - generation of photoproducts (C-T, CC-TT) UVA - induces guanine oxidation products in DNA (oxidative damage)
What is UV induced immunosuppression?
Dendritic cells lose ability to present antigen > T cells switch from helper to suppressor (regulatory T cells) > keratinocytes & dendritic cells secrete immunosuppressive cytokines
Is UV radiation a mutagenic or immunosuppressive carcinogen? How do these effects occur?
Mutagenic & immunosuppressive. -DNA damage (photoproducts) > activation of signal transduction pathways > inflammation/oxidative stress (AK) > acquires hallmarks of cancer
What are the risk factors for skin cancer?
Sunlight (latitude, childhood sunburn, intense & intermittent exposure), genetics, chemicals, age, immunosuppression, HPV, skin type, phototoxic/sensitising drugs
Tanning is a reaction to sun damage. T/F
True
What is the difference between type 1 skin and other skin types?
Possess pheomelanin instead of eumelanin which absorbs light less effectively
What are the chronic skin changes due to photodamage?
UVB - sunburn & solar lentigo UVA - solar ageing
Freckles mean you cannot tan and must protect your skin from the sun. T/F
True
Which mutation causes Gorlin’s syndrome?
Germline mutation in PTCH gene (causing hedgehog signalling)
BCC tend to be homogenous tumours. T/F
True
Hedgehog inhibitors and BRAF inhibitors are useful for which types of cancer?
HI - BCC BRAFI - melanoma
The mutation of which gene is common in NMSC?
p53
As cancers become more invasive they acquire more and more mutations. T/F
True
Give examples of some phototoxic drugs/classes
Voriconazole (antifungal), thiazide diuretics, NSAIDs, anti-TNF, azathioprine
Immunosuppressed individuals have a particularly high risk of developing which type of skin cancer?
SSC
Which factors contribute to the development of transplant associated SSC?
Drugs, UV radiation, viruses and genetics
How does azathioprine increase skin cancer risk?
When metabolised produces 6-TG > 6-TG is incorporated into the DNA of replicating cells > 6-TG acts as a UVA chromophore > induces DNA lesions
Cutaneous HPV infection contributes to the development of SSC in which ways?
inhibition of apoptosis, delay of DNA repair, promotion of keratinocyte invasion
How can skin cancer be prevented?
Surveillance & monitoring of transplant/immunosuppressed patients, treatment of premalignancy, behavioural, sunscreen, minimisation of immunosuppression (mTORi), retinoid use
How can premalignancy be treated?
Cryotherapy, Surgery, Topicals, Photodynamic therapy
