Mechanisms of Oncogenesis Flashcards
What are general diseases of disordered cell death?
Diseases of disordered cell death:
Cell death > new cell = immunodeficiency, neurodegeneration, infertility
Cell death < new cells = autoimmune and cancer
Describe how cancer is a multistage process involving many hits
Outline carcinogenesis
Cancer arises from a single cell that develops 2-8 oncogenic driver mutations:
* confer growth/survival advantage
* ‘passenger’ mutations occur due to DNA repair genes losing their function
What is the difference between the traditional vs modern view of cancer?
ie describe the difference between chemo and modern therapy
Primary treatment: chemo inhibits DNA replication, disrupt microtubule function in rapidly dividing cells inc tumours
Now we use our knowledge of different tumours to give targeted treatments based on their molecular profile
Describe how cancer is a disease of the genome
Epi/Genetic/genomic alterations–> altered Protein
(e.g. mutant form, overexpression)
This leads to altered Pathways e.g. activated cell survival, loss of apoptotic signals
This leads to altered Biology (e.g. limitless replication, angiogenesis, tissue invasion)
What are the main types of carcinogens?
Carcinogens can damage DNA or affects metabolic processes
Describe the chemical carcinogens
What is the difference between the procarcinogens and carcinogens
Procarcinogens= must be enzyme activated, don’t form colonies by themselves
They need eg microsomal liver enzymes (P450) for benzopyrene = carcinogenic product bc it contains epoxide
For carcinogens, cells form colonies straight away e.g. alkylating agents
Some chemotherapies can actually be carcinogens and lead to the development of secondary cancers.
Describe these
Alkylating- like agents: cisplatin + carboplatin irreversibly bind at guanines & crosslink the 2 DNA strands, inhibiting strand separation + therefore stopping DNA replication.
These type of drugs are cytotoxic = kill fast replicating cells so increased risk of secondary cancer, esp myeloid bone cancer
3 groups of physical carcinogens + egs
Non ionising radiation: UV, associated w skin cancer
Ionising radiation: Gamma, X-rays= low linear energy transfer
Particulate radiation (protons, n, e-)= high linear energy transfer
Give some sources of ionising radiation in order of highest annual dose
Natural background 87.0
Medical irradiation
Atomic weapons fallout
Early luminous watches, air travel etc.
Occupational exposure
Nuclear industry releases 0.1
Explain the effect of UV on DNA using CPD (Cyclobutane Pyrimidine Dimers) as an example
How is repair done?
Exposure to UV induces dipyrimidine photoproducts: CPDs 6-4 + 6-4PP in DNA by linking 2 adj pyrimidine bases.
This causes inactivating CC:TT mutations in TP53 gene in SCC and BCC cancer.
Repair by nucleotide excision repair (NER)
Describe viral carcinogens
Some viral infected cells can transform into cancer cells due to expression/activation of viral oncogenes - results in integration of viral genes into the host genome
What conditions are needed for a virus to be a carcinogen?
Stable association with cells via chromosomal integration, or the viral episome
Mustn’t kill host cells
Must evade immune surveillance of infected cells via immune suppression - Viral Ags aren’t expressed at cell surface e.g. HPV (E6, E7, E2F)
3 Hereditary cancer predisposition syndromes?
TP53- Li-Fraumeni syndrome, NF1- Neurofibromatosis, Lynch syndrome
3 other hereditary carcinogens involving chromosomes?
- Translocations (e.g. BCR-ABL in Leukaemia).
- Numerical disorders (e.g. trisomy 21-Down syndrome).
- Inherited immune problems (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome).
4 common causes for double stranded DNA breaks VS chemical bond formation between nucleotides?
4 common causes for chemical modification VS 3 reasons chemical linkage of 2 DNA strands?
