3) Carcinogenesis Flashcards
What proportion of people will get a cancer?
33%
What proportion of people will die of a cancer?
25%
Why is the incidence of cancer increasing?
Changes in lifestyle, increasing age and better screening
What are the stages of carcinogenesis?
Initiation, promotion, transformation (potential regression), evolution (drug resistant), metastasis
Give examples of mutations involved in colorectal carcinogenesis:
Inactivation of APC - increase in stem cells
Activation of RAS - increased proliferation
Inactivation of p53
What are some environmental causes of gene mutation?
Carcinogens bind to DNA and alter sequence
Ionising radiation/UV causing strand breaks and cross links
DNA translocation
What are some intracellular causes of gene mutation?
Misinterpretation of code, polymerase slippage, ineffective repair
What are some initiating stimuli for cancers?
Chemical carcinogens
Oncogenic viruses e.g. HPV
Radiation, UV and radicals
Replication errors
Give examples of direct acting carcinogens:
Alkylating and acylating agents e.g. dichloromethane
Cytotoxic drugs e.g. used in lymphoma and leukaemia
Give examples of pro-carcinogens:
Often in tobacco, body metabolises them into active form
Polycylic aromatic hydrocarbons e.. benzopyrene
Combustion of organic compounds e.g. coal, tobacco
In what ways can genes be mutated?
Alteration/deletion of bases Strand break Bases oxidation Adducts of carcinogen and base Chromosome rearrangment or deletion Gene amplification
What are clastogens?
Structural chromosomal changes e.g. translocation, deletion
What are aneugens?
Genome mutations e.g. aneuploidy
How can adducts cause mutation?
Reactive molecules bind to nucleophilic sites on DNA bases and cause slippage or prevent repair
Describe excision repair:
Error free removal of modified bases by DNA glycosylases. Nucleotide excision removes bases with bulky adducts
Describe error prone repair:
Response to severe DNA damage. DNA polymerases recognises specific lesions and restore original sequence
Describe mismatch repair:
Proofreading by exonuclease part of DNA polymerase which corrects mismatched bases
Give examples of promoting agents:
Chemical promoters - phenols in tobacco tar, saccharin
Hormones
Inflammation - pipe smoking
Microbial infection - H. pylori
What is the bad luck hypothesis?
Only 1/3rd of cancer risk is due to environmental factors and inherited predispositions. Majority is due to bad luck, random mutations
What things increases our risk of getting cancer?
Hereditary Carcinogens Radiation - UV and ionising Chemicals - asbestos Viruses - HPV Diet - alcohol Smoking
How is obesity linked to cancer?
High BMI increases risk and obesity causes a low level inflammation (promotion)
What foods can cause a higher risk of cancer?
Red meat, salted fish, BBQ food, salt-preserved food, fungus
What are heterocyclic amines?
Highly mutagenic molecules that are produced when we cook meat. They are absorbed and metabolised by liver to genotoxic metabolites.
How can we reduce our levels of heterocyclic amines?
Marinating and reducing cooking time of red meat reduces HA levels
