Carcinogenesis - Causes of Cancer Flashcards
What sort of food causes colorectal cancer?
Processed meat.
-also association with red meat
What chemicals in rubber can cause cancer?
- B-napthylamine
- 4-aminobiphenyl
What are the main categories of human carcinogens?
- Chemicals
- Infectious agents (e.g. HPV)
- Radiation
- Minerals
- Physiological (e.g. androgens)
- Chronic inflammation
What is a common factor when carcinogens cause cancer?
Prolonged exposure.
What organ does aflaxtoxin target?
Liver.
What type of tissue do x-rays normally target?
Bone.
-leukaemia
What type of tissue does oestrogen normally target?
Breast.
What organ does Hep B target (HBV)?
Liver.
What is a carcinogen?
Any agent that significantly increases the risk of developing cancer.
Carcinogens are often genotoxic. What does this mean?
Can chemically damage DNA and cause mutations.
What sort of carcinogens are genotoxic?
Initiators.
What is the effect of non-genotoxic carcinogens?
Induce proliferation and DNA replication.
What sort of carcinogens are non-genotoxic?
Promoters.
What are ‘complete’ carcinogens?
Both initiators and promoters.
-e.g. UV light
What does initiation require? (2)
- Chemical modification of DNA
- Replication of modified DNA and mis-incorporation by DNA polymerase
What does initiation lead to?
An inherited mutation.
-if replicated twice
How do promoters contribute to carcinogenesis? (2)
- Stimulate 2 rounds of DNA REPLICATION for mutation fixation
- Stimulate CLONAL EXPANSION of mutated cells
Describe the general processes of initiation, promotion and progression.
- Initiating agent damage DNA
- Promoting agent fixes damage as mutation, and converts normal cell to mutant
- Promoting agent stimulates clonal expansion»_space; papillomas
- Further clonal expansion; papilloma»_space; carcinoma
What is the smallest change in DNA sequence that can cause a change in gene function?
Point mutation.
What is a Philadelphia chromosome?
Translocation chr(9,22). -associated with chronic myeloid leukaemia
What is the most common type of genetic abnormality in cancer genes?
Translocation.
What aneuploidy?
Abnormal number of chromosomes in a cell.
-e.g. 45 or 47
What proportion of our genes have CpG islands associated with promoter sequences?
~70%.
-cytosine followed by guanine
What is the function of CpG islands?
Help to control gene expression.
-methylation only effective if within the promoter sequence
What does abnormal methylation of gene promoters in TSGs lead to?
Epigenetic inactivation of tumour suppressor genes.
-most common inactivation
What is the effect of mutations in oncogenes?
Gain of function.
What mutations lead to loss of function in oncogenes but not tumour suppressor genes? (3)
- Amplification
- Translocations
- Inversions
What is the effect of mutations in tumour suppressor genes?
Loss of function.
What mutations lead to loss of function in tumour suppressor genes but not oncogenes? (5)
- Frameshifts
- Insertions / deletions
- Chromosomal rearrangements
- Promoter methylation
- Chromosome loss
What dud Charlotte Auerbach show?
That chemicals can induce heritable genetic changes in organisms.
-induced eye colour change in flies
What do the majority of carcinogens require to introduce a genetic influence?
Require metabolic activation by enzymes.
Carcinogens; what does direct acting mean?
Interact directly with DNA.
-e.g. UV light, O2 radicals
What is a procarcinogen?
A chemical that requires enzymatic activation before becoming carcinogenic.
-e.g. aromatic amines
How is benzopyrene generated?
Combustion of organic material.
What type of carcinogen is benzopyrene?
A pro-carcinogen.
-requires metabolic activation»_space; BPDE to become carcinogenic
What is xeroderma pigmentosum?
Autosomal recessive disorder.
- defect in NER repair pathway
- UV sensitivity, abnormal pigment, etc
What do inherited defect in the ATM gene cause?
Ataxia telangiectasia (A-T). - ^ cancer risk
What is another name for Lynch syndrome?
Hereditary Non-Polposis Colorectal Cancer (HNPCC).
What do mutations in repair processes lead to?
Increased disease.
What are the main effects of carcinogenic exposure?
- Metabolic activation
- DNA damage
Genetic polymorphisms of which stages of carcinogen exposure affect susceptibility? (3)
- Metabolic activation
- DNA repair
- Detoxification excretion
How many carcinogens have been identified in tobacco smoke?
19.
-e.g. acrolein (acrid smell)
What increases the risk of tobacco smoke leading to cancer?
Alcohol.
-100x increased risk of head / neck cancer
What is alcohol converted to that can cause damage?
Acetaldehyde.
-damages DNA
What are the main harmful effects of alcohol?
- Increased oestrogen and testosterone
- Increased uptake of chemicals into cells within upper GI
- Reduced folate
- Kills surface epithelium»_space; proliferation
What is folate needed for?
Accurate DNA replication and repair.
What is the effect of oestrogen on breast cancer risk?
Increased oestrogen increases the risk of breast cancer.
How does oestrogen increase the risk of breast cancer? (2)
- Stimulates cell division
- Induces DNA damage
What effect does delayed menarche (1st period) have on breast cancer risk?
Delayed menarche decreases breast cancer risk by 20% each year.
What is oopherectomy?
Removal of the ovaries.
What effect does oophrectomy have on the risk of breast cancer?
Oopherectomy decreases breast cancer risk by 90%.
What is orchidectomy?
Removal of the testicles.
What effect does orchidectomy have on the risk of prostate cancer?
Orchidectomy reduces the incidence of prostate cancer.
What is the effect of chronic inflammation on cancer?
Chronic inflammation increases the risk of many types of cancer.
-e.g. colitis, hepatitis
What is one the main cells in the link between inflammation and cancer?
Tumour-associated macrophages (TAMs).
-recruited by cytokines released from tumour cells
What are the 2 main stages in the inflammatory response?
INITIATION - DNA damage from release of free radicals
PROMOTION - growth factor induced cell division
What are the main categories of environmental factors that contribute to cancer?
- Diet
- Tobacco
- Infection
