Carcinogenesis: Causes of Cancer Flashcards
What type of occupations can lead to exposure to carcinogens?
- Heavy metals, such as cadmium and nickel, in aluminium production, coal gasification, coke production, iron and steel industries
- Mining of hematite and uranium exposes workers to radon
- Painters and furniture makers are exposed to various solvents and preservatives.
- Asbestos
What occupation is many cases of cancer of the sinonasal cavities and paranasal sinuses associated with?
Woodworkers (solvents and preservatives)
What is asbestos?
Asbestos is a natural mineral and carcinogen
What occupation is nasal adenocarcinoma often associated with?
Employment in boot and shoe manufacture and repair, particularly where there is exposure to leather dust.
What are the 5 categories of human carcinogens?
- Chemicals e.g. PAHs, nitrosamines
- Infectious agents e.g. HPV, Helicobacter pylori
- Radiation e.g. UV light, radon
- Minerals e.g. asbestos, heavy metals
- Physiological e.g. oestrogen, androgens
What can prolonged exposure to carcinogens lead to?
Prolonged exposure to each of these agents (or combinations) can lead to the accumulation of genetic alterations in clonal populations of cells
What is PAH?
Polycyclic aromatic hydrocarbons. These are a class of chemical agents that are produced whenever organic material is burnt e.g. toast, meat, fossil fuels, tobacco.
What are nitrosamines?
A class of chemical agent that are produced in the diet when amino acids have nitrogen groups attached to them.
Nitrites added as a preservative to processed foods are able to nitrosate amino acids in our diet and convert them into carcinogenic agents.
What is a carcinogen?
Any agent that significantly increases the risk of developing cancer
Carcinogens are often genotoxic. What does this mean?
Can chemically modify or damage DNA - INITIATORS
Carcinogens can also be non-genotoxic. What does this mean?
Induce proliferation and DNA replication - PROMOTERS
Some non-genotoxic carcinogens induce proliferation as part of their normal physiological function, e.g. oestrogen
What are ‘complete’ carcinogens?
Can initiate and promote e.g. UV light
What does a mutation induction (initiation) require?
- Chemical modification of DNA
2. Replication of modified DNA and mis-incorporation by DNA polymerase of modification
DNA polymerase make errors at a very low but significant rate. What does this result in?
This results in the accumulation of genetic variation or polymorphisms in coding and non-coding sequences in the genome.
Some can be deleterious –> mutations
How can the presence of chemical modifications (miscoding or non-coding adducts or lesions) in the DNA affect the tendency of polymerases to make mistakes?
Exacerbates the tendency of polymerases to make mistakes (point mutations) by misincorporation.
Or can cause the polymerase to stall leaving a break in the DNA strand that can end up as a double stranded DNA break – a substrate for deletions, insertions or translocations
How can chemical modification of the nucleotides involved in base-pairing occur?
Through environmental insult or through the action of endogenous reactive molecules such as free radicals produced by normal physiological processes.
What are the 2 ways that promoters can contribute to carcinogenesis?
- Can stimulate two rounds of DNA replication required for mutation fixation
- Can stimulate clonal expansion of mutated cells, which enables the accumulation of further mutations
How does initiation work?
Promoting agent fixes damage as a mutation and converts normal cell into mutant cell
How does promotion work?
Promotion stimulates clonal expansion of initiated cell to produce papillomas
How does progression work?
Further rounds of mutation and clonal expansion allows progression of papilloma to carcinoma
How does cancer risk relate to cell division?
Strong correlation
What are point mutations / base pair substitutions?
The smallest change in DNA sequence that can give rise to a change in gene function.
What can point mutations result in?
- Missense: an amino acid substitution (missense)
- Non-sense: can introduce a stop codon into the coding sequence of a gene resulting in a truncated protein product
- Gain of function: can make protein products more active
- Loss of function: less active
What is a frameshift mutation? What does it result in?
Gain or loss of one to several base pairs that results in a shift in the reading frame of a gene transcript.
This changes the amino-acid sequence downstream of the frameshift, which usually inactivates the protein product
What is the result of deletions or insertions of DNA fragments from or into a gene?
Will usually disrupt the amino acid sequence and lead to a loss of function
What is the result of gene amplification?
Can result in a cell having anything up to a hundred copies of a gene, which it would normally only have two copies of. This results in excessive amounts of protein, which represents a gain of function for the cell.
What is translocation?
Exchange of material
What is the Philadelphia chromosome/translocation?
A specific chr 9:22 exchange which is responsible for chronic myeloid leukaemia
What is the result of translocations?
Can result in genes being moved to a more transcriptionally active region of the chromosome, or can result in genes being recombined into new gene fusions.
What is aneuploidy?
any departure from the normal structure or number of chromosomes.
What is a proto-oncogene?
A normal gene which, when altered by mutation, becomes an oncogene that can contribute to cancer
E.g. Some provide signals that lead to cell division. Others regulate apoptosis
What are tumour suppressor genes?
Normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die
What is an oncogene?
A gene with the potential to cause cancer
What gene has been mutated when a loss of function mutation has happened?
Tumour suppressor gene (i.e. tumour suppressor genes are normal genes)
What is DNA methylation?
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence.
When methylation is located in a gene promoter, what is the likely outcome?
typically acts to repress gene transcription
What is the most common TSG inactivation event?
Methylation of gene promoters –> epigenetic change
What is an epigenetic change?
phenotype changes that do not involve alterations in the DNA sequence
Where does DNA methylation occur?
At CpG sites within the DNA
When is the only time that CpG methylation is only effective at shutting down the expression of a gene?
If it occurs within the promoter sequence of the gene
What are procarcinogens?
Require enzymatic (metabolic) activation before they react with DNA, e.g. aromatic amines, polycyclic aromatic hydrocarbons (PAHs)
What are direct acting carcinogens?
Interact directly with DNA, e.g. oxygen radicals, nitrosamines, UV light, ionising radiation
What causes a genetic influence on the extent to which we are sensitive to genotoxic attack by different agents?
The majority of carcinogens that we ingest require metabolic activation by enzymes that normally function in the detoxification and excretion of toxic chemicals
Why do not all mutations lead to cancer?
Repair processes
What is Xeroderma pigmentosum (XP)?
A group of rare autosomal-recessive inherited disorders characterised by extreme skin sensitivity to ultraviolet (UV) light, abnormal skin pigmentation, and high frequency of skin cancers
What causes XP?
An inherited defect in the NER (nucleotide excision repair) repair pathway (unable to effectively repair damage by UV)
What is Ataxia telangiectasia (A-T)?
An autosomal recessive disorder.
These patients have an elevated incidence of cancers:
In children, more than 85% of neoplasm cases are acute lymphocytic leukaemia or lymphoma. In adults with A-T, solid tumours are more frequent
What causes AT? What gene is implicated?
Inherited defects in the ATM gene involved in recombinational repair pathway
What is Hereditary non-polyposis colorectal cancer (HNPCC)?
Also known as Lynch syndrome.
It is an autosomal dominant disorder that confers an increased lifetime risk of developing colorectal cancer (and others)
How can polymorphisms in cytochrome P450s affect cancer development?
Genetic polymorphisms in genes encoding metabolic activation, detoxifying, or DNA repair enzymes may confer greater or lesser susceptibility to the effects of carcinogenic exposure.
What are our defences against carcinogenesis?
– Dietary antioxidants
– Detoxification mechanisms
– DNA repair enzymes
– Apoptotic response to unrepaired genetic damage
– Immune response to infection and abnormal cells
How many carcinogens are identified in tobacco smoke?
33
How can alcohol affect oestrogen and testosterone?
Can increase them (these are known promoters) which can increase risk of cancer
What compound can alcohol be converted into that can cause DNA damage?
Acetaldehyde
How does alcohol affect the uptake of carcinogenic chemicals?
Increases uptake of carcinogenic chemicals into cells within the upper GI
How does alcohol affect folate?
Reduces levels of folate which is needed for accurate DNA replication
How can alcohol affect surface epithelium?
Can kill surface epithelium leading to unscheduled proliferation
What are all of the strongest risk factors of breast cancer associated with? Why is this?
Increased exposure to oestrogen - can both stimulate cell division and induce DNA damage
How does menarche affect breast cancer risk?
Breast cancer risk decreases 20% for each year that menarche is delayed
How can menopause affect breast cancer risk?
Late menopause increases risk (prolonged oestrogen exposure)
How does chronic inflammation increase risk of cancer?
– DNA damage from release of free radicals by immune cells - initiation
– Growth factor induced cell division to repair tissue damage - promotion
What is the key cell in the link between inflammation and cancer?
tumour-associated macrophages (TAMs)
What are TAMs?
These cells are recruited by cytokines released by tumour cells
What do TAMs produce?
- TNF-a
- Reactive oxygen and nitrogen species (ROS and RNS)
How does TNF-a affect inflamamtion?
a cytokine that induces and maintains the inflammatory response
What is affect of ROS and RNS?
Complete carcinogens, resulting in mutation by damaging DNA and stimulating proliferative through induction of growth factors
ROS can also induce fibroblasts to undergo autophagy, which releases important nutrients that tumour cells can “feed” on
How can diet affect cancer risk?
Carcinogens in foods such as red meat and burnt food
Absence of protective factors such as fibre and antioxidants
Summary: how do carcinogens act?
by inducing mutations or inducing cell proliferation
Summary: how does carcinogeneis process (3 steps)
initiation, promotion and progression
What is an initiator carcinogen?
Any agent that will chemically modify DNA
Why if a group of people are all exposed to the same carcinogen do they not all get cancer?
- Different metabolic activation (cytochrome P450s)
- Differences in DNA repair mechanisms
- Differences in detoxification and excretion
Events sequence in chemical carcinogenesis?
Initiation, promotion, proliferation
How does the body usually get rid of carcinogens?
Detoxification via the liver –> excretion via kidneys
OR
Metabolic activation of carcinogen –> electrophilic intermediates –> detoxification via liver –> excretion via kidneys
Describe initiation phase of carcinogens in body
Carcinogen –> electrophilic intermediates –> binding to DNA: adduct formation (this can lead to DNA repair or cell death)
If not, then a permanent DNA lesion has formed: initiated cell
Describe promotion phase of carcinogens in the body
Cell proliferation: altered differentiation –> PRENEOPLASTIC CLONE –> malignant neoplasm (after proliferation and additional mutations)
What do promoters cause?
Promoters cause clonal expansion of the initiated cell, thus producing a preneoplastic clone.
Further proliferation induced by the promoter or other factors causes accumulation of additional mutations and emergence of a malignant tumour.
What do indirect acting carcinogens require?
Require metabolic conversion, often by cytochrome P450-dependent monooxygenases
What is the CYP1A1 gene?
This gene, CYP1A1, encodes a member of the cytochrome P450 superfamily of enzymes.
Light smokers with induced CYP1A1 gene have 7 fold higher risk of developing lung cancer
What is an ultimate carcinogen?
Activated, and chemically reactive, form of a carcinogen or procarcinogen that is capable of direct covalent binding to nucleic acid and/or protein macromolecules.
Causes DNA mutagenesis.
What is the most frequent DNA damage caused by UV rays?
Pyrimidine bases covalent cross-linking
What are some examples of RNA and DNA viruses that have oncogenic capacity?
- Human T-cell leukaemia virus type 1
- HPV viruses
- Epstein-Barr virus
- Helicobacter Pylori
What is Human T-cell leukaemia virus type 1? What cancer can it cause?
RNA virus
Causes adult T-cell leukaemia. Viral genome contains HBZ transcription factor, altering host cell signalling gene transcription
What are the HPV viruses? What cancers can they cause?
DNA viruses causing range of tumours, including SCC of cervix
What is the Epstein-Barr virus? What cancer can it cause?
DNA herpesvirus causing Burkitt lymphoma
What is Helicobacter Pylori? What cancer can it cause?
Microbe can cause chronic inflammation, metaplasia, dysplasia and finally, adenocarcinoma of stomach
What is the net effect of HPV E6 and E7?
to immortalise cells and remove the restraints on cell proliferation
How does HPV E6 lead to increased cell proliferation and cell immortalisation?
Increased TERT expression –> TERT increases telomerase expression
Inhibits p53
How does telomerase contribute to cancer?
Telomeres are crucial for the survival of cancer cells. They are maintained by an enzyme called telomerase in the vast majority of tumours.
What is p53? How does the inhibition of this by HPV E6 lead to cancer?
p53 is a tumour suppressor targeted by HPV E6
How does HPV E7 lead to increased cell proliferation and cell immortalisation?
- Inhibition of p21
- Inhibition of RB
What is p21? How does the inhibition of this by HPV E7 lead to cancer?
Tumour suppressor activities that inhibits the activity of CDK4/cyclin D
This leads to increased CDK4/cyclin D which are important for progression of cancer
What is RB? How does its inhibition lead to increased cell proliferation and cell immortalisation?
RB is a tumour suppressor gene
What is p53?
Guardian of the genome:
- central monitor of stress, activated by DNA damage, anoxia, inappropriate cell signalling
- is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumour suppression.
What does p53 upregulation cause?
P53 upregulation causes cell cycle arrest to allow time for cell repair
What gene is essential as a tumour suppressor?
p53
How is p53 affected in cancer?
P53 is frequently mutated in cancer
How does DNA polymerase contribute to genome stability?
inherent exonuclease activity, allowing pause and excise mismatched bases and insert correct nucleotide
Function of mismatch repair factors?
To replace mismatched nucleotides. Microsattelite instability is a sign of mismatch repair factors deficit.
Function of nucleotide excision repair (NER) factors?
repairs UV-caused pyrimidine residues cross-linking.
Function of homologous recombination repair factors?
repairs double stranded DNA breaks
What repair mechanism defect leads to hnpcc?
DNA mismatch repair factors
What repair mechanism defect leads to ataxia telangiectasia?
Mutation in ATM –> 3 – homologous recombination defect
What repair mechanism defect leads to xeroderma pigmentosum?
Caused by mutations in genes involved in nucleotide excision repair (NER) of damaged DNA.
What repair pathway is implicated in Xeroderma Pigmentosum?
NER (nucleotide excision repair)
What gene is implicated in Ataxia Telangiectasia?
ATM gene
Function of ATM gene?
involved in recombinational repair pathway
What type of cancers are those with Xeroderma Pigmentosum at an increased risk of?
Skin cancers
