Carcinogenesis - Causes of Cancer Flashcards
In what 5 ways are human carcinogens identified?
- studies in migrant populations represent geographical variations in risk
- occupational exposure
- accidental exposure
- big epidemiological surveys
- laboratory experiments involving rodents, human cells or bacteria
How does cancer incidence vary across the globe?
How does this affect migrants?
the incidence of cancer varies massively from one part of the world to another
this suggests that the environment plays a significant role in rates of cancer occurrence
migrants gradually adopt the pattern of cancer incidence of the country to which they emigrate
Why is occupation related to cancer risk?
Depending on occupation, workers may be exposed to specific types of carcinogens
What is the carcinogen that workers involved in iron and steel industries are exposed to?
heavy metals such as cadmium and nickel
workers in aluminium production, coal gasification, coke production and iron and steel industries are affected
What carcinogen are workers involved in mining of hematite and uranium exposed to?
radon
What cancer is common in workers involved in painting and making furniture?
they are exposed to various solvents and preservatives
many cases of cancer of the sinonasal cavities and paranasal sinuses have been reported among woodworkers
What carcinogen are workers in the rubber and dye industry exposed to?
ß-napthylamine and 4-aminobiphenyl
working in these industries is associated with bladder cancer
What type of cancer is often seen in patients employed in the boot and shoe manufacture and repair industry?
nasal adenocarcinoma
particularly when there is exposure to leather dust
How are carcinogens classified and identified?
by IARC monographs
the potentially carcinogenic agents are put into groups depending on their cancer risk
What are the 5 categories of human carcinogens with examples?
chemicals:
- PAHs
- nitrosamines
Infectious agents:
- human papilloma virus
- Helicobacter pylori
radiation:
- UV light
- radon
minerals:
- asbestos
- heavy metals
physiological:
- obesity
- oestrogens and androgens
What do all the human carcinogens have in common?
prolonged exposure to each agent (or a combination) can lead to the accumulation of genetic alterations in clonal populations of cells
What does PAH stand for?
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 and convert them into carcinogenic agents
What are the target tissues for the following carcinogens?
HPV = human papilloma virus
HCV = hepatitis C virus
What is the definition of a carcinogen?
What are the 2 types?
an agent that significantly increases the risk of developing cancer
they can be initiators or promoters
What is the difference between an initiator and a promoter?
initiator:
- genotoxic
- chemically modifies or damages DNA
promoter:
- non-genotoxic
- induces proliferation and DNA replication
What is meant by a “complete carcinogen”?
they act as both an initiator and a promoter
What are the similarities and differences in the way oestrogen and reactive oxygen species (free radicals) act as carcinogens?
they are both promoters (non-genotoxic)
oestrogen induces proliferation as part of its normal physiological function
ROS are cytotoxic and lead to proliferation through the replacement of dead or damaged cells
What 2 things are required for mutation induction (initiation) to go ahead?
- chemical modification of DNA
- replication of modified DNA and mis-incorporation by DNA polymerase
What errors usually occur during DNA replication?
What do these errors result in?
DNA polymerases make mistakes at a very low but significant rate
this results in the accumulation of genetic variation or polymorphisms in coding and non-coding sequences in the genome
some of these changes are deleterious and known as mutations
How can the presence of chemical modifications (miscoding or non-coding adducts or lesions) in DNA have negative effects?
the presence of chemical modifications exacerbates the tendency of polymerases to make mistakes (point mutations) by misincorporation
or it can cause the polymerase to leave a break in the DNA strand that can end up as a double-stranded DNA break
this is a substrate for deletions, insertions or translocations
What causes chemical modification of the nucleotides involved in base-pairing?
- environmental factors
- through the action of endogenous reactive molecules
e. g. free radicals produced by normal physiological processes
In what way do agents that are good promoters contribute to carcinogenesis?
- they can stimulate the 2 rounds of DNA replication required for mutation fixation
- they can stimulate clonal expansion of mutated cells, which allows for accumulation of further mutations
In the following model, what happens during initiation?
- genotoxic initiating agent damages DNA
- promoting agent fixes damage as a mutation and converts the normal cell into a mutant cell
In the following model, what happens during promotion and progression?
- promotion stimulates clonal expansion of initated cell to produce papillomas
- further rounds of mutation and clonal expansion allows progression of papilloma to carcinoma
What is meant by an agent being “good” at initiating cancer?
the agent is good at inducing mutations
when these mutations occur in certain genes (e.g. RAS) they make the cell more susceptible to promotion
What is meant by a promoter agent being cytotoxic?
it results in cell death, inflammation and stimulation of cell division in surviving cells
Why is cell division in response to a cytotoxic agent vitally important in mutation generation?
DNA replication in the presence of DNA damage is an error-prone process that can result in permanent changes in DNA sequence
What would repeated treatments with promoting agents lead to?
the gradual accumulation of mutations as a result of exposure to exogenous mutagens and endogenous mutagens
What is the relationship between cancer risk and cell turnover?
cancer risk is directly related to the levels of cell division
in cells with a higher turnover (e.g. in the bowel), there is a higher rate of DNA replication and more chance of developing cancer
What is the smallest change in DNA sequence that can give rise to a change in gene function?
a point mutation
this involves a change in a single nucleotide
What are the 2 types of point mutations?
missense:
caused by an amino acid substitution
nonsense:
caused by introduction of a stop codon into the coding sequence
this results in a truncated protein product
How can point mutations affect protein function?
they can make protein products more active - gain of function
or make protein products less active - loss of function
What is a frameshift mutation?
How does this affect the protein product?
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
this usually inactivates the protein product
What types of mutation usually lead to a loss of function?
deletions or insertions of DNA fragments from or into a gene
this disrupts the amino acid sequence and leads to a loss of protein function
What type of mutation usually leads to a gain of function for the cell?
gene amplification
this can result in a cell having anything up to a hundred copies of a gene, which it would normally only have 2 copies of
this leads to excessive amounts of protein and a gain of function
What is meant by Philadelphia chromosome?
a translocation between chromosome 9 and 22
(a part of 22 breaks off and attaches to 9)
this causes chronic myeloid leukaemia
How can chromosomal translocations affect genes?
- genes may be moved to a more transcriptionally active region of the chromosome
- genes may be recombined into new gene fusions
What is meant by aneuploidy?
any departure from the normal structure or number of chromosomes
Which types of mutations tend to lead to a gain of function?
What type of gene is implicated in gain of function in cancer?
proto-oncogenes are activated
this can occur by base pair substitutions, amplification, translocations or inversions
What types of mutations lead to a loss of function?
Which genes are implicated in cancer?
inactivation of tumour suppresor genes
this can occur by base pair substiturions, frameshifts, deletions, insertions, chromosomal rearrangements, chromosome loss or promoter methylation
What is the difference between an oncogene and a proto-oncogene?
when a gain of function mutation in a gene confers a particular tumour characteristic to a cell, the mutant gene is an oncogene
the non-mutated version of the gene is the proto-oncogene
What is meant by a “CpG island”?
What happens when it is methylated?
70% of genes have CpG islands associated with their promoter sequences
CpG methylation shuts down the expression of a gene if it occurs within the promoter sequence of a gene
What is the most common way in which tumour suppressor genes are inactivated?
methylation of CpG islands within the promoter region of the gene
What is the difference between a direct acting carcinogen and a procarcinogen?
direct acting:
- interacts directly with DNA
- e.g. oxygen radicals, nitrosamines, radiation
procarcinogens:
- require enzymatic (metabolic) activation before they react with DNA
- e.g. aromatic amines, PAHs
What do the majority of carcinogens that we ingest require?
How is this affected by genetics?
the majority of carcinogens we ingest require metabolic activation by enzymes that normally function in the detoxification and excretion of toxic chemicals
there is a genetic influence on the extent to which we are sensitive to a genotoxic attack by different agents
What would make someone more likely to get cancer after ingesting a carcinogen, relating to their genetics?
if someone activated a particular chemical more efficiently
or
they excrete an activated chemical less efficiently
How is benzopyrene generated?
How does it act as a carcinogen?
it is generated through the combustion of most organic material, such as meat, tobacco and fuel
it is a procarcinogen that requires metabolic activation before it can react with DNA
How has benzopyrene been used in laboratory experiments?
hotspots of DNA damage formed by the reaction of BPDE with the TP53 gene match the hotspots of mutation seen in this gene in the lung tumours of smokers
What effects do different genotoxic agents (mutagens) have on DNA?
different mutagens can modify DNA in different ways
this results in lots of different mutational outcomes ranging in size and severity
What helps to maintain the integrity of the genome?
various DNA repair processes
mutational defects in several of these processes can lead to cancer predisposition
What can inherited defects in the NER repair pathway lead to?
xeroderma pigmentosum (XP)
this is a group of rare autosomal-recessive inherited disorders characterised by extreme skin sensitivity to UV light, abnormal skin pigmentation and high frequency of skin cancers
What is the effect of inherited defects in the ATM gene involved in recombinational repair pathways?
ataxia telangiectasia (AT)
this is an aurosomal recessive disorder in which patients have an elevated incidence of cancers
this is 100-fold compared to normal
How do AT cells react to X-rays?
AT cells have abnormal sensitivity to X-rays and radiomimetic chemicals
this leads to chromosome and chromatid breaks
W
How does the ATM gene product interact with other genes?
it interacts with the products of tumour suppressor genes, such as TP53 and BRCA1
AT families have reported an increased risk of breast cancer in women with one mutated ATM gene
What mutation is responsible for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome?
it is an autosomal dominant condition caused by mutations in one of several mismatch repair genes
the most common are MSH2 and MLH1
What are patients with HNPCC at increased risk of?
an increased lifetime risk of developing colorectal cancer (amongst others)
Why may groups of people suffering the same levels of exposure display a wide range of responses?
genetic polymorphisms in genes encoding metabolic activation, detoxification or DNA repair enzymes may confer greater or lesser susceptibility to the effects of carcinogenic exposure
What are the 5 main levels of defence against carcinogens?
- dietary antioxidants
- detoxification mechanisms
- DNA repair enzymes
- apoptotic response to unrepaired DNA damage
- immune response to infection and abnormal cells
How is the immune response involved in protecting against cancer?
if an abnormal protein is expressed on the surface of a cell, this is recognised by T cells
an immune response is started against the abnormal protein
How many carcinogens are present in tobacco smoke?
Which are the most relevant?
33 carcinogens
- polycyclic aromatic hydrocarbons e.g benzopyrene
- acrolein
- nitrosamines
- radioactive lead and polonium
- heavy metals - cadmium, chromium
What happens to cancer risk when tobacco smoke is combined with alcohol?
alcohol acts as a promoter and leads to a 100-fold increase for head and neck cancer
What cancers are associated with alcohol consumption?
at least 7 types of cancer:
- mouth
- oesophagus
- pharynx
- larynx
- breast
- bowel
- liver
In what ways can alcohol act as a carcinogen?
- it is converted to acetaldehyde, which causes DNA damage
- increases levels of oestrogen and testosterone
- increases uptake of carcinogenic chemicals into cells within the upper GI tract
- reduces levels of folate, needed for accurate DNA replication
- can kill surface epithelium and lead to unscheduled proliferation
What are all the strongest risk factors for breast cancer related to?
they are all associated with increased exposure to oestrogen
this can both stimulate cell division and induce DNA damage
What reduces risk of breast cancer?
breast cancer risk reduces 20% for each year the menarche is delayed
oopherectomy leads to 90% decrease in breast cancer
(orchiectomy reduces incidence of prostate cancer)
What types of cancer are associated with chronic inflammation?
- colitis
- hepatitis
- Barrett’s metaplasia
- gastritis
- gallstones
How does the inflammatory response act as both an initiator and a promoter?
initiation:
DNA damage from released free radicals by immune cells
promotion:
growth factor induced cell division to repair tissue damage
What is the key cell in the link between inflammation and cancer?
What is their role?
tumour-associated macrophages (TAMs)
they are recruited by cytokines released by tumour cells and produce tumour necrosis factor alpha (TNF-a)
TNF-a induces and maintains the inflammatory response
In what other ways can TAMs lead to cancer?
they release reactive oxygen and nitrogen species that act as complete carcinogens
this results in mutation by damaging DNA and stimulating proliferation through induction of growth factors
How can ROS secreted by TAMs and tumour cells affect fibroblasts?
they induce fibroblasts to undergo autophagy
this releases important nutrients that tumour cells can “feed” on
How can diet affect risk of cancer?
exposure to carcinogens in red meat, burnt food and heavy metals can raise incidence
absence of protective factors such as fibre and antioxidants can also raise incidence
