carcinogenesis Flashcards
what are lab experiments done on?
rodents, human cells and bacteria
what are two types of unavoidable exposure?
occupational due to carcinogenic agents such as heavy metals cadmium and nickel, and accidental exposure
how would you identify geographical variation in risk?
study migrant populations - shows that environment can play a significant role in rates of cancer as there are enormous variation in the incidence of specific cancers in one part of world to another
what does mining of hematite and uranium expose workers to?
radon
what has a high prevalence among woodworkers?
paranasal sinuses and sinonasal cavities cancer
what is high in boot manufacture and leather dust exposure occupations?
nasal adenocarcinoma
what is EPIC?
it is the european prospective investigation into cancer and nutrition and is to investigate lifestyles etc and the incidence of cancer and other chronic disease
what are the categories of human carcinogens and an example?
chemicals (PAHs), radiation (radon), infectious agents (HPV), minerals (asbestos) and physiological (oestrogen)
how can human carcinogens lead to cancer?
prolonged exposure can lead to an accumulation of genetic alteration in clonal populations of cells
what are PAHs?
polycyclic aromatic hydrocarbons - class of chemical agent that is produced when organic matter is burnt
what are nitrosamines?
class of chemical agent that are produced in diet when amino acids have a nitrogen group attached to them which are then converted to carcinogenic agents
what does aflatoxin, alcohol and asbestos target?
aflatoxin -liver
alcohol - liver, larynx, pharynx, oesophagus
asbestos - lung pleura
what odes tobacco smoke, UV and HPV target?
tobacco smoke - mouth, lung and oesophagus
HPV - liver
UV - skin
what does HCV, oestrogen and X rays target?
HCV - pancreas, kidneys, bladder
oestrogen - breast
X rays - bone marrow resulting in leukaemia
what is a carcinogen?
any agent that significantly increases the risk of developing cancer
what does genotoxic mean?
it is a carcinogen that can chemically modify or damage DNA i.e. is an initiator
what is a complete carcinogen?
one that can initiate and promote e.g. UV light
what is a non - genotoxic carcinogen?
on that induces proliferation and DNA replication i.e. is a promoter
what is the difference between oestrogen and ROS?
they are both non-genotoxic carcinogens, however oestrogen will induce proliferation as it’s normal physiological function, whereas reactive oxygen species (free radicals) will lead to proliferation through the replacement of dead or damaged cells so are cytotoxic
what does mutation induction require?
initiation requires chemical modification of DNA and replication of the modified DNA and misincorporation by DNA polymerase
how is misincorporation possible?
DNA replication is not error free so that evolution can occur. DNA polymerase makes mistakes at a very low rate but this is significant as it results in accumulation of genetic variation or polymorphisms in coding and non coding region of genome - can be deleterious - mutations
what increases the risk of point mutations/misincorporation?
the presence of a modification (miscoding or on coding adducts or lesions) in the DNA
what else can these modifications result in?
cause the polymerase to stall - double stranded break in DNA which is a target for deletions, translocations or insertions
how can chemical modification occur?
environmental insult or endogenous reactive molecules e.g. free radicals produced by normal physiological processes
what do good promoters to for carcinogenesis?
they stimulate the two rounds of DNA replication that is required for mutation fixation
they stimulate clonal expansion mutated cells which enables the accumulation of further mutations
how will a papilloma progress to a carcinoma?
further rounds of mutations and clonal expansions
progression is also known as persistence
what is the link between cell division and cancer?
the lifetime risk of cancer in certain tissues and the number of stem cell divisions over a lifetime in these tissues has a very strong correlation
what is a point mutation?
a base pair substitution
it is the smallest change in DNA sequence that can give rise to a change in DNA function
they can results in missense or nonsense / truncated protein
this can overactivate or underactivate the protein
which mutation usually results in a inactive protein?
frameshift - where there is a gain or loss of one or several base pairs meaning that downstream the reading frame is different
what mutation results in a large gain of function of protein in a cell?
gene amplification where the cell can have anything up to a hundred copies of a gene which it would usually have two of
what is the chr 9;22 exchange?
it is the philadelphia chromosome that is responsible for chronic myeloid leukaemia
how can genes be recombined into new gene fusions?
chromosomal translocations where genes are moved to a more transcriptionally active area of chromosome
what is aneuploidy?
any change from the normal structure or number of chromosomes
how many of the known cancer genes are affected by translocations, frameshifts, nonsense and missense mutations?
300/570 for translocations
100 each for rest
what mutations can lead to loss of function?
substitutions, frameshifts, deletions, insertions, chromosomal rearrangement or loss, promoter methylation - inactivation of tumour supressor gene
what mutations can lead to gain of function?
substitutions, amplification, translocations and inversions - activation of proto-oncogenes
what is a proto-oncoene?
non-mutated version of a gene. The mutated version of this gene must confer a particular tumour characteristic - oncogene.
what is a tumour supressor gene?
it is a gene that has been mutated that results in loss of function and therefore transforms the cell to neoplastic condition
what is the key concept of oncogenes and TSGs?
oncogenes are mutated versions of normal genes but TSGs are normal genes. However in both cases, a malignant phenotype is only achieved through mutation of the normal gene.
what is an important epigenetic change that can result in TSG inactivation?
methylation of the gene promoter - most common TSG inactivation event
gene promoters are aberrantly methylated in tumours
What are CpG islands?
around 70% of our genes will have these that are associated with promoter sequences
when is methylation sufficient to cause TSG inactivation?
only when the methylation occurs in the CpG region ib the promoter sequence of the gene
what happens in cancer cells?
the mechanisms that control normal methylation are highjacked and used to inactivate TSGs
what is significant about promoter methylation?
it is more important in inactivation of TSGs than somatic mutation - more than half of the TSGs that are involved in familial cancer syndromes due to germline mutations have been found to be silenced in sporadic cancers by promoter methylation
what are the two factors in metabolic activation?
an agent can be direct acting or procarcinogenic
what does direct acting mean?
interact directly with DNA such as UV, nitrosamines, ionising radiation and oxygen radicals
what does procarcinogenic mean?
require enzymatic or metabolic activation before they react with DNA - aromatic amines or polycyclic aromatic hydrocarbons
what can chemical do?
they can induce heritable genetic changes in organisms such as nitrogen mustard (alkylating) to change the eye colour or fruit flies
what do the majority of carcinogens we ingest require?
they require metabolic activation by enzymes that are normally involved in detoxification and excretion of toxins
what are the implications of procarcinogens?
genetic influence on the extent to which we are sensitive to a particular genotoxic attack by different agents - people who activate these chemicals more readily will be more likely to get cancer and those who excrete it are less likely to
what is benzopyrene?
it is generated through the combustion of organic material such as meat, tobacco and fuel and is a pro-carcinogen that requires metabolic activation before it can react with DNA
what are the implications and findings on benzopyrene?
it is a hotspot for DNA damage - formed by the reaction of BPDE with TP53 gene - hotspot mutations that are seen in the tumours in smokers lungs
how do genotoxic agents mutate genes?
different genotoxic agents - mutagens can modify DNA in lots of different ways and this can result in lots of different mutational outcomes that range in size and severity from a single nucleotide substitutions all the way to a chromosome breakage
what protects the genome and how can this be implicated in cancer?
the various DNA repair processes protect the integrity of the genome - mutational defects in several of these processes can lead to a predisposition to cancer
what is xeroderma pigmentosum?
it is a group of rare autosomal recessive inherited disorders that are characterised by extreme skin sensitivity to UV, abnormal pigmentation, high frequency of skin cancers especially on sun exposed skin. The mandatory clinical diagnostic sign is dermatological changes. It is caused by inherited defects in the NER pathway - predisposition.
what is the ATM gene involved in?
the recombinational repair pathways
what can inherited defects in the ATM gene result in?
ataxia telangiectasia - autosomal recessive disorder
what is AT?
it gives an elevated risk of cancers - around 100 fold compared to the general population
in AT what are the expected cancers?
85% in children will be lymphocytic leukaemia or lymphoma
adults will have more solid tumours
what is a basic defect of AT?
increased sensitivity to Xrays or radiomimmetic chemicals resulting in chromosome and chromatid breaks
what do the ATM gene products do?
they interact with the products of TSGs TP53 and BRCA1 - these are involved in breast cancer - increased risk of breast cancer in women with one mutated ATM gene
what is HNPCC?
hereditary non polyposis colorectal cancer or Lynch syndrome. It is an autosomal dominant disorder that results in predisposition to cancer
which cancers does HNPCC give a predisposition to?
there is a lifetime risk of 70-82% of CRC, but also 12% for ovarian and 60% for endometrial. also biliary tract, renal pelvis, brain, uterine, stomach, SI, liver
what are the majority of cases of HNPCC due to?
mutations on several mismatch repair genes: chromosome 2: PMS1, MSH2 and 6
chromosome 3: MLH1
chromosome 5: MSH3
chromosome 7: PMS2
what account for the majority of familial HNPCC cases?
MSH2 and MLH1 mutations
why do people who have the same level of exposure have varying levels of expression?
gene or environmental effects - genetic polymorphisms in genes encoding detoxification, metabolic activation and DNA repair enzymes may confer greater or lesser susceptibility to the effects of carcinogenic exposure
why is cancer extremely rare at the cellular level?
there are many cells in the body and cancers arise from a single cell. Mutation is an extremely rare process in cells and many things have to go wrong before a heritable genetic alteration occurs and is expressed in a stable cell lineage
what is the body’s defence against carcinogenic agents?
the immune response to infection or abnormal cells, the apoptotic response to unrepaired genetic/DNA damage, dietary antioxidants, detoxification mechanisms and DNA repair enzymes
what activity is associated with most forms of human cancer?
smoking
what risk does smoking lead to?
with alcohol promotion there is an 100 fold increase risk of head and neck cancer
how many carcinogens are in tobacco smoke?
33 - PAHs such as benxopyrene, acrolein (acrid smell, direct acting mutagen), nitrosamines, radioactive lead and polonium and heavy metals including cadmium and chromium
what cancers is alcohol linked to?
maybe pancreatic
breast, bowel, liver, mouth, oesophagus, larynx, pharynx
how does alcohol affect DNA?
reduced levels of folate which is needed for accurate DNA replication
converted into acetaldehyde that can cause DNA damage
what other harmful effects does alcohol have?
increases levels of oestrogen and testosterone, increases the uptake of carcinogenic agents into cells within the upper GIT, kills surface epithelium which leads to unscheduled proliferation
what are the strongest risk factors for breast cancer linked to?
all are associated with increased exposure to oestrogen which stimulates cell division and induces DNA damage
what is menarche?
menopause - for every year that menarche is delayed the risk of breast cancer decreases by 20%
what is the link of breast cancer in identical twins?
the one who reaches menarche first has a 5.4x chance of developing breast cancer first
what risk reducing measures are there for breast and prostate cancer?
90% reduction in risk of breast cancer with oopherectomy
orchiectomy reduces the incidence of prostate cancer
what conditions of chronic inflammation are associated with cancer?
Barretts metaplasia, gastritis, hepatitis, colitis, gallstones
what does the inflammatory response do?
it results in DNA damage from release of free radicals by immune cells - initiation
it also releases growth factors which induce cell division to repair sites of tissue damage - promotion
what can cause inflammation that results in cancer?
non infective mechanisms or microbial infection
what cell is a key link between inflammation and cancer?
tumour associated macrophages
how do TAMs work?
they are recruited by cytokines that the tumour cell produces and then secrete TNF which induces and maintains the inflammatory response. They also produce reactive oxygen and nitrogen species which act as complete carcinogens and result in mutation by damaging DNA and stimulating proliferation through the induction of growth factors
what else can ROS do?
they can stimulate fibroblasts to undergo autophagy which will release nutrients for the tumour to feed on
how can diet influence cancer?
can be the absence of antioxidants and fibre - protective
can be the exposure to carcinogens such as red meat
mostly a combination of two
overall how does carcinogenesis act?
initiation, promotion, progression
