Carcinogenesis - Causes of Cancer Flashcards

Question

In the following model, what happens during promotion and progression?

Answer 1

1. promotion stimulates clonal expansion of initated cell to produce papillomas 2. further rounds of mutation and clonal expansion allows progression of papilloma to carcinoma

Answer 2

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

Answer 3

it results in cell death, inflammation and stimulation of cell division in surviving cells

Answer 4

DNA replication in the presence of DNA damage is an error-prone process that can result in permanent changes in DNA sequence

Answer 5

the gradual accumulation of mutations as a result of exposure to exogenous mutagens and endogenous mutagens

Answer 6

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

Answer 7

a point mutation this involves a change in a single nucleotide

Answer 8

**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

Answer 9

they can make protein products more active - **gain of function** or make protein products less active - **loss of function**

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

a translocation between chromosome 9 and 22 (a part of 22 breaks off and attaches to 9) this causes chronic myeloid leukaemia

Answer 14

1. genes may be moved to a more transcriptionally active region of the chromosome 2. genes may be recombined into new gene fusions

Answer 15

any departure from the normal structure or number of chromosomes

Answer 16

**proto-oncogenes** are activated this can occur by base pair substitutions, amplification, translocations or inversions

Answer 17

inactivation of **tumour suppresor genes** this can occur by base pair substiturions, frameshifts, deletions, insertions, chromosomal rearrangements, chromosome loss or promoter methylation

Answer 18

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

Answer 19

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

Answer 20

methylation of CpG islands within the promoter region of the gene

Answer 21

**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

Answer 22

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

Answer 23

if someone activated a particular chemical more efficiently or they excrete an activated chemical less efficiently

Answer 24

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

Answer 25

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

Answer 26

different mutagens can modify DNA in different ways this results in lots of different mutational outcomes ranging in size and severity

Answer 27

various DNA repair processes mutational defects in several of these processes can lead to cancer predisposition

Answer 28

**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

Answer 29

**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

Answer 30

AT cells have abnormal sensitivity to X-rays and radiomimetic chemicals this leads to chromosome and chromatid breaks

Answer 31

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

Answer 32

it is an autosomal dominant condition caused by mutations in one of several mismatch repair genes the most common are MSH2 and MLH1

Answer 33

an increased lifetime risk of developing colorectal cancer (amongst others)

Answer 34

genetic polymorphisms in genes encoding metabolic activation, detoxification or DNA repair enzymes may confer greater or lesser susceptibility to the effects of carcinogenic exposure

Answer 35

1. dietary antioxidants 2. detoxification mechanisms 3. DNA repair enzymes 4. apoptotic response to unrepaired DNA damage 5. immune response to infection and abnormal cells

Answer 36

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

Answer 37

**33 carcinogens** 1. polycyclic aromatic hydrocarbons e.g benzopyrene 2. acrolein 3. nitrosamines 4. radioactive lead and polonium 5. heavy metals - cadmium, chromium

Answer 38

alcohol acts as a promoter and leads to a 100-fold increase for head and neck cancer

Answer 39

at least 7 types of cancer: 1. mouth 2. oesophagus 3. pharynx 4. larynx 5. breast 6. bowel 7. liver

Answer 40

1. it is converted to acetaldehyde, which causes DNA damage 2. increases levels of oestrogen and testosterone 3. increases uptake of carcinogenic chemicals into cells within the upper GI tract 4. reduces levels of folate, needed for accurate DNA replication 5. can kill surface epithelium and lead to unscheduled proliferation

Answer 41

they are all associated with increased exposure to oestrogen this can both stimulate cell division and induce DNA damage

Answer 42

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)

Answer 43

1. colitis 2. hepatitis 3. Barrett's metaplasia 4. gastritis 5. gallstones

Answer 44

**initiation:** DNA damage from released free radicals by immune cells **promotion:** growth factor induced cell division to repair tissue damage

Answer 45

**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

Answer 46

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

Answer 47

they induce fibroblasts to undergo autophagy this releases important nutrients that tumour cells can "feed" on

Answer 48

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