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Y3 Biology Of Cancer > Week 2 > Flashcards

Week 2 Flashcards

1
Q

What is a mutagen?

A

An agent that causes a genetic mutation.

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2
Q

What is a carcinogen?

A

An agent that increases the likelihood of developing cancer.

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3
Q

Are all carcinogens mutagens? Why?

A
  • Most carcinogens are also mutagens, but some are not as their influence is not through genetic change.
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4
Q

How do physical agents cause cancer?

A

Damage DNA and can cause mutations following DNA replication.

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5
Q

How do infectious agents cause cancer?

A

Can cause and contribute to cell transformation and tumour progression.

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6
Q

Name some physical agents which cause cancer.

A

Radiation by natural light and sunbeds.

X-rays

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7
Q

Name some chemical agents that cause cancer.

A

Cigarette smoke, Nitrate and Nitrate preservatives, BBQ, Benzoyl Peroxide.

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8
Q

Name some infectious agents which can contribute to cancer formation.

A

HIV, Helicobacter pylori

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9
Q

Is all cancer genetic and inhertied?

A

All cancer is genetic but not all cancer is inherited.

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10
Q

What are genotoxic agents?

A

A chemical or another agent that damages cellular DNA, resulting in mutations or cancer.

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11
Q

Explain how BP (Benzoapyrene) can be carcinogenic and how it is thought to work.

A

BP-7-8-dihydrodiol-9,10-epoxide is the carcinogenic product of BP. This results in mutations in p53 and results in the loss of function muttions in tumour suppressor genes. BP causes G to T transversion mutations.

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12
Q

When are aromatic amines produced?

A

They are produced when muscle meat is cooked using high heat as amino acids and sugars are broken down by the high heat.

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13
Q

How are PAH’s produced?

A

PAH are present in smoke so are enriched when any smoked meat or food is cooked at high temperature.

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14
Q

WHat is genotoxicity testing?

A

This is the study of chemicals which can damage the genetic structure of living organisms (including humans) and thus cause problems such as mutations, cancer and birth defects.

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15
Q

What are the tiers of genotoxicity testing?

A

Tier 1 - In silico SAR/QSAR
Tier 2a - In vitro bacterial gene mutation assay
Tier 2b - In vitro mammalian assay using the Ames test
TIer 3 - in vivo mammalian assay using the micronucleus test
Tier 4 - supplementary tests

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16
Q

Explain how the tier 2a in vitro Ames test during genotoxic testing works and what it looks for.

A

A Salmonella auxotroph (which requires histidine) is used to screen for revertants which are histidine independent. The number of revertants relates to the strength of the mutagen.

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17
Q

What is the downside of using the Ames test during genotoxic testing to identify mutagens?

A

It can miss some mutagens such as bile acids.

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18
Q

Explain how the tier 2b in vivo micornucleus test during genotoxic testing works and what it looks for.

A

A variety of human and mammalian cell lines are utilised. A clastogen is a mutagenic agent giving rise to or including disruption or breakages of chromosomes, leading to sections of the chromosome being deleted, added or re-arranged.

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19
Q

What is a transversion mutation ?

A

o A transversion mutation is when purines have mutated to pyrimidines

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20
Q

WHat is a transition mutation?

A

A transition mutation a purine mutates to the other purine or a pyrimidine mutates to the other pyrimidine.

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21
Q

Why is regulatory testing carried out and what is used for this?

A

All new products are tested for DNA damaging ability using regulators such as FDA and EMA.

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22
Q

What happens if a medicine is found to be DNA damaging in regulatory testing?

A

Blocked in development or discarded by the company.

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23
Q

Outline issues with current in vitro testing approaches to identify cancer and changes in DNA.

A
  • Sensitivity not specificity behind test design
    o Leads to false positives
  • Precautionary, but leads to discarding some potentially safe products
  • Heavy reliance on animals, used to de-risk misleading positive results in vitro.
  • Most In vitro tests use non-human cell lines, producing confusing data.
  • Simple cell models not always relevant to exposed human tissues.
  • Simple single dosing experiments also not reflecting human exposure.
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24
Q

Name some scientific, environmental and ethical reasons why animal replacement science may be stopped.

A
  • Scientific argument – humans are not big mice
  • Economic argument – extremely high costs associated with animal testing
  • Ethical concerns- broadly speaking, public opinion wants to reduce animal testing
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25
Q

How does in vitro testing identify any chemicals which may cause genetic damage.

A

In vitro, we can assess intrinsic cell factors. Any deviations from linear should be exacerbated in vivo due to excretion, detoxification etc.

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26
Q

Outline the linear dose methods to assess genetic damage that medicines / chemicals may cause.

A
  • Regulatory agencies are conservative and label any substance producing a positive result in a test as a genotoxin.
  • This is part of the ‘precautionary principle’ aimed at protection populations for DNA threats.
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27
Q

What is the purpose of standardising toxicology testing?

A

Standardising in vitro toxicology testing means that results are kept the same worldwide

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28
Q

What are the limitations of using the linear dose method to assess how genetically damaging some chemicals can be.

A
  • But, may be overcautious and may lead to many new drugs not making the market.
  • Tests often done at high doses, rather than at exposure doses.
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29
Q

Why must we be realistic in terms of dose when testing possibly harmful chemicals using the linear dose method.

A

Almost any compound can be found to be positive ina mutagenicity test if a high enough dose is used. This would be the case with salt and sucrose.

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30
Q

What types of cancer are likely to form due to over consumption of alcohol?

A

Larynx, Oesophagus, Oral cavity, Pharynx or Liver

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31
Q

What types of cancer are likely to be prevented due to diets that are high in fruit or vegetables?

A

bladder, cervix, pancreas, oesophagus, larynx, prostate, stomach, colorectal, lung and breasts

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32
Q

What type of cancer does a high fibre diet protect against?

A

Colorectal

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33
Q

How and why does obesity increase the risk of cancer?

A

Obesity influences the levels of a number of growth factors (IGF-1, insulin, leptin) which can promote the growth of cancerous cells.

Sex steroid hormones, some of which are synthesised in the adipose tissue, can be at increased levels and play a role in some cancers.

Elevated concentrations of a number of inflammatory biomarkers. Chronic inflammation is a conducive environment for cancer to develop and progress.

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34
Q

What are the WCRF recommendations for cancer prevention?

A
  1. Be as lean as possible within the normal range of body weight
  2. Be physically active as part of everyday life
  3. Limit consumption of energy-dense foods; avoid sugary drinks
  4. Eat mostly foods of plant origin
  5. Limit intake of red meat; avoid processed meat
  6. Limit alcoholic drinks
  7. Limit consumption of salt; avoid mouldy cereals (grains) or pulses (legumes)
  8. Aim to meet nutritional needs through diet alone (i.e. without dietary supplements)
    Also:
  9. Mothers to breastfeed; children to be breastfed
  10. Cancer survivors should follow same recommendations
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35
Q

What are the types of DNA damage associated with Alkylating agents?

A

Direct reversal

36
Q

What are the types of DNA damage associated with X-ray, oxygen radicals and spontaneous reaction.

A

Single strand break repairs

Base excision repair

37
Q

What are the types of DNA damage associated with UV light and polycyclic aromatic hydrocarbons

A

Nucleotide excision repairs ( global genomic repair and transcription coupled repair).

38
Q

What are the types of DNA damage associated with replication errors.

A

Mismatch repairs

39
Q

What are the types of DNA damage associated with IR, UV light, X-rays, Hydroxyurea and Anti-tumour agents?

A

DSB repair (Non-homologous end joining and homologous recombination.

Checkpoint signalling leading to cell cycle arrest.

40
Q

IS 7MeG DNA damage via alkylating agents an issue?

A

It is structurally less of an issue than other adducts and can be tolerated within the cell.

41
Q

Are 1MeA and 3MeA DNA damages caused by alkylating agents an issue?

A

If a 1MeA or 3MeA not repaired, can block DNA replication and result in cell death. Or tolerance mechanisms can occur that can result in mutation

42
Q

What is OMeG and how does it affect DNA and what can happen if it is not repaired?

A

OMeG is a mutagenic lesion. If it is not repaired it can mis-pair with thymine when replicated and produce GC-TA transversion mutations.

43
Q

WHat is the repair mechanism for OMeG.

A

MGMT DNA repair protein specifically repairs OMeG. The mechanism is by direct transfer of methyl group to active site cysteine residue in the protein. This causes inactivation of the protein. A single protein is utilised to repair each single lesion. This is energetically expensive for the cell to do and highlights the importance of repairing this lesion.

Because of the significance of this DNA damage lesion, a costly repair system has evolved through direct reversal of damage by methylguanine DNA methyltransferase (MGMT)

44
Q

Define the term mutagen.

A

is an agent [physical or chemical] that can cause/induce changes to the genetic material of an organism and thus increase the frequency of mutations above the natural rate.

45
Q

Define the term carcinogen.

A

is a substance that promotes carcinogenesis [formation of cancer]. Some carcinogens exert their effects through altering the genetic material of an organisms, so some carcinogenic agents are also mutagenic

46
Q

Define the term clastogen

A

is a mutagenic agent that causes breakage or disruption of chromosomes. This leads to section of chromosomes being added, deleted or rearranged.

47
Q

Define the term Aneugen

A

is a substance that causes a daughter cell to have an abnormal number of chromosomes. Simply put, they cause aneuploidy.

48
Q

Which global agency endeavours to collate and report on research relating to cancer and carcinogens and how is data disseminated?

A

The World Health Organisation [WHO], through different agencies. The key one being the International Agency for Research on Cancer [IARC]. The main source for dissemination is through annual reports on broad and sometime specific topics relating to cancer. For example, IARC monographs on carcinogens.

49
Q

Cancer is a genetic disease. How do mutations in some genes cause some people to have a genetic pre-disposition to cancer?

A

Give one example of such.- for cancer to develop a series of mutations need to build up within a cell that cause specific actions of the cell to be changed [eg, cell cycle progression etc]. People with a pre-disposition to cancer already possess mutations in their genomes that speed up the process of cancer progression. A generic example of such predisposition is if someone has a reduced DNA repair system, which then increases the rate of mutation accumulation and increases the chances of developing deleterious mutations in important genes related to cell growth and development [a specific example being mutations MLH1 and other mismatch repair genes cause HNPCC].

50
Q

Cancer is a genetic disease. What is the current thinking regarding how a chemical that is classified as a carcinogen, exerts such influence on a cell?

A

Current thinking states that prolonged exposure to a chemical carcinogen can promote cancer progression through gradual accumulation of DNA damage resulting in increased mutation frequency

51
Q

What are the two most common type of exogenous chemical carcinogens humans will most likely come into sustained contact with during their lifespan and how do these chemicals exert their mutagenic effect?

A

Polycyclic Aromatic Hydrocarbons [PAH] and Aromatic Amines [AA]. This is due to their natural occurrence in smoke [PAH] and cooked foodstuffs [meat cooked at high temperature results in breakdown of proteins and AA production]. Additionally, PAHs are produced in tobacco smoking, so individuals can be exposed directly through smoking or through secondary smoke. Most prevalent and studied PAH is benzo[a]pyrene, which is endogenously metabolized to active carcinogenic variants. PAHs and AAs have the ability to inter-chelate between base pairs in DNA and to increase the error rate of DNA polymerase when replicating the DNA. Typically they causes GC-TA transversions.

52
Q

Define the term genetic toxicology and explain why it is an important process.

A

this is the study of substances that can damage the genetic material of an organism and cause mutations, cancer and birth defects. It is an important process as it allows the identification of potential mutagenic and carcinogenic substances that can inform many aspects of life related to human health. Some examples being: H&S in the workplace [or anywhere- reduced exposure and risk], labelling in foodstuffs, development of new drugs, testing of any product that the public will be exposed to in some way.

53
Q

What national and international agencies exist that engage in regulatory genetic toxicology testing and application/ implementation of scientific findings?

A

Food and Drug Administration [FDA] in the USA, European Medicines Agency [EMA]…..additionally, the Organisation of Economic Co-operation and Development [OECD] countries have standardized guidelines for carrying out a number of genetic toxicology tests, which are published on their website.

54
Q

Give 2 examples of wet-lab tests routinely used in genetic toxicology labs. In a few sentences, outline the salient features of how these tests work.

A

Ames test. This is a bacterial test that relies on a strain of Salmonella that is auxotrophic [can’t make its own, need to supply in the medium or won’t grow] for the amino acid histidine. When exposed to a mutagenic agent the rate of reversion to histidine prototrophy [can now make its own His] will be increased over the natural reversion rate. ii) Micronucleus assay. This is a mammalian cell-based assay [various cell types have been utilized], and involves the addition of the test chemical to actively growing mammalian tissue culture cells and monitoring the appearance of fractionated chromosomes and/or nuclei.

55
Q

What is the best strategy a genetic toxicology lab can employ to characterize and assess the toxicology of a chemical?

A

No toxicology test is capable of monitoring the accumulation of all types of DNA damage caused by chemicals. Hence, the best approach is to employ a battery of different toxicology test to ensure, as much as possible, all ranges of DNA damage and hence potential mutagenic outcomes, are detected.

56
Q

What are some of the key issues/problems with current methods for assessing genetic toxicity of chemicals?

A

Issues with false positives as tests are very sensitive rather than specific. The precautionary nature of the process can lead to possibly “safe” products/substances being pulled from further production due to being genotoxic. Can get confusing/conflicting results in some assays due to inconsistency in cell lines being used. Cell assay results are not always translatable to whole organism. Still heavily reliant on animal studies as the final testing point.

57
Q

Outline the way/routes where the human population may become exposed to exogenous chemical carcinogens.

A

Humans are exposed to exogenous chemicals during their everyday lives. This can be through the workplace, through smoking [primary or secondary], food consumption [depending on someone’s diet the levels of exposure will be variable and specific to the individual], drinking alcohol.

58
Q

What is the current thinking for how obesity increases cancer risk?

A

Obesity has been shown to increase the expression levels of growth factors [such as IGF-1, insulin, leptin], which can promote cancer cell growth. Also, increased expression of sex hormones, which can play a role in promoting some cancers. Importantly, seems obesity is seen as a chronic inflammatory response by an organism due to the increase of NFkappaB levels. There is a link between chronic inflammation and cancer progression and it seems that many of the risk factors in cancer progression seem to increase NFkappaB levels, so may be the common link perhaps?

59
Q

Name some occupations were employees are potentially more at risk of cancer development. What type of cancers are more and why, and how can risk be reduced in such circumstances.

A

Obesity has been shown to increase the expression levels of growth factors [such as IGF-1, insulin, leptin], which can promote cancer cell growth. Also, increased expression of sex hormones, which can play a role in promoting some cancers. Importantly, seems obesity is seen as a chronic inflammatory response by an organism due to the increase of NFkappaB levels. There is a link between chronic inflammation and cancer progression and it seems that many of the risk factors in cancer progression seem to increase NFkappaB levels, so may be the common link perhaps?

60
Q

Why have so many different DNA repair systems evolved in cells?

A

No DNA repair system can repair all types of DNA damage [some can repair more than one type]. Simply, many DNA repair systems have evolved to allow the efficient repair the many types of DNA damage that can occur in the cell [whether arising from exogenous or endogenous processes].

61
Q

What are the possible outcomes for a DNA damage lesion within a DNA molecule and subsequently for the cell, containing the lesion?

A

A DNA lesion could be repaired or not repaired [if the cell is overwhelmed by damage, some lesions may not be repaired]. If a lesion is repaired, there are no adverse outcomes for the cell. If lesions are unrepaired this can lead to cell death [necrosis], programmed cell death [apoptosis] or can lead to mutations being induced to the genetic material, which if this caused functional changes in important proteins associated with cancer progression, could result accumulation of mutations that promote cancer progression. Do bear I mind that not all mutations will cause a major problem to protein function, so sometimes no big consequences for the cell in certain mutations are maintained.

62
Q

Why is it more important to repair some types of DNA damage compared to others? Give one example to demonstrate and support your answer.

A

Some types of DNA damage can be relatively well tolerated by the cell [eg, 7-MeG], others if not repaired [eg, 1MeA or 3MeA] can block DNA replication and cause cell death. Some DNA damage results in mutation accumulation so needs to be prioritized for repair- eg of this is O6-Me-G, which if not repaired [by MGMT protein] can result in GC-TA transversion mutations at a high rate.

63
Q

What are the 4 non-covalent bonds that dictate the protein folding process? List then in terms of their relative strength - strongest to weakest.

A

Ionic, Hydrogen, Van der Walls, Dipole-Dipole (hydrophobic).

64
Q

What part of the generic amino acid dictates the chemical properties ?

A

The R side chain characterizes the size, polarity and pH for each type of amino acid.

65
Q

With the aid of a diagram show how a peptide bound is formed between two amino acids. (2 marks)

A

In notes.

66
Q

Draw the structure of an amino acid.

A

In notes

67
Q

In terms of structure, which amino acid is the simplest and why?

A

Glycine. The R group of Glycine is a hydrogen.

68
Q

Give an example of a hydrophobic amino acid and draw it.

A

Glycine

69
Q

Draw and name an example of a basic amino acid.

A

Lysine
Arginine
Histidine

70
Q

Drawn and name an example of an acidic amino acid.

A

Aspartic acid

Glutamic acid

71
Q

Which amino acids can form ionic bonds?

A

Amino acids with charged amino acid side chains (‘R regions’) can form ionic bonds with amino acids of oppositely charged side chains.

72
Q

Name the amino acids that will have a tendency to cluster on the inside of protein 3D structures? Why is this so?

A

Hydrophobic amino acids are likely to be clustered inside of a 3D protein. Their hydrophobic qualities are caused by aliphatic side chains which are insoluble or only slightly soluble in water. This causes the amino acid forces to repel away from the aqueous environment of the cell

73
Q

Which amino acid is capable of forming disulphide bridges? (1 mark) Why is a disulphide bridge significant in terms of formation of 3D protein structure? (1 mark)

A

Cysteine.
Disulphide bonds are important post-translational modifications of proteins. They stabilize the 3D tertiary structure of proteins by allowing different parts of the protein side chains to be held together covalently. They also have catalytic regulatory functions.

74
Q

What are the four stages of protein structure/folding? Briefly provide a maximum of two sentences describing these stages (4 marks)

A

a) Primary – sequence of amino acids in a polypeptide chain.
b) Secondary – formation of alpha helices and beta pleated sheets within a polypeptide chain due to interactions between ‘R groups’ of amino acids within the polypeptide chain. This is stabilized by hydrogen bonds.

c) Tertiary – The overall three dimensional structure of a polypeptide. Uses hydrogen bonding, ionic bonding, dipole-dipole interactions and London dispersion forces/ Van der walls.
d) Quaternary – When prosthetic groups are added to the protein or multiple polypeptide chains join together. Each subunit has its own primary, secondary and quaternary structure. Held together by hydrogen bonds and van der walls forces between non-polar side chains.

75
Q

Assuming the mutation is located in an important structural region of a hypothetical protein. Summarise what consequences (minor or major, and functionality) ma occur if the following mutation occurred … Glycine to Alanine

A

Glycine is the simplest amino acid. If this was changed to Alanine, the change would only be minor. This is the case because the amino acids are very similar sizes so the overall structure of the protein would change very little.

76
Q

Assuming the mutation is located in an important structural region of a hypothetical protein. Summarise what consequences (minor or major, and functionality) ma occur if the following mutation occurred … Glycine to Tryptophan.

A

If Glycine is change to Tryptophan, which is one of the largest amino acids, major changes will be caused because the structure of the protein will change significantly.

77
Q

Assuming the mutation is located in an important structural region of a hypothetical protein. Summarise what consequences (minor or major, and functionality) ma occur if the following mutation occurred … Lysine to Arginine.

A

Lysine is slightly bigger than arginine by CH3. The structural difference is small and the charge hasn’t changed ( still positive). This means ionic bonds can still be made and the change is minor.

78
Q

Assuming the mutation is located in an important structural region of a hypothetical protein. Summarise what consequences (minor or major, and functionality) ma occur if the following mutation occurred … Lysine to Aspartic Acid.

A

Aspartic acid is negatively charged whereas Lysine is positively charged. Ionic bonds made with the initial Lysine will no longer be made and repulsion will occur. Major change.

79
Q

Assuming the mutation is located in an important structural region of a hypothetical protein. Summarise what consequences (minor or major, and functionality) ma occur if the following mutation occurred … Aspartic acid to glutamic acid.

A

Minor change.
Both have negative charge so ionic bonds still made.
Very little structural change.

80
Q

Assuming the mutation is located in an important structural region of a hypothetical protein. Summarise what consequences (minor or major, and functionality) ma occur if the following mutation occurred … Glutamic acid to Lysine.

A

Glutamic acid has a negative charge whereas lysine has a positive charge. This is a major change as the same ionic bonds can no longer form.

81
Q

Assuming the mutation is located in an important structural region of a hypothetical protein. Summarise what consequences (minor or major, and functionality) ma occur if the following mutation occurred … Cysteine to Alanine.

A

Very little structural change. Cystein can form disulphide bridges. If an important Cysteine was changed to Alanine, disulphide bridges won’t form and this could affect the overall structure of the protein.

Un-imporant cysteine - minor.
Important Cysteine - major

82
Q

What are the main purpose of Kinases?

A

Phosphorylate other molecules.

83
Q

What is the main purpose of phosphatases?

A

Remove phosphate molecules from other molecules.

84
Q

What may be the consequence of the following mutation in a protein molecule?
- Serine or theronine or tyrosine mutated to Alanine.

A

These 3 amino acids are phosphorylated by kinases. Alanine cannot be phosphorylated. So if one of these molecules is mutated to alanine, phosphorylation will not occur. The protein/ molecule won’t be activated and the signalling cascade that the alanine is within will be terminated.

85
Q

What may be the consequence of the following mutation in a protein molecule? Serine or threonine or tyrosine mutated to glutamic or aspartic acid?

A

Aspratic acid can be phosphorylated. However, it cannot be dephosphorylated so the signalling will be constant and could cause possible harm.

86
Q

What is meant by Aspartic Acid being phosphomimetic?

A

Phosphomimetics are amino acid substitutions that mimic a phosphorylated protein, thereby activating (or deactivating) the protein.

87
Q

Name a phosphomimetic molecule.

A

Aspartic acid

Y3 Biology Of Cancer (8 decks)

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