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EMS - MoD > 20. Carcinogenesis - causes of cancer > Flashcards

20. Carcinogenesis - causes of cancer Flashcards

1
Q

Give some examples of occupational carcinogens

A
  • cadmium and nickel
  • radon (mining)
  • solvents and preservatives (painters and furniture makers)
  • tannins (leather footwear manufacture)
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2
Q

Give examples of chemical carcinogens

A
  • PAHs

- nitrosamines

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3
Q

Give examples of infectious agents as carcinogens

A
  • HPV

- H. pylori

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4
Q

Give examples of radiation as a carcinogen

A
  • UV light

- radon

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5
Q

Give examples of mineral carcinogens

A
  • asbestos

- heavy metals

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6
Q

Give examples of physiological carcinogens

A
  • oestrogen

- androgens

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7
Q

What are the carcinogens involved in chronic inflammation?

A
  • free radicals

- growth factors

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8
Q

There is a very wide variety of agents implicated in carcinogenesis. What do they all have in common?

A

Prolonged exposure to each of these agents can lead to the accumulation of genetic alterations in clonal populations of cells

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9
Q

Which organ does aflatoxin target?

A

Liver

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10
Q

Which organs does alcohol target?

A

Pharynx, larynx, oesophagus, liver

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11
Q

Which organ does asbestos target?

A

Lung pleura

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12
Q

Which organ do X-rays target?

A

Bone marrow (leukaemia)

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13
Q

Which organ does UV light target?

A

The skin

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14
Q

Which organ does oestrogen target?

A

Breast

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15
Q

Which organs does tobacco smoke target?

A

Mouth, lung, oesophagus, pancreas, kidney, bladder etc

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16
Q

Which organ does HBV (hepatitis B virus) target?

A

Liver

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17
Q

Which organ does HPV (human papilloma virus) target?

A

Cervix

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18
Q

Carcinogen can also by non-genotoxic. What does this mean?

A

Induce proliferation and DNA replication

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19
Q

What is an INITIATOR?

A

A carcinogen that can modify or damage DNA (genotoxic)

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20
Q

What is a PROMOTER

A

A carcinogen that can induce proliferation and DNA replication (non-genotoxic)

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21
Q

What is a “complete” carcinogen?

A

A carcinogen that can both initiate and promote. eg. UV light

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22
Q

What does mutation induction (initiation) require?

A
  • chemical modification of DNA

- replication of modified DNA and mis-incorporation by DNA polymerase

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23
Q

DNA polymerases make mistakes at a very low but significant rate. What does this result in?

A

Accumulation of genetic variation or polymorphisms in coding and non-coding sequences in the genome. Some of these changes are deleterious (mutations)

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24
Q

How might chemical modification of the nucleotides involved in base-pairing occur?

A

Through environmental insult or through the action of endogenous reactive molecules such as free radicals produced by normal physiological processes

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25
Q

Agents that are good promoters contribute to carcinogenesis in 2 important ways. What are they?

A
  • stimulate the 2 rounds of DNA replication required for mutation fixation
  • stimulate clonal expansion of mutated cells, which enables the accumulation of further mutations
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26
Q

Give an example to explain the stages of initiation, promotion and progression

A
  • mouse skin tumour model
  • genotoxic initiating agent damages DNA
  • promoting agents fixes damage as a mutation and converts normal cell into mutated initiated cell
  • promoting agent stimulates clonal expansion of initiated cell to produce papillomas
  • further rounds of mutations and clonal expansion allows papilloma to progress to carcinoma
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27
Q

What makes DNA replication a more error-prone process?

A

DNA damage

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

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28
Q

Repeated treatment with promoting agents/ exposure to exogenous or endogenous mutagens can result in what?

A

Gradual accumulation of mutations

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29
Q

Exogenous mutagens are environmental and endogenous mutagens occur naturally within cells. Give examples of the latter

A
  • oxygen radicals

- lipid metabolism byproducts

30
Q

Give some common genetic abnormalities

A
  • base pair substitution
  • frameshift
  • deletion
  • gene amplification
  • chromosomal translocation
  • chromosomal inversion
  • aneuploidy
31
Q

What is a base pair substitution also known as?

A

Point mutation

32
Q

Explain base pair substitutions/point mutations

A
  • smallest change in DNA sequence that can give rise to change in gene function
  • can result in amino acid substitution (missense)
  • or can introduce stop codon resulting in truncated protein product
33
Q

What is a frameshift mutation?

A

Gain or loss of one to several base pairs that results in a shift in the reading frame of a gene transcript

34
Q

What can gene amplification result in?

A

A cell having anything up to a hundred copies of a gene that it would normally only have two copies of

35
Q

How can we illustrate that some chromosomes are present in appropriate numbers/exchange of material?

A

By chromosomal painting

36
Q

Chr 9:22 exchange is a specific translocation. What is it known as and what is it associated with?

A

Philadelphia chromosome

Associated with chronic myeloid leukaemia

37
Q

Chromosomal translocations can result in what?

A
  • genes being moved to a more transcriptionally active region of the chromosome
  • genes being recombined into new gene fusions
38
Q

What is aneuploidy?

A

Any departure from the normal structure or number of chromosomes

39
Q

How many cancer genes have been found with translocations?

A

about 300 of the 500 cancer genes

40
Q

What causes epigenetic inactivation of TSGs? (most commonly)

A

Abherrent methylation of gene promoters (happens in in tumours)

41
Q

Mutations found in oncogenes lead to what?

Mutations found in TSGs lead to what?

A

Mutations found in oncogenes lead to a gain in function

Mutations found in TSGs lead to a loss of function

42
Q

What are direct acting carcinogens?

A

Interact directly with DNA eg. oxygen radicals, nitrosamines, UV light, ionising radiation

43
Q

What are procarcinogens?

A

Require enzymatic (metabolic) activation before they react with DNA eg. aromatic amines, polycyclic aromatic hydrocarbons (PAHs)

44
Q

Are the majority of carcinogens that we ingest direct acting or procarcinogens?

A

The majority are pro carcinogens and require metabolic activation by enzymes that normally function in the detoxification and excretion of toxic chemicals

45
Q

The majority of carcinogens that we ingest require metabolic activation by enzymes that normally detoxify and excrete toxic chemicals. In what way does thin introduce a genetic influence to our sensitivity to cancer?

A

People who activate a particular chemical more efficiently are more likely to get cancer

But those who excrete the activated chemical less efficiently are also more likely to get cancer

46
Q

What are the products in the metabolic activation of benzopyrene?

A

Benzo pyrene

Benzo pyrene 7,8-epoxide

Benzo pyrene 7,8-dihydrodiol

Benzy pyrene 7,8-diol, 9,10-epoxide

Ultimate carcinogen = BPDE

47
Q

What are the enzymes involved int he activation of benzopyrene?

A

P450 mixed function oxidases

Epoxide hydrolase

P450 mixed function oxidases

48
Q

Give a classic example of a pro carcinogen and state how it can be generated

A

Benzopyrene

Can be generated through the combustion of most organic material such as meat, tobacco and fuel

49
Q

BPDE causes mutation in which gene?

A

TP53

seen in this gene in the lung tumours of smokers

50
Q

What are the 4 general stages in DNA damage and repair?

A
  1. Damaging agent
  2. DNA lesions
  3. Repair process
  4. Disease syndrome
51
Q

Give a pathway from carcinogen exposure to cancer

A
  • carcinogen exposure
  • metabolic activation (eg. cytochrome P450s)
  • DNA damage
    (- DNA repair)
  • DNA replication
  • DNA mutation (eg. in proto-oncogene or tumour supressor gene)
  • progression
  • cancer
52
Q

Rather than metabolic activation leading to DNA damage, what else may occur?

A

Detoxification
Excretion

(eg. glutathione S-transferase)

53
Q

At which stages of the pathway from carcinogen exposure to cancer may genetic modulation occur?

A
  • metabolic activation
  • detoxification and excretion
  • DNA repair

(may explain why exposure does not always lead to cancer)

54
Q

Give some defences against carcinogenesis

A
  • dietary antioxidants
  • detoxification mechanisms
  • DNA repair enzymes
  • apoptotic response to unprepared genetic damage
  • immune response to infection and abnormal cells
55
Q

Which cancers is alcohol linked to?

A 
Oral
Oesophageal
Pharynx
Larynx
Breast
Bowel
Liver
(Pancreatic)
56
Q

What is alcohol converted into that can cause DNA damage?

A

Acetaldehyde

57
Q

Alcohol increases levels of which hormones?

A

Oestrogen and testosterone

58
Q

Alcohol increases the uptake of what?

A

Carcinogenic chemicals into cells within the upper GI

59
Q

Alcohol reduces levels of what?

A

Folate, needed for accurate DNA replication

60
Q

Alcohol can kill what?

A

Surface epithelium leading to unscheduled proliferation

61
Q

All of the strongest risk factors for breast cancer are associated with what?

A

Increased exposure to oestrogen - can both stimulate cell division and induce DNA damage

62
Q

Breast cancer risk decreases 20% for what?

A

Risk decreases 20% for each year that menarche is delayed

63
Q

What procedure leads to 90% decrease in risk of breast cancer?

A

Oopherectomy

removal of ovaries

64
Q

What procedure reduces incidence of prostate cancer?

A

Orchidectomy

removal of a testis

65
Q

Which types of chronic inflammation have an association with cancer?

A
  • colitis
  • hepatitis
  • Barret’s oesophagus
  • metaplasia
  • gastritis
  • gallstones
66
Q

Inflammatory response results in a ‘double whammy’. What does this mean?

A
  • DNA damage from release of free radicals by immune cells - initiation
  • growth factor induced cell division to repair tissue damage - promotion
67
Q

Which cell is key in the link between inflammation and cancer?

A

Tumour-associated macrophages (TAMs)

68
Q

What do TAMs release?

A
  • TNFa
  • ROS
  • RNS
69
Q

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are released by TAMS. What do they do?

A

They can act as complete carcinogens, resulting in mutation by damaging DNA and stimulating proliferation through induction of growth factors

ROS can also induce fibroblasts to undergo autophagy, which releases important nutrients that tumour cells can “feed” on

70
Q

TNFa is also released by TAMs. Why does this do?

A

It is a cytokine that induces and maintains the inflammatory response

71
Q

What are TAMS recruited by?

A

Recruited by cytokines released by tumour cells

EMS - MoD (17 decks)

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