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PATH3309 > 5. Carcinogenesis > Flashcards

5. Carcinogenesis Flashcards

1
Q

What proportion of cancers are related to smoking and alcohol?

A

1 in 9 cancers - smoking (1 in 5 deaths)

3% - alcohol

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2
Q

Do we know the cause of most cancers?

A

Nope, most causes are unknown

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3
Q

How are carcinogens identified?

A

Human studies
Animal Studies
Lab Studies

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4
Q

What carcinogens are there?

A

Viruses
Radiation
Inherited familial syndromes
Diet

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5
Q

What is a tumor initiator?

A

Something that causes transformation of normal cells into tumor cells

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6
Q

What are some examples of tumour initiators?

A

X-rays
UV light
DNA alkylating agents

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7
Q

What is a tumor promoter?

A

A proliferation inducer

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8
Q

What are some examples of tumor promoters?

A

Phorbol Esters (croton oil)

Inflammation (Hepatitis)
Estrogens + Androgens
EBV

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9
Q

What types of oncogenic radiation are there?

A 
Ultraviolet
X-ray
Radioisotopes 
Nuclear fallout
Background radiation
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10
Q

How does radiation impact oncogenesis?

A

Direct effect on DNA

Activation of cellular oncogenes

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11
Q

Why do Australians have the highest incidence rate for skin cancers globally?

A
  1. Attitude
  2. Genes - inherited - mutated
  3. Geological Circumstance = unlikely
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12
Q

How does UV radiation damage DNA?

A

Induce covalent bonds between pyrimidines
Bends helix
Polymerase can no longer read DNA template

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13
Q

What cancer is UVB light the principle cause of?

A

Squamous cell carcinoma
Basal cell carcinoma
Malignant melanoma

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14
Q

What type of UV light is the principle cause of cancer?

A

UVB SPF sunscreens block

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15
Q

Can UV light penetrate deeper than the skin?

A

No
UVA = acellular dermis
UVB = basal layer of epidermis
UVC = superficial skin

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16
Q

What did early use of X-rays cause?

A

Skin cancer
Leukemia
Papillary thyroid cancer

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17
Q

How long is radiation induced malignancy lag?

A

10-30 yrs

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18
Q

What increased risk is associated with diagnostic X-rays, if any?

A

Not much at all

Except in abdominal x-rays and fetal exposure - increased incidence of leukemia

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19
Q

When was the first link between radiotherapy and cancer established?

A

Around 1965 when paper released showed link between Ankylosing Spondylitis and Leukaemia

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20
Q

What cancer type is commonly associated with radiotherapy?

A

Sarcomas

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21
Q

What type of cancer is common among workers using radium-containing paints?

A

Osteosarcoma

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22
Q

Radioactive mineral mining is associated with…

A

Lung cancer

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23
Q

Thorium increases risk of?

A

Hepatocellular
Angiosarcoma
Cholangiocarcinoa

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24
Q

What are some potential radioactive isotopes that cause cancer?

A

Radioactive iodine (I131) = thyroid cancer

Radioactive phosphorous (P32) = AML

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25
Q

Where is radioactive iodine (I 131) found?

A

Nuclear energy
Medical diagnostics
Natural Gas production
Nuclear fission

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26
Q

When does cancer typically develop after exposure to radioactive iodine (I 131)?

A

15 - 25 years later (Chernobyl)

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27
Q

What risk did a 1.0 GY exposure to radiation result in?

A

50% increase cancer risk

28
Q

What was the first cancer associated with atomic bomb radiation (within 5 yrs)?

A

Leukaemia

29
Q

What co-factor is a key activator of carcinogens?

A

Cytochrome P450

30
Q

What accounts for individual differences in responses to carcinogens?

A

Genetic polymorphisms

31
Q

How does tumour initiation occur via chemical carcinogens?

A

DNA-adduct derived mutations in cancer susceptibility genes

Benzo[a]pyrene binds DNA
Induces base pair / frame shift mutation

Nucleotide Excision repair (NER) inhibition

32
Q

How does tumor promotion occur via chemical carcinogens?

A

Arylhydrocarbon receptor (AhR) mediated signal transduction

33
Q

Describe the process of tumor promotion in terms of benzo[a]pyrene and aryl-hydrocarbon receptor (AhR)

A

Benzo[a]pyrene binds arylhydrocarbon receptor and translocates to nucleus

AhR heterodimerises with AhR nuclear translocator (ARNT)

Complex binds xenobiotic responsive elements (XREs)

This induces expression of genes involved in carcinogen metabolism
Changes expression of cellular growth and differentiation factors

34
Q

What are the mode of actions Chemical carcinogens take in cancer formation?

A 
Induce change in DNA
Base alkylation, deletion, breakage, cross-linkage
Epigenetic mechanisms
Synergistic action with viruses
Promoter for other carcinogens
Potency: varies with carcinogen
35
Q

Why is it difficult to identify a specific carcinogen?

A

Many carcinogens in low levels everywhere

Exposed to large numbers of chemicals in lifetime

Long lag phase

36
Q

What cancer is Benzidine associated with?

A

Bladder Cancer in dye industry

37
Q

What is an example of a polycyclic Aromatic Hydrocarbon and what type of cancer does it cause?

A

Benzo[a]pyrene, gardeners and chimney sweeps

Enough S’nuff - Sot weed factor

Coal Tar

38
Q

What is Benzo[a]pyrene found in?

A

Coal tar
Cigarette smoke
Well-cooked meat
“Pro-carcinogen” - metabolites mutagenic

39
Q

How does benzo[a]pyrene damage DNA?

A

Intercalates DNA
Disrupts DNA copying

Specifically targets p53 gene

40
Q

What % of cancers does smoking cause?

A

20-30%

41
Q

How many cancers p/a in australia?

A

12,000

42
Q

How many carcinogenic chemicals in cigarettes?

A

> 60

43
Q

What is asbestos?

A

Naturally occuring fibrous material

44
Q

What does asbestos induce?

A

Mutagenicity
Chromosomal alterations
Aneuploidy

45
Q

What cancer is asbestos associated with?

A

Lung cancer and mesothelioma

46
Q

What are Aflatoxins?

A

Naturally occuring mycotoxins

Produced by Aspergillus flavus and aspergillus parasiticus

47
Q

What is the most toxic form of aflaoxin?

A

B1 - liver carcinogen

48
Q

What do aflatoxins reside in?

A 
Food
Peanuts
Corn
Grain
Pistachios
49
Q

How do they cause cancer?

A

Absorbed into GI tract
Transported by portal vein to liver - Oxidized by cytochrome P450
Results in error in DNA replication, G-T mutation in p53
Inactivation of tumor supressor genes = Hepatocellular carcinoma

50
Q

What types of cancer does Vinyl chloride cause?

A

Liver angiosarcoma

51
Q

How much evidence is there linking Diet to carcinogenesis?

A

Barely any
Small associations with low-fiber diet and colonic carcinoma
Fatty diet = breast cancer

52
Q

What possible protective agents are there?

A

Beta-carotene
Vitamin C, D, E
Selenium

53
Q

Can lack of nutrients enhance risk of Ca?

A

Yes, folate deficiency related to colorectal carcinoma

54
Q

What cancer risks are associated with obesity?

A

Colon, breast kidney, pancreas

Tumorogenic: Increased tumor promoting cytokines and insulin

55
Q

What portion of alcohol metabolism causes cancer?

A

Acetylaldehyde

56
Q

What cancers are associated with alcohol?

A 
Oesophageal
Pharyngeal
Stomach
Liver
Breast
57
Q

Are endogenous hormones typically initiators or promoters of cancer?

A

Typically initiators

58
Q

What are some hormone-related cancers?

A 
Breast
Endometrium
Prostate
Testis
Thyroid
59
Q

What are the two mechanisms associated with Hormone carcinogenesis?

A

Induction of neoplasia by hormones

Hormonal dependence of neoplasms

60
Q

What type of cancer does Diethylstilbestrol cause?

A

Vaginal and uterine carcinomas

61
Q

What cancers do steroid hormones cause?

A

Hepatic neoplasms

62
Q

What does hormonal dependence mean?

A

Some cancers rely on hormonal stimulation

63
Q

What hormone is breast cancer associated with?

A

Oestrogen

64
Q

How does Oestrogen cause breast cancer?

A
  1. Error in DNA replication
    • Oestrogen promoting rapid prolif
    • no time for DNA repair = errors
  2. Oestrogen metabolites are genotoxic
    • Oestradiol induces DNA mutations
      - Increased susceptibility with BRCA mutations
65
Q

What genetic aberrations can contribute to cancer?

A

Somatic mutations occur often
Inherited germline mutations occur in rare familial cancers
Aneuploidy occurs often

66
Q

What are the phases of the multi-step hypothesis?

A

Initiation = First event
Promotion = Subsequent events
Multiple hits occur, producing change in genome
Lag period

PATH3309 (14 decks)

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