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[ONCG2003] Colorectal Cancer & Ovarian Cancer > 6b: Mutagenesis In Cancer > Flashcards

6b: Mutagenesis In Cancer Flashcards

1
Q

Fill in the blanks:
Despite repair mechanisms, the mutation rate in normal tissue is ______ mutations per base per cell division.
Every time a cell divides, there are _____ base changes.

A

1) 1 x 10^-9
2) 3

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2
Q

What is intrinsic mutation rate increased by?

A

Failure to:
- detect mutations
- correct mutations
- induce apoptosis

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3
Q

Failure to detect mutations is associated with what dysfunctional genes?

A

POLD1, POLE
(Mismatch repair deficiency genes)

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4
Q

The mutation of which gene is associated with failure of apoptosis induction?

A

TP53

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5
Q

Failure of which genes is associated with failure of the repair of double and single strand breaks, respectively?

A

Double: BRCA2
Single: PARP

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6
Q

What is extrinsic mutation rate increased by?

A
  • Chemical carcinogens
  • Physical carcinogens (Eg radiation)
  • Viral factors
  • Bacterial
  • Parasitic infection
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7
Q

By which 2 mechanisms can viruses increase the rate of mutation?

A
  • Inserting into the promoter region of oncogenes, increasing their activity
  • By producing proteins which negate/mimic activities of endogenous proteins
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8
Q

How may parasitic infection increase rate of mutation in tissues indirectly?

A

Via chronic inflammation, which increases tissue turnover.

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9
Q

Fill in the gaps:
The ______ in the _____ region of the provirus, _____ of the c-Myc gene, ______ c-Myc expression. Enhancers are ___-directional.

A

1) enhancer
2) 5’LTR
3) upstream
4) enhances/increases
5) bi

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10
Q

Outline how the HPV virus can lead to increased risk of cancer via E6/7

A

HPV can insert into the E6/E7 genes, disrupting their function.
E6:
- causes ubiquitinaion of P53, therefore degrading the protein, meaning it fails to carry out its function (induction of apoptosis and cell cycle arrest)
- leads to unctrolled cell proliferation and resistance to cell death
E7:
- disruption of E7 activity results in the release of E2F from pRB. E2F can affect activity of S-Phase cyclin genes (CYclin A/E)
- leads to unrestricted entry into S phase

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11
Q

How does human gut E. coli increase risk of carcinogenesis

A

induces double strand breaks via alkylation (addition of adducts) of DNA

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12
Q

What is schistosomiasis and how does increase risk of cancer?

A

A parasite which imbeds into the bladder, causing chronic inflammation.
Thisinduces metaplasia of transitional to squamous epithelium.
Commonly associated with squamous epithelium cancer

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13
Q

How may non-genotoxic mechanisms of injury contribute to risk of cancer?

A
  • cause tissue damage, increasing proliferative activity
  • chemical stimulation of proliferation through signalling activity
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14
Q

Fill in the gaps:
Increased proliferation increase the risk of _____ mutation and _____ _____ production due to enhanced _____.
Chemicals may also directly stimulate proliferation through activation of _____ ______.

A

1) spontaneous
2 & 3) free radical
4) metabolism
5 & 6) signalling pathways

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15
Q

How may genotoxic carcinogens cause mutations:
- directly
- indirectly

A

Direct: DNA damaged caused directly by carcinogen
Indirect: caused by other molecules induced/altered by carcinogen, eg free radicals.

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16
Q

The balance between what factors determines the rate of mutation?

A
  • Severity of DNA damage
  • Efficiency of repair mechanisms
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17
Q

What are some examples of organic chemical carcinogens?

A

Aflatoxin B1
Benzo(a)pyrene
Methyl-nitrosourea

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18
Q

What are some examples of inorganic chemical carcinogens?

A

Heavy metals - cadmium, chromium, arsenic

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19
Q

What are 4 types of chemical carcinogens?

A
  • organic
  • inorganic
  • inert fibres/particles
  • hormones
20
Q

What is an example of an inert fibre/particle that acts as a chemical carcinogen, and why?

A

Asbestos
Body cannot remove/breakdown the particles, so they are constantly causing neoplasia.
They induce cell proliferation and free radicals

21
Q

What are 2 examples of carcinogenic hormones

A

Tamoxifen - synthetic
Testosterone

22
Q

What cancer are specifically associated with the below carcinogens:
- smoking
- aflatoxin B1
- aniline dyes
- vinyl chloride

A
  • smoking: lung
  • aflatoxin B1: liver
  • aniline dyes: bladder
  • vinyl chloride: hepatic angiosarcoma
23
Q

Why may naturally occurring metabolic pathways convert pro-carcinogens into carcinogens? Give an example

A
  • Pathways used to detoxify chemicals (eg phase I/II enzymes in liver) may activate pro-carcinogens
  • Organic chemicals directly act due to active functional groups, and these pathways can activate the pro-carcinogens
24
Q

How do free radicals cause genotoxicity?

A

Free radicals can cause
- Hydroxylation (eg of guanine -> 8-hydroxyguanosine)
- Loss of bases to produce a basic sites
- DNA strand breaks (single and double)

25
Q

How can the addition of DNA adducts cause genotoxicity

A
  • adducts are caused by covalent bonding of carcinogen to DNA bases
  • addicted can lead to mutation during replication
  • nature of adduct can dictate subsequent mutations
26
Q

What are 2AAF and 2AF. How do they differ and what do they cause?

A
  • 2AAF: acetylaminoflurine.
    Adducts intercalate within DNA and cause frame shift mutations
  • 2AF: aminoflourine
    Intercalates in external part of helix, causes transversion mutations

Differ by the presence of only a single carbonyl group
Leave different mutational signatures

27
Q

What mutation in what codon is aflatoxin B1 associated with in liver cancer?

A

G-to-T transversion in codon 249 of p53

28
Q

How can smoking induce both direct and indirect genotoxic damage?

A
  • Chemical carcinogens in smoke cause DNA adduct formation
  • Heat from smoke causes local trauma to oesophagus/lungs, followed by proliferation.
  • There is metaplasia of columnar epithelium to squamous cell.
29
Q

What is the predominant form of damage caused by radiation?

A

Indirect damage due t formation of free radicals and reactive oxygen species

30
Q

What are the 4 ways to classify radiation?

A
  • Particulate, eg neutrons, a-particles
  • Electromagnetic, eg x-rays, g-rays
  • Ionizing, cause ejection of electron from atomic orbit
  • Non-ionizing, eg UV light, low energy causing electronic excitation
31
Q

What are some examples of ionizing and non-ionizing radiation?

A

Ionizing: X-rays, g-rays, a-particles, neutrons
Non0-ionizing: UV, microwave, RF radiation, ultrasound, electric and magnetic fields (EMF)

32
Q

What is the eV of ionizing and non-ionizing radiation?

A

Ionizing: >10-15eV
Non-ionizing: <10eV

33
Q

What does expose to UV commonly do to the structure of DNA?

A
  • formation of pyramiding (C/T) dimers
34
Q

T or F:
Pyramidine dimers induced by UV radiation only form within the same strand

A

F: can cross link within strands OR dimerisation across strands

35
Q

Which repair pathways repairs damage caused by UV radiation?

A

Nucleotide excision repair (repairs C to T transitions at pyramidine sites)

36
Q

What factors must be considered when assessing the relationship between radiation and carcinogenesis?

A
  • dosage and nature of radiation
  • site of exposure
  • underlying efficiency of damage repair
  • tissue specific sensitivity to radiation damage
37
Q

What are some examples of cancers that are:
- sensitive
- moderately sensitive
- resistant
To radiation?

A
  • sensitive: thyroid, breast, blood-forming tissues
  • moderately sensitive: lung, colon, liver, pancreas, lymphatic system
  • resistant: kidney, bone, skin, salivary gland, brain
38
Q

Fill in the blanks:
Chemicals and _____ can cause consistent changes to the DNA _____.
This is called _____ _____.

A

1) radiation
2) sequence
3 & 4) mutational signatures

39
Q

T or F:
- POLE mutations result in failure to detect mutations during DNA synthesis
- Mismatch repair mutations fail to correct SSBs
- BRCA2 mutations result in failure to correct indels

A
  • T
  • F: PARP not MMR
  • F: DSBs not indels
40
Q

How can HOV promote carcinogenesis

A

Degradation of Rb proteins

41
Q

T or F
- Schistosoma infection of the bladder can cause transitional cell carcinoma
- Some E. coli bacteria produce colibactin carcinogen
- Both E. coli and Aspergillus fungus produce colibactin

A
  • F: bladder, squamous epithelium
  • T
  • F: aphlotoxin not fungus
42
Q

Which is correct: Non-genotoxic mechanisms of mutagenesis:
A) inducemutations by inhibiting DNA repair
B) never cause DNA damage
C) may induce proliferation and produce damaging metabolic by-products
D) always cause metaplastic change

A

C

43
Q

Which is correct: Genotxic mechanisms of mutagenesis:
A) May induce DNA damage
B) May induce indirect DNA damage
C) Occur in both radiation and chemical induced mutagenesis

A

All are correct

44
Q

Which of the following pairing of toxin and cancer is correct?
A) Smoking - colorectal
B) Aniline dyes - hepatic
C) Vinyl chloride - bladder
D) Aflatoxin B1 - liver

A

D

45
Q

Which are correct:
- DNA adducts are a firm of direct genotoxicity
- Aflatoxin B1 is associated with P53 mutations in liver cancer
- Liver enzymes may convert chemicals into carcinogens

A

2 and 3

46
Q

Which one of the following is ionizing radiation:
A) UV light
B) Ultrasound
C) a-particles
D) electric fields

A

C

47
Q

Which of the following is correct regarding mutation signatures induced by UV light:
A) Pyrimidine dimers are common
B) Apurinic sites are common
C) They are commonly seen in oesophagael squamous cell carcinoma

A

A

[ONCG2003] Colorectal Cancer & Ovarian Cancer (7 decks)

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