6b: Mutagenesis In Cancer Flashcards
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.
1) 1 x 10^-9
2) 3
What is intrinsic mutation rate increased by?
Failure to:
- detect mutations
- correct mutations
- induce apoptosis
Failure to detect mutations is associated with what dysfunctional genes?
POLD1, POLE
(Mismatch repair deficiency genes)
The mutation of which gene is associated with failure of apoptosis induction?
TP53
Failure of which genes is associated with failure of the repair of double and single strand breaks, respectively?
Double: BRCA2
Single: PARP
What is extrinsic mutation rate increased by?
- Chemical carcinogens
- Physical carcinogens (Eg radiation)
- Viral factors
- Bacterial
- Parasitic infection
By which 2 mechanisms can viruses increase the rate of mutation?
- Inserting into the promoter region of oncogenes, increasing their activity
- By producing proteins which negate/mimic activities of endogenous proteins
How may parasitic infection increase rate of mutation in tissues indirectly?
Via chronic inflammation, which increases tissue turnover.
Fill in the gaps:
The ______ in the _____ region of the provirus, _____ of the c-Myc gene, ______ c-Myc expression. Enhancers are ___-directional.
1) enhancer
2) 5’LTR
3) upstream
4) enhances/increases
5) bi
Outline how the HPV virus can lead to increased risk of cancer via E6/7
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
How does human gut E. coli increase risk of carcinogenesis
induces double strand breaks via alkylation (addition of adducts) of DNA
What is schistosomiasis and how does increase risk of cancer?
A parasite which imbeds into the bladder, causing chronic inflammation.
Thisinduces metaplasia of transitional to squamous epithelium.
Commonly associated with squamous epithelium cancer
How may non-genotoxic mechanisms of injury contribute to risk of cancer?
- cause tissue damage, increasing proliferative activity
- chemical stimulation of proliferation through signalling activity
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 _____ ______.
1) spontaneous
2 & 3) free radical
4) metabolism
5 & 6) signalling pathways
How may genotoxic carcinogens cause mutations:
- directly
- indirectly
Direct: DNA damaged caused directly by carcinogen
Indirect: caused by other molecules induced/altered by carcinogen, eg free radicals.
The balance between what factors determines the rate of mutation?
- Severity of DNA damage
- Efficiency of repair mechanisms
What are some examples of organic chemical carcinogens?
Aflatoxin B1
Benzo(a)pyrene
Methyl-nitrosourea
What are some examples of inorganic chemical carcinogens?
Heavy metals - cadmium, chromium, arsenic
What are 4 types of chemical carcinogens?
- organic
- inorganic
- inert fibres/particles
- hormones
What is an example of an inert fibre/particle that acts as a chemical carcinogen, and why?
Asbestos
Body cannot remove/breakdown the particles, so they are constantly causing neoplasia.
They induce cell proliferation and free radicals
What are 2 examples of carcinogenic hormones
Tamoxifen - synthetic
Testosterone
What cancer are specifically associated with the below carcinogens:
- smoking
- aflatoxin B1
- aniline dyes
- vinyl chloride
- smoking: lung
- aflatoxin B1: liver
- aniline dyes: bladder
- vinyl chloride: hepatic angiosarcoma
Why may naturally occurring metabolic pathways convert pro-carcinogens into carcinogens? Give an example
- 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
How do free radicals cause genotoxicity?
Free radicals can cause
- Hydroxylation (eg of guanine -> 8-hydroxyguanosine)
- Loss of bases to produce a basic sites
- DNA strand breaks (single and double)
How can the addition of DNA adducts cause genotoxicity
- 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
What are 2AAF and 2AF. How do they differ and what do they cause?
- 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
What mutation in what codon is aflatoxin B1 associated with in liver cancer?
G-to-T transversion in codon 249 of p53
How can smoking induce both direct and indirect genotoxic damage?
- 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.
What is the predominant form of damage caused by radiation?
Indirect damage due t formation of free radicals and reactive oxygen species
What are the 4 ways to classify radiation?
- 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
What are some examples of ionizing and non-ionizing radiation?
Ionizing: X-rays, g-rays, a-particles, neutrons
Non0-ionizing: UV, microwave, RF radiation, ultrasound, electric and magnetic fields (EMF)
What is the eV of ionizing and non-ionizing radiation?
Ionizing: >10-15eV
Non-ionizing: <10eV
What does expose to UV commonly do to the structure of DNA?
- formation of pyramiding (C/T) dimers
T or F:
Pyramidine dimers induced by UV radiation only form within the same strand
F: can cross link within strands OR dimerisation across strands
Which repair pathways repairs damage caused by UV radiation?
Nucleotide excision repair (repairs C to T transitions at pyramidine sites)
What factors must be considered when assessing the relationship between radiation and carcinogenesis?
- dosage and nature of radiation
- site of exposure
- underlying efficiency of damage repair
- tissue specific sensitivity to radiation damage
What are some examples of cancers that are:
- sensitive
- moderately sensitive
- resistant
To radiation?
- sensitive: thyroid, breast, blood-forming tissues
- moderately sensitive: lung, colon, liver, pancreas, lymphatic system
- resistant: kidney, bone, skin, salivary gland, brain
Fill in the blanks:
Chemicals and _____ can cause consistent changes to the DNA _____.
This is called _____ _____.
1) radiation
2) sequence
3 & 4) mutational signatures
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
- T
- F: PARP not MMR
- F: DSBs not indels
How can HOV promote carcinogenesis
Degradation of Rb proteins
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
- F: bladder, squamous epithelium
- T
- F: aphlotoxin not fungus
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
C
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
All are correct
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
D
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
2 and 3
Which one of the following is ionizing radiation:
A) UV light
B) Ultrasound
C) a-particles
D) electric fields
C
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
