Carcinogenesis Flashcards
what do people with ataxia telangiectasia have a defect in
ATM protein defect
what does ATM do
detects DNA damage
what site do most endogenous mutations for p53 occur at
CpG (cytosine- guanine nucleotides next to each other)
what happens in cytosine deamination
gets turned into uracil
why can cytosine deamination be repaired
because uracil is a RNA base so seen as abnormal in DNA
what is deamination of 5-methylcytosine
it is deaminated into thymine
what is biotransformation
enzymatic process transforming chemicals into entities to be excreted from the body
3 exogenous things causing mutations of p53
UV light
Aflatoxin
Benzopyrene in tobacco smoke
what mutation in p53 does UV light cause
CC to TT
what cancer can aflatoxin (from diet) cause
liver cancer
mutation of p53 in aflatoxin damage
codon 249 AGG to AGT
why can deamination of 5-methylcytosine to thymine not be repaired
as thymine is a normal DNA base so is seen as normal
size of alkylation damage
a small change (not a bulky lesion)
what enzyme repairs alkylation damage
MGMT suicide enzyme
how does MGMT suicide enzyme repair alkylation damage
by removing the akyl group from the DNA and placing it into the cytosine residue on the enzyme
what tumours are responsive to treatment with alkylating agents
tumours with reduced MGMT expression
what 2 enzymes perform base excision repair
DNA glycosylases
AP endonuclease
what is DNA glycosylases job
removes base leaving empty AP site
what is AP endonuclease job
repairs AP site
what can reactive oxygen species cause thousands of per day in the human genome
“hits” creating AP sites
what kind of damage does UV cause
bulky lesions (e.g thymine dimers)
when is nucleotide excision repair (NER) used
when DNA damage is not recognised by DNA glycosylases (so base excision repair isn’t possible) -bulky lesions
what does NER remove from DNA
oligonucleotide fragments containing the damaged bases
what lesion is the primary cause of melanomas in humans
pyrimidine dimers
in NER what replaces the gap
DNA polymerase
what is xeroderma pigmentosum (XP)
genetic defect in NER (nucleoside excision repair) of UV damage
what does XP lead to
1000x increased risk of skin cancer
in a double strand break how is the DNA repaired
non-homologous end joining (NHEJ)
a somatic mutations effect
only the individual
a germ line mutation effects
inheritance
what mutation can lead to familial melanoma
P16ink
what transcription factor does Rb sequester
E2F
what are lesions in colorectal adenoma called
polyps
what are polyps precursors of
colorectal cancer
2 types of inherited colorectal cancer
- familial adenomatous polyposis (FAP)
- hereditary non polyposis colon cancer (HNPCC)
inheritance pattern of FAP
autosomal dominant
what is present in the colon in FAP
1000s of polyps
what gene is mutated in FAP
APC gene
what is the APC gene
negative regulator of beta catenin
what signalling pathway is APC part of
APC-Wnt signalling pathway
when there is no need for cell division what does APC do
sequesters beta-cat
when beta-cat is not bound to APC what can it do
binds to DNA to activate Wnt target genes leading to cell proliferation
what is the syndrome called of HNPCC
lynch syndrome
what NOT present in HNPCC
polyps
which inherited colorectal cancer is early onset
HNPCC
which part of the colon is usually affected in HNPCC
right colon
what can a defect in mismatch repair lead to (3)
-mutator phenotype
what can mutator phenotype also be called
microsatellite instability
two main sporadic colorectal cancer pathways
CIN
CIMP
CIN=
chromosome instability pathway
CIMP=
CpG island methylator phenotype
which is the most common pathway for sporadic colorectal cancer
CIN (chromosome instability)
which side of the colon does CIN effect
left
