mutational signitures Flashcards
genomic instability- driver or passenger?
driver
what contributes to a mutational signiture
Dna infidelity
exogenous and endogeonous genotoxins
defective DNA repair
enzymatic editing
catalogue of somatic mutations in cancer
COSMIC
DNA proofreading infidelity
how precise is dna replication- not very!
dna ploymerase proofreads- exoniuc;ease mediated proof reading
progressive accumulation of mutations through mitosis
genotoxins
endogenous- C>T transition deamination
UV- pyrimidne pyrimidine dimers cc:gg> tt:aa repaired by NER
Alkyllating - alkylating chemotherapy eg tzm. alkyl group to DNA resulting in cross linking of dna strands
bulky adducts- tobacco. enrichment for c>a substitutions NER removes bulky adducts
UV signature
7
Alkylating sig
11
DNA repair deficiency
HR- DSB
MMR- microsatellite instability
enzymatic dna editing
cytidine deainase enzymes induce c>t transitions
how many signatures in COSMIC
30
Sig 1
most common- displayed in almost all cancer s
endogenous mutational process by spontaneous deamination of c>t
number of mutations correlates with age of diagnosis of tumour
sig 3
HR deficiency
increased burden of large indels (up to 50 nucleotides) with overlapping microhomology at breakpoint junctions due to NHEJ
brca 1/2
Sig 6
microsatellite instability due to MMR deficiency
enrichment of 1bp indels at mono/polynucleotide repeat regions
which sigs seen with MMR
6, 26, 15, 20
sig 10
dna proofreading
transcriptional bias
c>a substitutions in the TpCpT context as well as substitutions t>g in the TpTpTp context
DNA polymerase epsilon- deficient DNA proofreading
