Table of Contents
Mutational signatures of base substitutions #
- Smoking related damage: GC --> TA
- UV: CG --> TA Signature 6)
Mechanisms underlying substitution signatures #
Endogeneous DNA damage #
The hydrolytic deamination of 5-methylcytosines at CpG dinucleotides has occurred so frequently throughout Evolution that it is thought to be the reason for the depletion of the number of methylated CpGs observed in the human genome.
It's thought to be catalysed by
- AICDA (activation-induced cytidine deaminase) -- antibody diversification
- APOBEC (apolipoprotein B mRNA editing enzyme) -- restriction of retrovirus and mobile retroelements -- TpCpN -- Signature 2 and Signature 13
Exogenous DNA damage #
DNA repair processes #
- BER (Base excision repair) - APEX1
- NER (Nucleotide excision repair)
- DNA mismatch repair -- Microsatellite instability (Signature 6)
- Non-homologous end joining (NHEJ)
- Homologous recombination
DNA replication errors #
Somatic and germline mutations in Pol ε have been associated with Signature 10 in colorectal and endometrial carcinomas
Mutational signatures of indels #
Indel signatures #
Indel means <100bp
Small 1–3-bp indels within repetitive sequences correlate with a base substitution signature that is characterized by an excess of C∙G→T∙A mutations at NpCpG (Signature 6)
Larger indels (between 4 bp and ~50 bp) that show a degree of sequence similarity between the indel motif and the immediate junction sequence (that is, microhomology) have been associated with a base substitution signature that is characterized by a fairly uniform distribution of mutations across all 96 possible base substitution types (Signature 3)
Mechanisms of indel signature formation #
- MMR -- Microsatellite instability -- Colorectal cancer (Signature 6)
- overlapping microhomology -- NHEJ -- DNA double-strand breaks --BRCA1/BRCA2 (Signature 3)
Mutational signatures of structural variations #
Most rearrangements are passenger events.
Structural variations arise from DSBs (DNA double-strand breaks) through either direct or indirect mechanisms, which can determine the resulting molecular signature.
- Primary DSBs - direct lesion
- Secondary DSBs - complex DNA lesions
Microhomology-mediated end-joining (MMEJ) is a subtype of NHEJ, in which the ligation is facilitated by microhomologies between ssDNA exposed at the DNA ends as a result of limited end-processing activities.
Tandem duplications #
Identical sequences duplicated in head-to-tail formation.
Some of these cancers have shown biallelic loss of BRCA1.
Clustered structural variations #
Somatic structural variations — for example, oncogenic amplifications such as HER2 in breast cancer — are regional or topographically clustered.
The exact mechanisms that cause gene amplification in cancer remain unclear. 2 hypothesis
- intrachromosomal cycles of breakage–fusion–bridge initiated by a DSB can promote progressive acquisition of additional genomic alterations that result in localized amplification
Both intrachromosomal and interchromosomal rearrangements arise from chromothripsis, which can lead to the formation of small circular marker chromosomes (double-minutes) that may subsequently amplify (that is, increase in copy number), particularly if they harbour an Oncogene.
Recently, the term Chromoplexy was given to the appearance of complex rearrangements that involve multiple chromosomes linked in a chain of rearrangements.