SBS88 · GRCh37 · COSMIC v94

Mutational profile

Mutational profile using the conventional 96 mutation type classification. This classification is based on the six substitution subtypes: C>A, C>G, C>T, T>A, T>C, and T>G, as well as the nucleotides immediately 5’ and 3’ to the mutation.

Each of the substitutions is referred to by the pyrimidine of the mutated Watson—Crick base pair. Incorporating information on the bases immediately 5’ and 3’ to each mutated base generates 96 possible mutation types (6 types of substitution x 4 types of 5’ base x 4 types of 3’ base). Mutational signatures are displayed and reported based on the observed trinucleotide frequency of the genome, i.e., representing the relative proportions of mutations generated by each signature based on the actual trinucleotide frequencies of the corresponding reference genome.

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Genome: GRCh37

Proposed aetiology

Exposure to E.coli bacteria carrying pks pathogenicity island, producing genotoxic compound colibactin.

Comments

SBS88 appears to be most active in the first decade of life. Strong preference for adenines at positions -3 and -4 (i.e. 5' of the mutation).

Acceptance criteria

Summary of the technical and experimental evidence available in the scientific literature regarding the validation of the mutational signature.

Supporting evidence for mutational signature validity

Validated evidence for real signature
Unclear evidence for real signature
Evidence for artefact signature
Background Identification study First included in COSMIC
Lee-Six et al. 2019 Nature / Pleguezuelos-Manzano et al. 2020 Nature / Boot et al. 2019 BioRxiv v3.1
Identification NGS technique Different variant callers Multiple sequencing centres
WES & WGS Yes Yes
Technical validation Validated in orthogonal techniques Replicated in additional studies Extended context enrichment
Yes Yes Preference for A at -3 bp and -4 bp
Proposed aetiology Mutational process Support
Colibactin exposure Experimental confirmation
Experimental validation Experimental study Species
Pleguezuelos-Manzano et al. 2020 Nature Human

Tissue distribution

Mainly found in colorectal cancers, and normal and inflammatory bowel disease-affected colorectal epithelial cells, as well as in some samples derived from head and neck cancer, urinary tract cancer and oral squamous cell carcinoma.

Associated signatures

Associated with ID18, also arising from colibactin exposure.

Transcriptional strand bias

SBS88 exhibits transcriptional strand bias, with more mutations occurring when the T base is on the transcribed rather than on the untranscribed DNA strand. Interestingly, genotoxic compound colibactin is known to form adenine adducts (as well as double strand breaks), a type of DNA damage which is often repaired by the transcription-coupled nucleotide excision repair system, which is principally responsible for transcriptional strand bias.

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