SBS90 · 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.

v3.2_SBS90_PROFILE_GA_GRCh37.jpg

Genome: GRCh37

Proposed aetiology

Duocarmycin exposure.

Comments

Very strong sequence context enrichment, with a preference for thymines up to 4bp 3’ of mutated thymines.

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
Boot et al. 2019 BioRxiv / Priestley et al. 2019 Nature v3.1
Identification NGS technique Different variant callers Multiple sequencing centres
WGS Yes Yes
Technical validation Validated in orthogonal techniques Replicated in additional studies Extended context enrichment
Yes Yes Preference for T up to +4 bp
Proposed aetiology Mutational process Support
Duocarmycin exposure Experimental confirmation
Experimental validation Experimental study Species
Boot et al. 2019 BioRxiv Human

Tissue distribution

Found in breast and oesophagus metastatic cancers treated with duocarmycin-based antibody-drug conjugates.

Transcriptional strand bias

SBS90 shows strong transcriptional strand bias for T>A substitutions with more mutated A than T bases on the untranscribed strands of genes compatible with damage to adenine.

v3.2_SBS90_STRAND_BIAS.jpg