SBS13 · GRCh37 · COSMIC v95

Mutational profile

v3.2_SBS13_PROFILE_GA_GRCh37.jpg

Genome: GRCh37

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.

Proposed aetiology

Attributed to activity of the AID/APOBEC family of cytidine deaminases on the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems. APOBEC3A is probably responsible for most mutations in human cancer, although APOBEC3B may also contribute (these differ in the sequence context two bases 5’ to the mutated cytosine, see 1536 mutation classification signature extraction). SBS13 mutations are likely generated by error prone polymerases (such as REV1) replicating across abasic sites generated by base excision repair removal of uracil.

Comments

SBS13 is usually found in the same samples as SBS2. It has been proposed that activation of AID/APOBEC cytidine deaminases in cancer may be due to previous viral infection, retrotransposon jumping, or tissue inflammation. Currently, there is limited evidence to support these hypotheses. Germline polymorphisms involving APOBEC3A and APOBEC3B are associated with predisposition to breast and bladder cancer as well as with mutation burdens of SBS2 and SBS13. Mutations of similar patterns to SBS2 and SBS13 are commonly found in the phenomenon of local hypermutation present in some cancers, known as kataegis, implicating AID/APOBEC enzymes in this process as well.

Acceptance criteria

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
Nik-Zainal et al. 2012 Cell v1
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 Two forms: pyrimidine or purine at -2 bp
Proposed aetiology Mutational process Support
APOBEC activity Experimental confirmation
Experimental validation Experimental study Species
Chan et al. 2015 Nature Genetics Yeast

Tissue distribution

v3.2_SBS13_TISSUE.jpg

Numbers of mutations per megabase attributed to the mutational signature across the cancer types in which the signature was found. Each dot represents an individual sample and only samples where the signature is found are shown. The number of mutations per megabase was calculated by assuming that an average whole-exome has 30 Mb with sufficient coverage, whereas an average whole-genome has 2,800 Mb with sufficient coverage.

The numbers below the dots for each cancer type indicate the number of high confidence tumours in which at least 10 mutations were attributed to the signature (above the blue horizontal line) and the total number of high confidence tumours analysed (below the blue horizontal line). Only high confidence data are displayed: samples with reconstruction accuracy >0.90. The number of mutations per megabase was calculated by assuming that an average exome has 30 Mb with sufficient coverage, whereas an average whole genome has 2,800 Mb with sufficient coverage.

Associated signatures

SBS13 is closely associated with SBS2. SBS13 is also associated with DBS11, which is characterised predominantly by CC>TT doublet base substitutions as well as other CC>NN doublet base substitutions.

Transcriptional strand bias

v3.2_SBS13_STRAND_BIAS.jpg

Although there does not appear to be transcriptional strand bias when all transcribed genomic regions are considered (as above), there is transcriptional strand bias of mutations in exons.

Differences between current and previous profiles

v3.2_SBS13_DIFFERENCE_GA_GRCh37.jpg

Genome: GRCh37

The contribution of C>T mutations at TCN trinucleotides has diminished markedly compared to previous profiles indicating reduced contamination by SBS2. The cosine similarity between the prior and current versions of SBS13 is 0.97.