DBS2 · GRCh37 · COSMIC v94

Mutational profile

Proportion of a particular doublet base substitution (DBS) mutation type among all DBS mutation types in the signature is represented by the height of each bar. There are 78 strand-agnostic DBS mutation types.

The reason there are 78 strand-agnostic DBS mutation types is as follows. First, there are 4 x 4 = 16 possible source doublet bases. Of these, AT, TA, CG, and GC are their own reverse complement. We can represent the remaining 12 as 6 possible strand-agnostic doublets (e.g. AC represents both AC and its reverse complement, GT). Thus, there are 4+6=10 source doublet bases. Because they are their own reverse complements, AT, TA, CG, and GC can each be substituted by only 6 doublets . For example, AT can be substituted by 3 doublets starting with C: CA, CC, CG. But AT can be substituted by only 2 doublets starting with G: GA and GC. This is because the mutation from AT>GG is already represented by its reverse complement, AT>CC. Similarly AT can be substituted by only 1 doublet starting with T: TA. This is because AT>TC is represented by its reverse complement, AT>GA, and AT>TG is represented by AT>CA. For the remaining doublets, which are not their own reverse-complements, there are 3 x 3 = 9 possible DBS mutation types. Thus, in total there are 4 x 6 + 6 x 9 = 78 strand-agnostic DBS mutation types (see enumeration in the accompanying Excel document).

v3.2_DBS2_PROFILE_GA_GRCh37.jpg

Genome: GRCh37

Proposed aetiology

Exposure to tobacco smoking as well as other endogenous and/or exogenous mutagens (e.g., acetaldehyde).

Comments

DBS2 exhibits transcriptional strand bias with more GG>TT mutations than CC>AA on the untranscribed strands of genes indicative of damage on guanine and repair by transcription-coupled nucleotide excision repair. In addition to its presence in tobacco smoking induced cancers, DBS2 is also found in many cancer types unrelated to tobacco smoking. Its profile is similar to that of mutations in normal cells in mice. It may therefore also be an endogenously generated signature. Its mutation burden correlates with age of cancer diagnosis and this clock-like feature suggests that it is generated in normal human cells.

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
Chen et al. 2013 Human Mutation v3
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 -
Proposed aetiology Mutational process Support
Tobacco smoking / Acetaldehyde exposure Experimental confirmation (tobacco smoking)
Experimental validation Experimental study Species
Kucab et al. 2019 Cell Human

Tissue distribution

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 the signature was attributed (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.

v3.2_DBS2_TISSUE.jpg

Associated signatures

DBS2 is associated with SBS4 and ID3.