Mutational Signatures (v3.2 - March 2021)
SBS1 · GRCh37 · COSMIC v94
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.
An endogenous mutational process initiated by spontaneous or enzymatic deamination of 5-methylcytosine to thymine which generates G:T mismatches in double stranded DNA. Failure to detect and remove these mismatches prior to DNA replication results in fixation of the T substitution for C.
Signature SBS1 is clock-like in that the number of mutations in most cancers and normal cells correlates with the age of the individual. Rates of acquisition of Signature SBS1 mutations over time differ markedly between different cancer types and different normal cell types. These differences correlate with estimated rates of stem cell division in different tissues and Signature SBS1 may therefore be a cell division/mitotic clock.
Summary of the technical and experimental evidence available in the scientific literature regarding the validation of the mutational signature.
|Background||Identification study||First included in COSMIC|
|Nik-Zainal et al. 2012 Cell||v3|
|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|
|Proposed aetiology||Mutational process||Support|
|Spontaneous deamination of 5-methylcytosine||Mutational pattern|
|Experimental validation||Experimental study||Species|
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.
The activity of SBS1 is closely correlated with the activity of SBS5 within many types of cancer. However, between cancer types, mutation burdens of SBS1 and SBS5 do not clearly correlate consistent with them being due to different underlying processes.
Transcriptional strand bias
Differences between current and previous profiles
The contribution of C>T mutations not at NCG trinucleotides and of mutations other than C>T has diminished markedly compared to previous versions which were likely more contaminated by Signature SBS5 and other signatures. The cosine similarity between the prior and current versions of signature SBS1 is 0.95.