Alexandrov and colleagues [10,11,12] report single base substitution signatures (SBS) of mutagenesis in cancer using an algorithm-extraction of tri-nucleotide signatures from whole exome (WES) and whole genome (WGS) sequence data from thousands of cancer genomes. The present categories offer an alternative way of understanding these somatic mutation patterns based on the likelihood of the origin of the dominant deaminase-driven signature—C-site or A-site, or both C-site plus A-site. This categorisation is cognisant of the fact that certain apparent non-deaminase driven or ‘environmental exposure’ signatures (Tobacco Smoking, UV exposure, Reactive Oxygen Species viz. 8oxoG) are also present in certain cancer genomes. The most dominant signature is SBS5 occurring in all cancer genomes sequenced. SBS5 displays a ‘dysregulated Ig-Like SHM’ somatic mutation pattern [1,7,8,9,13,14] with transcriptional strand bias of mutations of A exceeding mutations of T (A>>T) and mutations of G exceeding mutations of C (G>>C), as in Table 1, Table 2 and Table 3, online Supplementary Tables S1–S3. This strand-biased mutation pattern is also observed at both Ig and non-Ig loci (the TP53 DNA binding region) that have undergone somatic mutagenesis [7,14]. Listed below are the authors’ main Deaminase Driven Categories. Superscript T indicates Transcriptional Strand Asymmetry. The SBS Mutational Signatures (v3.4—October 2023) are at The Catalogue of Somatic Mutations in Cancer (COSMIC) website at https://cancer.sanger.ac.uk/signatures/sbs/ (accessed on 15 April 2024)

C-site predominantly (putative AID/APOBEC driven)

SBS1T (at ACG strong strand bias, 5-meCpG, but slight reverse C>>G at CCG, GCG, TCG), SBS2, SBS6, SBS13, SBS19T (pure almost G>A >>C>T only), SBS7a, SBS7b

A-site predominantly (putative ADAR1 and coupled Target Site Reverse Transcription [TSRT], Pol-Eta and/or possibly DNA Pol-Theta driven)

SBS12T(Liver), SBS16T (Liver), SBS17aT, SBS17bT (but reverse strand bias not A>>T it is T>>A), SBS21T (DNA mismatch repair deficiency, but apparent reverse strand bias not A>>T it is T>>A)

C-site plus A-site more or less balanced “Ig-SHM-like” (AID/APOBEC/ADAR driven + TSRT via Pol eta, Pol theta?) SBS5T (SBS40 = SBS5?), SBS3T, SBS9T (but apparent reverse strand bias not A>>T it is T>>A).

SBS signatures not highlighted in above categories are discussed and analysed at length in Results and Analytical Discussion Section 2.1