Extended Data Fig. 4. Oxidative damage-associated mutational signatures.

(a) Relative mutation frequency of G>T/C>A in 256 possible channels which take two adjacent bases 5’ and 3’ of each mutated base (4×4×4×4=256) for &#ΔATP2B4, &#ΔOGG1, a head and neck cancer with strong Signature 18 and COSMIC Signature 18. (b) Left: tSNE plot of tissue-specific mutational signature 18. Two groups are featured with predominant peaks at TGC>TTC/GCA>GAA (highlighted in green) and AGA>ATA/TCT>TAT (highlighted in purple), respectively. Right: heatmap of 21 tissue-specific mutational signatures at C>A. We compared experimental signatures to previously published cancer-derived signatures, focusing on 21 tissue-specific variations of Signature 18. Interestingly, we found two distinct groups of Signature 18. Signatures of &#Δ OGG1, cellular models and signatures derived from head and neck tumors, pancreas, myeloid, bladder, uterus, cervix, lymphoid tumors were most similar to each other, with the predominant G>T/C>A peak at TGC>TTC/GCA>GAA. By contrast, an alternative version of this signature with a predominant G>T/C>A peak at AGA>ATA/TCT>TAT was noted in colorectal, esophagus, stomach, bone, lung, CNS, breast, skin, prostate, liver, head and neck tumors (Signature Head_neck_G), ovary, biliary and kidney cancers. Indeed, there are many types of oxidative species which could fluctuate between tissues, variably affecting trinucleotides resulting in the variation observed in Signature 18.