substitution (TBS) signature. Exploring all
triple-base possibilities, we obtain an 864-
channel profile that systematically reports an
excess of TTT>AAA followed by TTT>GAA,
TTT>CAA, and minor contributions of TTG>AAA
and TTC>AAA. We propose that this is called
TBS1 (Fig. 3E and table S27). However, the
numbers of mutations and implicated samples
are too low to perform a formal mutational
signature analysis.
Our curation steps uncovered several DBS
signatures, including previously reported ones,
that comprise adjacent substitutions that are
not in cis and are simply the mathematical
outcome of an associated SBS hypermutator
(fig. S8). For example, DBS3 and DBS10 weresimilar and correlated with polymerasee
(POLE)Ðattributed SBS10a (fig. S8, A to C). In
silico analysis showed that a DBS pattern that
recapitulates DBS3 and DBS10 could be repro-
duced from hypermutated samples of SBS10a
(fig. S8D). The alleged double substitutions
were not, in fact, in cis. Similarly, DBS12 (asso-
ciated with SBS105), DBS14 (associated withDegasperiet al.,Science 376 , eabl9283 (2022) 22 April 2022 4 of 15
SBS920.000.020.040.060.08C>A C>G C>T T>A T>C T>GGEL
1448Hartwig 384ICGC
79SBS930.00
0.020.04
0.060.08C>A C>G C>T T>A T>C T>GGEL
1605Hartwig 376ICGC
108SBS1000.000.020.040.060.080.100.12C>A C>G C>T T>A T>C T>GGEL
1229Hartwig 58ICGC
270SBS1210.000.050.100.15C>A C>G C>T T>A T>C T>GGEL
1611Hartwig 376ICGC
33SBS1270.000.010.020.03C>A C>G C>T T>A T>C T>GGEL
2501Hartwig 287ICGC
619SBS1250.0000.0050.0100.0150.0200.0250.030C>A C>G C>T T>A T>C T>GGEL
1244Hartwig 218ICGC
157SBS1010.000.010.020.030.040.050.060.07C>A C>G C>T T>A T>C T>GGEL
141Hartwig 0ICGC
117SBS1200.00
0.010.020.03
0.040.05C>A C>G C>T T>A T>C T>GGEL
383Hartwig 68ICGC
158SBS1220.00
0.010.020.030.040.05C>A C>G C>T T>A T>C T>GGEL
1003Hartwig 100ICGC
53SBS970.000.020.040.060.080.100.12C>A C>G C>T T>A T>C T>GGEL
3Hartwig 5ICGC
0SBS1160.000.020.04
0.06
0.08
0.10C>A C>G C>T T>A T>C T>GGEL
2Hartwig 1ICGC
0SBS1170.0000.0050.0100.0150.0200.0250.0300.035C>A C>G C>T T>A T>C T>GGEL
5Hartwig 2ICGC
0SBS1190.00
0.02
0.04
0.060.08C>A C>G C>T T>A T>C T>GGEL
1Hartwig 3ICGC
0SBS1290.00.10.20.3
0.4C>A C>G C>T T>A T>C T>GGEL
2Hartwig 0ICGC
0SBS1370.00
0.05
0.100.15
0.20C>A C>G C>T T>A T>C T>GGEL
2Hartwig 0ICGC
0C
D
E
Previously unreported or recently discovered common SBS signatures found in multiple organsPreviously unreported common SBS signatures found in specific organsExamples of previously unreported rare SBS signaturesABSBS reference signatures, all cohorts, linear scale SBS reference signatures, all cohorts, log scale
SBS1070.000.010.020.030.040.050.06C>A C>G C>T T>A T>C T>GGEL
1461Hartwig 92ICGC
403Biliary
Bladder
Bone_SoftTissueBreast
CNS
ColorectalEsophagus
Head_neck
KidneyLiver
Lung
LymphoidMyeloid
NET
Oral_OropharyngealOvary
Pancreas
ProstateSkin
Stomach
UterusSBS940.000.020.040.060.080.100.120.14C>A C>G C>T T>A T>C T>GGEL
13Hartwig 3ICGC
1SBS1100.000.01
0.020.03
0.04C>A C>G C>T T>A T>C T>GGEL
30Hartwig 29ICGC
0samples
020004000
60008000100001200014000SBS1SBS5SBS8SBS3SBS18SBS13SBS2SBS127SBS17SBS88SBS93SBS121SBS107SBS92SBS125SBS100SBS4SBS122SBS35SBS44SBS7aSBS31SBS120SBS16SBS28SBS101SBS12SBS102SBS9SBS126SBS38SBS111SBS57SBS23SBS10aSBS109SBS6SBS110SBS22SBS169SBS26SBS112SBS124SBS33SBS99SBS96SBS11SBS94SBS14SBS30SBS108SBS15SBS20SBS97SBS117SBS10dSBS103SBS32SBS114SBS7cSBS24SBS106SBS119SBS90SBS95SBS113SBS116SBS118SBS19SBS98SBS104SBS105SBS115SBS123SBS128SBS129SBS137SBS84SBS87SBS134SBS138SBS141In COSMIC
Not in COSMICsamples
110100100010000SBS1SBS5SBS8SBS3SBS18SBS13SBS2SBS127SBS17SBS88SBS93SBS121SBS107SBS92SBS125SBS100SBS4SBS122SBS35SBS44SBS7aSBS31SBS120SBS16SBS28SBS101SBS12SBS102SBS9SBS126SBS38SBS111SBS57SBS23SBS10aSBS109SBS6SBS110SBS22SBS169SBS26SBS112SBS124SBS33SBS99SBS96SBS11SBS94SBS14SBS30SBS108SBS15SBS20SBS97SBS117SBS10dSBS103SBS32SBS114SBS7cSBS24SBS106SBS119SBS90SBS95SBS113SBS116SBS118SBS19SBS98SBS104SBS105SBS115SBS123SBS128SBS129SBS137SBS84SBS87SBS134SBS138SBS141In COSMIC
Not in COSMICFig. 2. SBS signatures across 18,640 whole-genomeÐsequenced cancers.
(A) Frequency of SBS signatures in the present study. Orange bars highlight
42 signatures reported in this study and present in COSMIC v3.2; blue bars highlight
40 previously unreported signatures found in the present analysis. (B) Same
informationasin(A),withalogscaleontheyaxis. (C) Four previously unreported
(SBS107, SBS100, SBS110, and SBS121) and five recently reported (SBS92, SBS93,
SBS94, SBS125, and SBS127) common SBS signatures found in many organ systems.
(D) Previously unreported common SBS signatures found in single organs only.
(E) A few examples of previously unreported rare signatures. SBS signatures can be
viewed athttps://signal.mutationalsignatures.com/explore/study/6?mutationType=1.RESEARCH | RESEARCH ARTICLE