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 were
similar 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 with
Degasperiet al.,Science 376 , eabl9283 (2022) 22 April 2022 4 of 15
SBS92
0.00
0.02
0.04
0.06
0.08
C>A C>G C>T T>A T>C T>G
GEL
1448
Hartwig 384
ICGC
79
SBS93
0.00
0.02
0.04
0.06
0.08
C>A C>G C>T T>A T>C T>G
GEL
1605
Hartwig 376
ICGC
108
SBS100
0.000.02
0.040.06
0.080.10
0.12
C>A C>G C>T T>A T>C T>G
GEL
1229
Hartwig 58
ICGC
270
SBS121
0.00
0.05
0.10
0.15
C>A C>G C>T T>A T>C T>G
GEL
1611
Hartwig 376
ICGC
33
SBS127
0.00
0.01
0.02
0.03
C>A C>G C>T T>A T>C T>G
GEL
2501
Hartwig 287
ICGC
619
SBS125
0.0000.005
0.0100.015
0.0200.025
0.030
C>A C>G C>T T>A T>C T>G
GEL
1244
Hartwig 218
ICGC
157
SBS101
0.000.01
0.020.03
0.040.05
0.060.07
C>A C>G C>T T>A T>C T>G
GEL
141
Hartwig 0
ICGC
117
SBS120
0.00
0.010.02
0.03
0.040.05
C>A C>G C>T T>A T>C T>G
GEL
383
Hartwig 68
ICGC
158
SBS122
0.00
0.010.02
0.030.04
0.05
C>A C>G C>T T>A T>C T>G
GEL
1003
Hartwig 100
ICGC
53
SBS97
0.000.02
0.040.06
0.080.10
0.12
C>A C>G C>T T>A T>C T>G
GEL
3
Hartwig 5
ICGC
0
SBS116
0.000.02
0.04
0.06
0.08
0.10
C>A C>G C>T T>A T>C T>G
GEL
2
Hartwig 1
ICGC
0
SBS117
0.0000.005
0.0100.015
0.0200.025
0.0300.035
C>A C>G C>T T>A T>C T>G
GEL
5
Hartwig 2
ICGC
0
SBS119
0.00
0.02
0.04
0.06
0.08
C>A C>G C>T T>A T>C T>G
GEL
1
Hartwig 3
ICGC
0
SBS129
0.0
0.1
0.2
0.3
0.4
C>A C>G C>T T>A T>C T>G
GEL
2
Hartwig 0
ICGC
0
SBS137
0.00
0.05
0.10
0.15
0.20
C>A C>G C>T T>A T>C T>G
GEL
2
Hartwig 0
ICGC
0
C
D
E
Previously unreported or recently discovered common SBS signatures found in multiple organs
Previously unreported common SBS signatures found in specific organs
Examples of previously unreported rare SBS signatures
ABSBS reference signatures, all cohorts, linear scale SBS reference signatures, all cohorts, log scale
SBS107
0.000.01
0.020.03
0.040.05
0.06
C>A C>G C>T T>A T>C T>G
GEL
1461
Hartwig 92
ICGC
403
Biliary
Bladder
Bone_SoftTissue
Breast
CNS
Colorectal
Esophagus
Head_neck
Kidney
Liver
Lung
Lymphoid
Myeloid
NET
Oral_Oropharyngeal
Ovary
Pancreas
Prostate
Skin
Stomach
Uterus
SBS94
0.000.02
0.040.06
0.080.10
0.120.14
C>A C>G C>T T>A T>C T>G
GEL
13
Hartwig 3
ICGC
1
SBS110
0.00
0.01
0.02
0.03
0.04
C>A C>G C>T T>A T>C T>G
GEL
30
Hartwig 29
ICGC
0
samples
0
2000
4000
6000
8000
10000
12000
14000
SBS1SBS5SBS8SBS3SBS18SBS13SBS2SBS127SBS17SBS88SBS93SBS121SBS107SBS92SBS125SBS100SBS4SBS122SBS35SBS44SBS7aSBS31SBS120SBS16SBS28SBS101SBS12SBS102SBS9SBS126SBS38SBS111SBS57SBS23SBS10aSBS109SBS6SBS110SBS22SBS169SBS26SBS112SBS124SBS33SBS99SBS96SBS11SBS94SBS14SBS30SBS108SBS15SBS20SBS97SBS117SBS10dSBS103SBS32SBS114SBS7cSBS24SBS106SBS119SBS90SBS95SBS113SBS116SBS118SBS19SBS98SBS104SBS105SBS115SBS123SBS128SBS129SBS137SBS84SBS87SBS134SBS138SBS141
In COSMIC
Not in COSMIC
samples
1
10
100
1000
10000
SBS1SBS5SBS8SBS3SBS18SBS13SBS2SBS127SBS17SBS88SBS93SBS121SBS107SBS92SBS125SBS100SBS4SBS122SBS35SBS44SBS7aSBS31SBS120SBS16SBS28SBS101SBS12SBS102SBS9SBS126SBS38SBS111SBS57SBS23SBS10aSBS109SBS6SBS110SBS22SBS169SBS26SBS112SBS124SBS33SBS99SBS96SBS11SBS94SBS14SBS30SBS108SBS15SBS20SBS97SBS117SBS10dSBS103SBS32SBS114SBS7cSBS24SBS106SBS119SBS90SBS95SBS113SBS116SBS118SBS19SBS98SBS104SBS105SBS115SBS123SBS128SBS129SBS137SBS84SBS87SBS134SBS138SBS141
In COSMIC
Not in COSMIC
Fig. 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