SBS14), DBS29 (associated with SBS20), and
DBS37 (associated with SBS26) could all be gen-
erated mathematically from their associated
SBS signatures (fig. S8, E to H), indicating that
these were not true dinucleotides but simply
single-nucleotide variants occurring next to
each other by chance. One exception, DBS24—
associated with SBS90, attributed to duocarmy-
cin exposure—has a pattern that can be mostly
recapitulated by simulation of SBS90, apart from
the CT>AA component (fig. S8I). Three sig-
natures (DBS23, DBS32, and DBS35) were not
Degasperiet al.,Science 376 , eabl9283 (2022) 22 April 2022 5 of 15
DBS reference signatures, all cohorts
DBS26
0.00
0.02
0.04
0.06
0.08
CAAC>NNCGCTGAGGGTTATGTTAT>NNCACCCGGAGCTAAAAGCC>NNATGAGGGTTATGCG>NNTTATGCGTTATCTTAACT>NNACAGGAGCGGTATCTGGC>NNAAAGATCACGTAATTA>NNCGCTGCGGGTAAAGTC>NNATCACGCTGAGGGTAAACTG>NNATCACCCTGAGCGTAAACTT>NNAGCACCCGGAGCGG
GEL
62
Hartwig 60
ICGC
43
DBS22
0.000.01
0.020.03
0.040.05
0.06
CAAC>NNCGCTGAGGGTTATGTTAT>NNCACCCGGAGCTAAACC>NNAGATGAGGGTTATGTTATCG>NNGCGTTATCTTAAACAGCT>NNGAGCGGTATCTGGC>NNAAAGATCACGTATA>NNATCGCTGCGGGTAAAGTC>NNATCACGCTGAGGGTAATG>NNACATCACCCTGAGCGTAAACAGTT>NNCACCCGGAGCGG
GEL
4
Hartwig 14
ICGC
34
DBS25
0.000.05
0.100.15
0.200.25
0.30
CAAC>NNCGCTGAGGGTTATGTTAT>NNCACCCGGAGCTAAAAGCC>NNATGAGGGTTATGCG>NNTTATGCGTTATCTTAACT>NNACAGGAGCGGTATCTGGC>NNAAAGATCACGTAATTA>NNCGCTGCGGGTAAAGTC>NNATCACGCTGAGGGTAAACTG>NNATCACCCTGAGCGTAAACTT>NNAGCACCCGGAGCGG
GEL
254
Hartwig 3
ICGC
9
DBS20
0.00
0.05
0.10
0.15
CAAC>NNCGCTGAGGGTTATGTTAT>NNCACCCGGAGCTAAAAGCC>NNATGAGGGTTATGCG>NNTTATGCGTTATCTTAACT>NNACAGGAGCGGTATCTGGC>NNAAAGATCACGTAATTA>NNCGCTGCGGGTAAAGTC>NNATCACGCTGAGGGTAAACTG>NNATCACCCTGAGCGTAAACTT>NNAGCACCCGGAGCGG
GEL
3929
Hartwig 1384
ICGC
926
DBS13
0.000.05
0.100.15
0.200.25
0.30
CACGCTAC>NNGAGGGTTATGTTAT>NNCACCCGGAGCTAAAAGCC>NNATGAGGGTTATGTTATCG>NNGCGTTATCTTAACT>NNACAGGAGCGGTATCTGGC>NNAAAGATCACGTAATTA>NNCGCTGCGGGTAAAGATTC>NNCACGCTGAGGGTAAACTG>NNATCACCCTGAGCGTAAACTT>NNAGCACCCGGAGCGG
GEL
2737
Hartwig 1207
ICGC
983
DBS15
0.00
0.02
0.04
0.06
0.08
CAAC>NNCGCTGAGGGTTATGTTAT>NNCACCCGGAGCTAAAAGCC>NNATGAGGGTTATGTTCG>NNATGCGTTATCTTAACT>NNACAGGAGCGGTATCTGGC>NNAAAGATCACGTAATTA>NNCGCTGCGGGTAAAGTC>NNATCACGCTGAGGGTAAACTG>NNATCACCCTGAGCGTAAACTT>NNAGCACCCGGAGCGG
GEL
1015
Hartwig 0
ICGC
24
DBS16
0.00
0.020.04
0.060.08
0.10
CAAC>NNCGCTGAGGGTTATGTTAT>NNCACCCGGAGCTAAAAGCC>NNATGAGGGTTATGCG>NNTTATGCGTTATCTTAACT>NNACAGGAGCGGTATCTGGC>NNAAAGATCACGTAATTA>NNCGCTGCGGGTAAAGTC>NNATCACGCTGAGGGTAAACTG>NNATCACCCTGAGCGTAAACTT>NNAGCACCCGGAGCGG
GEL
4
Hartwig 1
ICGC
1
DBS17
0.00
0.05
0.10
0.15
CACGAC>NNCTGAGGGTTATGTTAT>NNCACCCGGAGCTAAACC>NNAGATGAGGGTTATGTTATCG>NNGCGTTATCTTAACT>NNACAGGAGCGGTATCTGGC>NNAAAGATCACGTAATTA>NNCGCTGCGGGTAAAGATTC>NNCACGCTGAGGGTAAACTG>NNATCACCCTGAGCGTAAACTT>NNAGCACCCGGAGCGG
GEL
1
Hartwig 0
ICGC
3
DBS23
0.00
0.05
0.10
0.15
CACGAC>NNCTGAGGGTTATGTTAT>NNCACCCGGAGCTAAACC>NNAGATGAGGGTTATGTTATCG>NNGCGTTATCTTAACT>NNACAGGAGCGGTATCTGGC>NNAAAGATCACGTAATTA>NNCGCTGCGGGTAAAGATTC>NNCACGCTGAGGGTAAACTG>NNATCACCCTGAGCGTAAACTT>NNAGCACCCGGAGCGG
GEL
0
Hartwig 0
ICGC
5
Biliary
Bladder
Bone_SoftTissue
Breast
CNS
Colorectal
Esophagus
Head_neck
Kidney
Liver
Lung
Lymphoid
Myeloid
NET
Oral_Oropharyngeal
Ovary
Pancreas
Prostate
Skin
Stomach
Uterus
GEL−2136826−11 (282 TNVs)
0
10
20
30
40
50
faff4626−615b−416a−b7a6−9d177dcc94a9 (62 TNVs)
0
5
10
15
CPCT02050104T (182 TNVs)
0
10
20
30
40
Examples of samples with TBS signatures (DBS25)
A
D
E
TTT>AAA
TTT>GAA
TTT>
CAA TTG>AAA TTC>AAA
-0.5
0.0
0.5
1.0
Pearson correlation
all
DBS11SBS2 DBS13SBS8 DBS20SBS8 DBS26SBS17 DBS5SBS111 DBS16SBS10d DBS22SBS9 DBS12SBS105 DBS24SBS90
GEL
ICGC
Hartwig
4 3 5 10 13 12 12 12 12 224 1 03 1 00 110 2 00 002
samples
0
1000
2000
3000
4000
5000
6000
DBS20DBS13DBS2DBS15DBS1DBS5DBS11DBS25DBS18DBS26DBS8DBS4DBS22DBS10DBS3DBS14DBS16DBS23DBS7DBS17DBS29DBS12DBS24DBS35DBS30DBS32DBS37
Smoking
UV lightPlatinum-based theraphyAPOBECPlatinum-based theraphy
POLE dysregulationPOLE dysregulationMMR+POLE deficiencyMMR deficiencyTreatmentTreatmentMMR deficiency
in COSMIC
not in COSMIC
-10-9-8-7-6-5position relative to CC>TT-4-3-2-1^0012345678910
count
0
50
100
150
(^200) A
C
T
G
B
C
Sequence context of the CC>TT mutations in GEL-2373213-11,
sample with high DBS11 exposure, associated with APOBEC-related SBS2
Correlation of DBS with SBS exposures across organs and cohorts
number of organsin which correlation
was observed
Previously unreported, in cis DBS signatures
TTT>AAA
TTT>GAA
TTT>
CAA TTG>AAA TTC>AAA
TTT>AAA
TTT>GAA
TTT>
CAA TTG>AAA TTC>AAA
Fig. 3. DBS signatures across the cohort.(A) Frequency of DBS signatures in
the present study. (B) Flanking sequence context surrounding mutated
dinucleotides of DBS11, which is correlated with APOBEC-related SBS2, to
demonstrate a preference for the TpCCpN context, similar to the TpCpN
sequence predilection of APOBECs. (C) Correlation of DBSs with SBS exposures
across cohorts. Numbers in each column report the number of organs implicated
in the correlative analyses. A correlation is computed independently for each
organ. Correlations are displayed as a box plots, which denote median (horizontal
line) and 25th to 75th percentiles (boxes). The lower and upper whiskers span
1.5 times the interquartile range (1.5 × IQR). (D) Examples of previously unreported
DBS signatures. (E) Samples with TBS1. The total numbers of samples and triple-
nucleotide variants are too low to perform a formal mutational signature analysis. All
DBS signatures identified in the present study can be viewed athttps://signal.
mutationalsignatures.com/explore/study/6?mutationType=2.
RESEARCH | RESEARCH ARTICLE