Science - USA (2022-04-22)

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