Degasperiet al.,Science 376 , eabl9283 (2022) 22 April 2022 7 of 15
SBS60.000.020.040.060.080.100.12C>A C>G C>T T>A T>C T>GGEL 53Hartwig 6ICGC 5SBS10a0.000.050.100.150.200.250.30C>A C>G C>T T>A T>C T>GGEL 65Hartwig 1ICGC 8 SBS10d0.00
0.05
0.10
0.150.20C>A C>G C>T T>A T>C T>GGEL 5Hartwig 1ICGC 0SBS140.00
0.02
0.04
0.06
0.08C>A C>G C>T T>A T>C T>GGEL 14Hartwig 2ICGC 0Hartwig 1SBS150.00
0.05
0.100.150.20C>A C>G C>T T>A T>C T>GICGC 0 GEL 7SBS200.000.020.040.060.080.100.12C>A C>G C>T T>A T>C T>GGEL 8Hartwig 0ICGC 0 SBS260.000.010.020.030.040.05
0.06C>A C>G C>T T>A T>C T>GGEL
23Hartwig 3ICGC
7SBS440.000.010.020.030.040.050.06C>A C>G C>T T>A T>C T>GGEL 582Hartwig 70ICGC 18SBS970.000.020.040.060.080.100.12C>A C>G C>T T>A T>C T>GGEL 3Hartwig 5ICGC 0F SBS signatures associated with MMR and POLE/POLD defectsSBS6
53
SBS14 14SBS15
7SBS20
SBS26^8
23SBS44
582SBS97
3SBS10a 65SBS10d
5MMR gene biallelic only
POLE mut onlyPOLD1 mut only
MMR gene biallelic + POLE mut
MMR gene biallelic + POLD1 mut
otherH with SBS signaturesDrivers in samples I with high HRDetect score Drivers in samplesBone_SoftTissue (2)Breast (291)Colorectal (4)
Lung (16)Ovary (158)
Pancreas (4)Prostate (2)Stomach (2)Uterus (28)proportion0.00.20.40.60.81.0BRCA1 biallelic
BRCA2 biallelic
PALB2 biallelic
RAD51C biallelic
RAD51D biallelic
otherSBS1080.000.050.10
0.15C>A C>G C>T T>A T>C T>GGEL 6Hartwig 4SBS96 ICGC 00.000.050.100.150.200.250.30C>A C>G C>T T>A T>C T>GGEL 18Hartwig 1ICGC 0 SBS300.000.020.040.060.080.10C>A C>G C>T T>A T>C T>GGEL 7Hartwig 2ICGC 4C D Ebiallelic patientsOGG1 G308E
in GELSBS108patients
in GELMBD4 biallelicpatients
in GELSBS96patients
in GELNTHL1 biallelicpatients
in GEL
patientsSBS30(^12351) in GEL
UterusOvary
Colorectal
Breast
PancreasStomach
LungNET
Prostate
Bone_SoftTissue
Bladder
CNS
Kidney
Oral_Oropharyngeal
BiliaryLiver
LymphoidMyeloid
Skin
0
50%
100%
MMR deficient
POLE/POLD dysregulation
HRDetect high score
others
G
proportion
Proportion of samples with signatures
or high HRDetect score
SBS1
0.00
0.05
0.10
0.15
C>A C>G C>T T>A T>C T>G
9858 GEL
Hartwig 2483
ICGC 2383 SBS95
0.00
0.05
0.100.15
0.20
C>A C>G C>T T>A T>C T>G
GEL 2
Hartwig 0
ICGC 1 SBS96
0.000.05
0.100.15
0.200.25
0.30
C>A C>G C>T T>A T>C T>G
GEL
18
Hartwig 1
ICGC
0
SBS87
0.00
0.05
0.100.15
0.20
C>A C>G C>T T>A T>C T>G
GEL 1
Hartwig 0
CCG ICGC 0
CCG
ACGGCG CCG ACG
CCG SBS105
0.000.02
0.040.06
0.080.10
C>A C>G C>T T>A T>C T>G
ICGC 0 GEL 2
Hartwig 0
CCGACGTCGCCG
A SBS signatures with mutations at CpG
B
64
mutations
cohort
GELICGC
Hartwig
SBS1 SBS95 SBS96 SBS87 SBS105
100
102
103
101
104
105
106
ColorectalEsophagusStomach
UterusBladder
Oral_Oropharyngeal
PancreasHead_neck
Lung
ProstateBiliary
CNSLiverOvaryBreastKidney
Lymphoid
Bone_SoftTissue
SkinNET
MyeloidLymphoidStomach
Head_neck
SkinBreast
Bone_SoftTissue
Breast BladderBreast
Fig. 4. Signatures associated with endogenous mutational processes.(A) Five
signatures characterized by substitutions at NCG nucleotides are contrasted with each
other. SBS profiles are shown, along with prevalence of signatures across three cohorts
(GEL, ICGC, and HMF), TSB, and RSB. (B) Mutation burdens associated with each
signature in all tumor types. SBS1 is common and seen in all cohorts in many tumor types.
SBS95, SBS96, SBS87, and SBS105 are rare and associated with a higher mutation
burden than that of SBS1. Theyaxis shows the mutation count on a log scale. Summaries
comparing signatures in etiological groupings can be found athttps://signal.
mutationalsignatures.com/explore/study/6.(C) SBS96 signature and prevalence among
samples in the three cohorts. The Venn diagram illustrates the number of patients in
the GEL cohort with SBS96 and biallelic loss ofMBD4.(D) SBS108 signature and
prevalence among samples in the three cohorts. The Venn diagram illustrates the number
of patients in the GEL cohort with SBS108 and a biallelicOGG1Gly^308 -Glu mutation.
(E) SBS30 signature and prevalence among samples in the three cohorts. The Venn
diagram illustrates the number of patients in the GEL cohort with SBS30 and biallelic loss
ofNTHL1. Only samples with SBS30 were inspected forNTHL1mutations. (F) SBSs
associated with MMR andPOLEandPOLDgene defects. (G) Proportion of samples across
GEL organs with signatures related to MMR orPOLEandPOLDdefects or with high
HRDetect scores. (H) Proportion of samples with MMR biallelic loss and/or POLE and
POLD dysregulation in each group of samples presenting an SBS mutational signature in
(F). (I) Proportion of HRDetect-high samples with biallelic loss in genes linked to
homologous recombination repair. Numbers in parentheses indicate numbers of samples.
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