Science - USA (2022-04-22)

From a biological perspective, it is essential
to distinguish signatures that provide diagnos-
tic insights or that are therapeutically infor-
mative from other signatures, particularly when

they share feature similarities. Notable exam-

ples deliberated earlier include distinguishing

MBD4-compromised SBS96 from other signa-

tures withCpG propensity or correctly differ-

entiating signatures that occur predominantly

at CCN and TCN from UV-related SBS7a.

Additionally, we highlight endogenous sig-

natures indicative of pathway defects that are

Degasperiet al.,Science 376 , eabl9283 (2022) 22 April 2022 11 of 15

cohort

GEL

ICGC

Hartwig

number of rare

signatures

in sample

0

1

2

3

CNS samples GEL ICGC Hartwig

Hartwig 78

ICGC

287

GEL

444

26

415 284 63

AB

H

14

GEL-CNS_common_SBS5 GEL-CNS_common_SBS8

GEL-CNS_common_SBS120

GEL-CNS_common_SBS3 GEL-CNS_common_SBS1 GEL-CNS_rare_SBS11_a

GEL-CNS_rare_SBS113

GEL-CNS_rare_SBS11_b

GEL-CNS_rare_SBS14 GEL-CNS_rare_SBS121

GEL-CNS_rare_SBS4

GEL-CNS_rare_SBS17

GEL-CNS_rare_SBS7a

GEL-CNS_rare_SBS119

GEL-CNS_rare_SBS137

GEL-CNS_rare_SBS2+13 GEL-CNS_common_DBS13+20

GEL-CNS_rare_DBS1

GEL-CNS_rare_DBS14

GEL-CNS_rare_DBS2

CDE F

G

mutations

mutations

Common SBS signatures Rare previously reported Rare previuslyunreported DBS signatures

TSB

RSB

Transcription strand bias

Replication strand bias

RSB TSB

TSB TSB

RSB TSB

TSB

TSB

RSB

TSB

T SBBST T SBBST

T SBBST

SBS5

DBS13+20

SBS120

SBS3

SBS1

rare previously reported

rare previously unreported

unassigned

DBS1

DBS14

DBS2

unassigned

100

102

103

101

104

105

106

100

101

102

103

mutations

357198643660 03701776235415561383158683 01 30 0 30 09 1 33 01 3 02 10 1 10 01 0 23 00 2 00

SBS1 SBS3 SBS5 SBS8

SBS120

SBS2 SBS4 SBS7a SBS11 SBS13 SBS14 SBS17

SBS113 SBS119 SBS121 SBS137

100

102

103

101

104

105

106

mutations

0 14110 20 0 1191 00 2 00 10 0 10 01

SBS18 SBS23 SBS126 SBS6 SBS26 SBS35 SBS97

100

102

103

101

104

105

106

mutations

899208983 60 0 40 03 0 20 13 0 03

DBS13 DBS20 DBS1 DBS2 DBS14 DBS11 DBS19

100

102

103

101

104

105

106

SBS8

Contribution of CNS signatures in the GEL cohort

Exposures of CNS SBS signatures found in GEL

Exposures of CNS SBS signatures found

in ICGC and Hartwig only Exposures of CNS DBS signatures

Fig. 6. Summary of SBS signatures and DBS signatures in CNS tumors from
the GEL dataset.(A) CNS tumors from GEL, ICGC and HMF cohorts. (B)MostCNS
tumors have common signatures only (light blue), and a fraction have one rare signature
(maroon). In the pie charts, numbers <5% are not shown. (C) Common SBS signatures
in CNS GEL tumors. (D) Previously reported rare SBS signatures in CNS GEL tumors.
(E) Previously unreported rare SBS signatures in CNS GEL tumors. (F) DBS signatures in

CNS GEL tumors. (G) Distribution of mutational signatures in all CNS GEL tumors.

For each sample, the total number of mutations is shown in a log scale, whereas

signature exposure proportions are colored linearly. Samples are clustered according

to the exposure proportions using hierarchical clustering with average linkage.

(H) Mutational frequencies of common and rare signatures of CNS GEL cancers.

Numbers at the bottom indicate the numbers of samples with each signature.

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