Science - USA (2022-04-22)

Degasperiet al.,Science 376 , eabl9283 (2022) 22 April 2022 2 of 15

GEL commonICGC common

Hartwig common

GEL rareICGC rare

Hartwig rare

0

5

10

15

20

Number of common and rare SBS signatures

GELICGC

Hartwig

0 500 1000150020002500

0

5

10

15

20

Number of rare SBS signatures and samples

(Pearson corr. 0.76)

samples in each organ

GELICGC

Hartwig

cohort

GEL

ICGC

Hartwig

Total WGS samples

ICGC

3001

Hartwig 3417

12222 GEL

A

1000

2000

3000

samples

SNVs

DNVs

100

102

103

101

10104

1056

107

100

102

103

101

104

10105

1067

Skin Lung

Esophagus

StomachColorectalBladder

Liver

Head_neck

Oral_Oropharyngeal

UterusOvaryBiliaryKidney

Pancreas

BreastProstate

Bone_SoftTissue

CNS

Lymphoid

NET

Myeloid

GEL

Clustering on

mutational profiles

Exclusion of

atypical profiles

(12,222 WGS) (3,001 WGS)

ICGC Hartwig

(3,417 WGS)

Breast Ovary Stomach Uterus Breast Ovary Stomach Uterus Breast Ovary Stomach Uterus

Samples with

commonprofiles

All

samples

Extraction

of commonsignatures

Identify samplesthat contain

additional rare

signatures

Common

Organ-specific

Signatures

Rare

Organ-SpecificSignatures

Total SBS signatures

across organs (757)

135 GELcommon

180 GELrare

135 ICGCcommon

58 ICGCrare

135 Hartwigcommon

114 Hartwigrare

For each organin each cohort

0 500 1000150020002500

0

5

10

15

20

Number of common SBS signatures and samples

(Pearson corr. 0.14)

samples in each organ

GELICGC

Hartwig

B

C

D G

E

F

signatures in each organ

common signatures in each organ

rare signatures in each organ

Organ-specificsignatures

of all three

cohorts

(757)

PatternsDistinct

(187)

Clustering

to determine

Distinct Patterns

Recurrent

Distinct

Patterns(88)

Mixed

Distinct

Patterns(29)

Singleton

Distinct

Patterns(70)

Clustering into

RecurrentReference

Signatures (74)

Determine

composition

Referenceby other

Signatures

Variants of

Recurrent

Reference

Signatures

(24)

Known

signatures

from

other studies

(8)

Additional

previously

unreported

(38)

Reference

Signatures(120 SBS

signatures)

82 QC green SBS signatures 38 QC amber and red SBS signatures

Fig. 1. Whole-genomeÐsequenced cancers across three independent cohorts:
GEL, ICGC, and HMF.(A) WGS cases included in analyses. (B)Numberofsamples
and mutational burden of somatic single-nucleotide variants (SNVs) and double-
nucleotide variants (DNVs) across 21 whole-genomeÐsequenced tumor types from
the GEL, ICGC, and HMF cohorts. Not all tumor types (e.g., esophagus, head and
neck, oropharyngeal) are represented in all three cohorts. (C) Schematic
representation of the workflow of mutational signature analysis. Three cohorts (GEL,
ICGC, and HMF) were evaluated independently. For each organ in each cohort,
mutational catalogs were clustered and samples with atypical catalogs were
excluded from the extraction process. Samples with similar catalogs were subjected

to signature extraction to obtain a set of common organ-specific signatures. These

common signatures were fitted into all samples, highlighting samples with a high

error profile that were subsequently used to identify rare signatures. The pie

chart shows the total number of SBS signatures identified for each independent

extraction of each organ in all three cohorts. (D) Number of common and rare SBS

signatures in each cohort. (E) Common SBS signatures as a function of number

of samples analyzed. (F) Rare SBS signatures as a function of number of samples

analyzed. (G) Procedure to determine the reference signatures from all identified

cohort-organ signatures. Numbers refer to the SBS signature analysis. For details,

see materials and methods.

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