Science - USA (2022-04-08)

them as being the result of a transcription-
related mutational process ( 9 ), and other studies
arrived at different conclusions regarding their
relevance in tumor signaling ( 19 , 21 ).

Furthermore, some noncoding events did

not fall into the protein-coding, regulatory, or

tissue-specific categories. This“other”cate-

gory exhibited mild enrichment for canonical

cancer genes (Fig. 2C) and includedMAD1L1

andMAD2L1(mitotic spindle assembly check-

point) in brain and ovarian tumors;NF1(tu-

mor suppressor) in breast tumors;DCC(known

Dietleinet al.,Science 376 , eabg5601 (2022) 8 April 2022 4 of 12

0 25 50 75 100 125 150

0

25

50

75

100

125

0 10 20 30 40 50 60 70 80

0

10

20

30

0 10 20 30 40 50 60 70

0

10

20

30

0 102030 4050 607080 90

0

10

20

C 30

no. known

cancer genes

no. significant regions

sorted by significance

coding regions regulatory regions tissue-specific other regions

no. significant regions

sorted by significance

no. significant regions

sorted by significance

no. significant regions

sorted by significance

sign. genes

random genes

sign. genes

random genes

sign. genes

random genes

sign. genes

random genes

1 2 3 4 5 6 7 8 9

10

11

12

13

14

15

16

17

18

19

20

21

22

X

SLITRK6

UBAP1

RAD51B

PIK3C2B

ZNF692

TERT

ZNF184

TRIM27

RABGEF1

LEPROTL1

TBC1D12

FGFR2

NEAT1

CDCA4

FAM174B

KCTD2

HAUS1DPP9

BTG3

ARID1A

ELF3

RHOB

CDKN1A

KMT2D

TP53

KDM6A

PIK3CA

FGFR3

RXRA

0510

Bladder(111 samples)

TMEFF2

HCN1

TERT

PIK3R1

PTCH1

PTEN

KMT2D

CTDNEP1

TP53

DDX3X

ATRX

IDH1

EGFR

SMO

0510

Brain(N = 337)

ZNF716

TRPS1

ANKRD30A

MGP

MAGED2

STC2

RAD51B

MIR21

XBP1

SMC6

STAG1

LEPROTL1

CCDC107

TBC1D12

MALAT1

ARID1A

MAP3K1

PIK3R1

KMT2C

GATA3

PTEN

TBX3

CBFB

CDH1

TP53MAP2K4

SF3B1

PIK3CA

ESR1

FOXA1

AKT1

0510

Breast(N = 440)

AGR2

LIPF

MALAT1

MIR21

CEP170

PTDSS1

ARID1A

APC

CDKN2A

MUC6

TP53

SMAD4

PIK3CA

0510

Esophag

us

(N = 157)

ALDOB

SLC5A12

GLYAT

SLC47A1

PCK1

TNFSF10

ARRDC3

ELMSAN1

TANGO2

TERT

CCDC107

NEAT1

VHLSETD2

BAP1PBRM1

PTEN

TP53

0510

Kidne

y

(N

= 26

4)

ST6GAL1

BTG2

CXCR4

BCL6

BACH2

BCL7A

IRF8

NOTCH1

SF3B1

0 510

Leukemia(N =

98)

ANGPTL3

CRP

GLUL

EPHX1

UGP2

CPS1

TF

CP

GC

ALB

ADH4

SELENOPHEXB

SLC22A7

PLG

IGFBP1

PON3

CYP3A5

BAAT

ALDOB

AKR1C1

CYP2C8

CYP2E1CKAP5

SLC38A4

HPD

SERPINA1

GATM

AQP9

HP

G6PCTTR

MIR122

C3

APOC4PCK1

SSX5

KNG1

RETREG1

PPP1R3C

MGST1

KHNYN

TERT

NEAT1

MED16

ARID1A

SETDB1

APOB

BAP1

FGA

CDKN1A

ARID2

AXIN1

TP53

NFE2L2

CTNNB1

0510

Liver(N =

375)

SFTPB

SFTPC

MIR21

SNAPC3

KLF6

FGFR2

B2M

SRCAP

FAM193B

CDKN2A

TP53

STK11

KEAP1

NFE2L2

CTNNB1

PIK3CA

EGFR

BRAF

KRAS

U2AF1

0510

Lung(N

= 223)

ZNF692

ZFP36L2

PCGF3

TP53

FOXL2

KRAS

0510

Ovary(N =

222)

CPB1

PNLIP

HIST1H1B

TMEM151A

ARID1A

ZFP36L2

TGFBR2

CDKN2A

TP53

RNF43

SMAD4

SF3B1

KRAS

GNAS

0510

Pancreas(N

= 302)

ELK4

PLPP1

KLK3

ERG

TMPRSS2

APC

TP53

CTNNB1

FOXA1

SPOP

0510

Prostate(N = 341)

TG

TERT

BRAF

0 510

Thyroid

(N = 56)

ARID1A

ZNF692

ZFP36L2

NFE2L2

SF3B1

CTNNB1;SETD2;BAP1IDH1

PIK3CA

TERT

PIK3R1

APC

CDKN1A

EGFR

BRAF

LEPROTL1

CDKN2A

CCDC107ALDOB

NOTCH1

PTEN;LIPF;TBC1D12

FGFR2

NEAT1;MALAT1

KRAS

KMT2D

FOXA1

RAD51B

TP53

MIR21

SMAD4

PCK1

ATRX

% of sign.

findings

Pan Cancer

(incl. 7 additional

cancer types)

0 2 4 6

no. cancer types -log10 (false discovery rate)

chromosome

coding region regulatory region tissue-specific gene other category

AB

* ***

* *

Fig. 2. Mutation events identified in a genome-wide analysis of the PCAWG
and HMF consortia.(AandB) Top: Pie charts showing the number of mutation
events per category (purple: coding, orange: regulatory, teal: tissue-specific,
gray: other) in aggregate (A) and individual cancer types (B). Bottom: Genomic
positions (y-axis) plotted against their significance in a genome-wide analysis
(x-axis) and colored by categories (B). The position (y-axis) of findings recurring

in more than one cancer type is plotted against the number of cancer types

(x-axis) (A).NEAT1andMALAT1are marked by asterisks because their

classification was ambiguous. (C) Mutation events sorted by their significance in

a genome-wide analysis (x-axis, orange) and plotted against the number of

findings involving known cancer genes (y-axis, top). Random overlap between

findings and cancer genes serves as a negative control (purple).

RESEARCH | RESEARCH ARTICLE