18DCIS 18IDC Supplementary FigureS4 22DCIS 22IDC C D B A E (0.77) (0.78) 16DCIS 14DCIS 28DCIS 16IDC 28IDC (0.43) (0.49) 0 ADAMTS12 (p.E1469K) 14IDC ERBB2, LASP1,CDK12( CCNE1 ( NUTM2B SDHC,FCGR2B,PBX1,TPR( CD1D, B4GALT3, BCL9, FLG,NUP21OL,TPM3,TDRD10,RIT1,LMNA,PRCC,NTRK1 0 ADAMTS16 (p.E67K) (0.67) (0.89) (0.54) 0 ARHGEF38 (p.P179Hfs*29) 0 ATG9B (p.P823S) (0.68) (1.0) ARID5B, CCDC6 CCNE1, TSHZ3,CEP89 CREB3L2,TRIM24 BRAF, EGFR (7p11); 0 ABRACL (p.R35H) 0 CATSPER1 (p.P152H) 0 ADAMTS18 (p.Y799C) 19q12 0 CCDC88C (p.X1371_splice) (0) 0 ADRA1A (p.P327L) (10q22.3) 0 CCNF (p.D637N) −4 −2 −4 −2 0 AKAP4 (p.G454A) 0 CDYL (p.Y353Lfs*5) −4 −2 Log2 Ratio Log2 Ratio −4 −2 Log2 Ratio Log2 Ratio 0 2 4 0 2 4 0 ARID2 (p.R1068H) 0 COL27A1 (p.G646E) 0 2 4 0 2 4 2 EDRF1 (p.E521K) 0 ARPP21 (p.P791L) ) 0 DDX11 (p.E78K) 2 GPR101, p.A174V 0 ARPP21 (p.P791T) 0 DMGDH (p.W606C) 5 ANP32B, p.G237S 16IDC (Ploidy:2.01) 16DCIS (Ploidy:2.02) 14IDC (Ploidy:2.01) 14DCIS (Ploidy:2.9) -3 -2 -1 -3 -2 -1 -3 -2 -1 -3 -2 -1 -3 -2 -1 -3 -2 -1 Log Ratio Log Ratio Log Ratio Log Ratio 12DCIS 0 ASPM (p.S222T) Log Ratio Log Ratio 0 FMN2 (p.G941A) 20 1 2 3 2 0 1 2 3 2 ERBB3 (p.D297Y) 2 0 1 2 3 20 1 2 3 0 ATRX (p.L1276I) 20 1 2 3 2 0 1 2 3 0 GALNT18 (p.F92L) 2 MAPK4, p.H147Y 0 GALNTL6 (p.E236K) 5 C11orf1, p.Y53C (10q21.2); 0 ATRX (p.R1401W) PIK3CA, p.H1047R 28IDC (Ploidy:2.0) 28DCIS (Ploidy:2.0) 22IDC (Ploidy:3.7) 22DCIS (Ploidy:4.1) 18IDC (Ploidy:3.9) 18DCIS (Ploidy:2.3) 17q12 0 HCFC1 (p.S2025C) 2 LCMT1 (p.S34A) 0 ATXN7L2 (p.X453_splice) SPEN, p.P677Lfs*13 CBFB 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 0 IGFN1 (p.D1166N) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 2 PIK3CA, p.H1047R 0 CCDC60 (p.E209K) TP53, p.R273C 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 0 INO80E (p.K86Sfs*45) 5 CBFB, p.X55_splice MYCL1, MPL WGD 0 CLIP2 (p.R448H) 0 IRF4 (p.Q395H) 2 MYH1 (p.Y353C) (19q12-q13.11) 0 CRY2 (p.D381H) ) TBX3 TP53, p.R249T PIK3CA, p.H1047R (0.37) 0 DACT3 (p.R286H) 0 ITGA9 (p.E967K) 2 RREB1, p.P997Rfs*40 0 KCTD3 (p.H403Y) CDK4 5 COPG1, p.I92V SDHC, FCGR2B,PBX1,TPR SDHC, FCGR2B,PBX1,TPR LMNA, PRCC, NTRK1, CD1D, B4GALT3, LMNA, PRCC,NTRK1,CD1D,B4GALT3, LMNA, PRCC, NTRK1, CD1D, B4GALT3, LMNA, PRCC,NTRK1,CD1D,B4GALT3, BCL9, FLG,NUP21OL,TPM3,TDRD10,RIT1 2 PIK3CA (p.H1047R) 0 DPPA2 (p.C96R) BCL9, FLG,NUP21OL,TPM3,TDRD10,RIT1 0 FLNA (p.I1620F) +61 0 KDM5B (p.G576R) +12 2 SPINK5, p.A621T BRAF, CREB3L2,TRIM24,EGFR BRAF, 0 KIAA1462 (p.Q893R) BRAF, CREB3L2,TRIM24,EGFR BRAF, 0 FLNA (p.K1621E) 0 MAATS1 (p.R419T) 5 LDB3, p.R31Q 2 PTPRZ1 (p.M710I) +38 +27 0 FYCO1 (p.E734Q) (12q14.1) 0 NELL1 (p.P628S) ERBB2, CDK12 +18 0 GRK5 (p.R190Q) 0 NOC2L (p.R213K) 2 SRF, p.V454I 2 SACS (p.S3505*) 0 GUF1 (p.P457S) 0 NUP210L (p.G612R) 5 PPAP2B, p.S254N 0 HEG1 (p.S722Y) 0 OR10AG1 (p.V193L) (7q33-q34) 2 SSFA2, p.G324E 0 IGF1R (p.E1037K) +13 0 PCSK2 (p.E90K) +3 0 IL17RA (p.V127L) 1q21.2-q31.1 2 SLC17A8 (p.N435H) TERT 0 PLCH2 (p.F717L) 5 SPEN, p.P677Lfs*132 0 KHDRBS2 (p.P202S) 0 PRRC2A (p.G1682E) 2 ZNF79, p.V156I +5 +32 0 KIAA1524 (p.N67S) 0 PTPN20B (p.L193F) 2 TBX3 (p.F133V) 0 KIAA1731 (p.P1682Qfs*5) 0 SEC24B (p.Q496K) 5 WIZ, p.R100W 0 KLRB1 (p.L12V) 0 SLC4A3 (p.L747R) (17q12) 3 CCSAP, p.Q104K 2 TP53 (p.R249T) 0 KPNA7 (p.T51M) 0 SLC6A13 (p.Q341E) GATA3p.R366* 0 LUZP4 (p.R5W) 0 SLFN14 (p.S83C) 4 TCF7L2, p.G308Sfs*16 0 MAMLD1 (p.W303C) ) 0 SNX13 (p.E515K) 3 SCN4A, p.E452K 2 WASF3 (p.P324R) 0 SRCRB4D (p.E459Q) FLGN TP53, p.Q192* ARID2 ATRX 0 MED12L (p.A1237S) +2 RECQL4 EPPK1 0 MUC16 (p.V3336F) 0 TIAM2 (p.P579S) 5 CKAP5, p.R1453C 2 GLUD2, p.R76H 2 ZC3H12B (p.E316K) 0 NKAPL (p.R321K) 0 TNFRSF1A (p.A357V) 0 NR1H3 (p.V218I) 0 TP53 (p.R273C) TCF7L2 0 NUP188 (p.S1126Cfs*9) 0 TRIM13 (p.E387K) 1 BCL11B, p.T435I 3 ATR (p.T1798A) 0 TSTD2 (p.G364D) 5 FHAD1, p.E1034V +3 +4 +93 0 OPRM1 (p.A19V) 0 OR2A14 (p.R219H) Chromosome 0 TTN (p.I21107L) Chromosome Chromosome 1 FAM149A, p.L332I 0 ZFYVE27 (p.E148Q) Chromosome Chromosome 3 USP24 (p.S581N) 0 OR2B11 (p.A48T) +6 5 GATA3, p.E359Afs*44 RECQL4 EPPK1 TERT 0 ZNF407 (p.S586C) 0 OTUD3 (p.E172Vfs*19) 0 HSPA13 (p.S10L) +3 0 PARP14 (p.L223F) +4 +7 +9 1 FAM174A, p.A31V 1 CDC27 (p.N486H) 0 PCGF6 (p.Y340*) 5 PDCD7 (p.A2T) 5 S1PR5, p.S104F WGD 5 SPTBN4 (p.A2141V) GATA3, p.E359Afs*44 +5 (5p15.33) 0 PEX14 (p.G110S) 6 ERBB2 (p.D769H) ARID5B, CCDC6 ARID5B, CCDC6 +2 NUTM2B 1 KNOP1 (p.I218Sfs*41) 0 RAPGEF6 (p.F742Y) NUTM2B 6 ERBB2 (p.D904N) 5 SERPINI2, p.E341A 1 KLHL26, p.S179L 0 RRAGB (p.Q194*) 6 HYDIN (p.Q3905Rfs*5) +26 0 RSRC2 (p.R253Q) +0 22IDC 6 OR4K2 (p.D175G) 1 TBC1D16 (p.D210Y) 0 SETDB2 (p.K563*) 2 GPR119 (p.S6L) 16IDC 1 GATA3, p.R366* 1 MACF1, p.X4015_splice 18D 28IDC 0 SI (p.T279I) 2 SLITRK5 (p.R208W) MYC, p.V421I (8q24.3) 0 SIGLEC5 (p.A464P) 2 ADAMTS3 (p.Q430K) 16IDC 1 TBC1D16 (p.E214*) 14IDC NUTM2B 0 SLC46A2 (p.P273Lfs*31) 2 ADAMTS5 (p.R516C) 1 HOXD4, p.T162Ifs*7 1 PHF19, p.R217K 11 11 11 CDK4 CDK4 0 SLC7A5 (p.L349H) 2 BMP10 (p.W198R) 2 CDH26 (p.E267K) 0 GSTO1 (p.R147S) 0 SNCAIP (p.D257N) SPEN, p.L2247Cfs*106 0 SORCS3 (p.R794Q) 2 CDK5R1 (p.R153C) 4 AMPD1, p.R112W 1 SAG, p.R179C 12 13 14 16 18 21 X 12 13 14 16 18 21 X 0 SP8 (p.D237N) 12 13 14 16 18 21 X 2 CPXM2 (p.A118V) SMO 0 PIBF1 (p.T757N) CDK12 NUTM2B MYCL1, MPL 0 ST6GAL2 (p.D191N) ERBB2, LASP1 2 GTPBP4 (p.N5T) CDK12 ERBB2, LASP1 4 ARL14EP, p.D38N 0 SYNCRIP (p.N285Tfs*22) 2 HIC1 (p.P265S) 1 SERPINA3, p.M290L +25 +4 +4 0 TUBGCP3 (p.E884K) 0 TFAP2D (p.X179_splice) 2 HSPG2 (p.D3515N) +26 MTOR BRIP1 2 KCNH8 (p.V1034L) MACF1 BCL11B 22DCIS 0 THRAP3 (p.N110D) 4 CPA1, p.R234C +20 2 KIF13A (p.A211V) 1 SERPINA3, p.M290K 0 TP53 (p.Q192*) +14 +13 +34 +2 0 ABCA13 (p.S3457R) CEP89 CCNE1, TSHZ3 CEP89 CCNE1, TSHZ3 2 KRT15 (p.R202C) (10q22.3) 0 TRIM4 (p.G465R) 0 USP29 (p.N188K) 2 NR2F1 (p.P23T) 4 EDN3, p.V179I +3 2 OIT3 (p.G428S) 6 GK2, p.N92S 28DCIS 28IDC 0 UTP20 (p.X1014_splice) (1p34.2) 0 ALDH1L2 (p.A848E) 2 PARS2 (p.P444R) 0 VPS4B (p.S248Kfs*2) 2 PTGS1 (p.R60H) 4 IRS2, p.R871W +15 0 WDFY3 (p.E928*) 2 RREB1 (p.L163Q) 6 MAPK8IP2, p.G227S 0 BRINP1 (p.D701E) 0 WRN (p.F763Lfs*14) 2 SERPINA11 (p.A15D) 0 ZBTB33 (p.S297*) 2 SERPINB13 (p.F201L) 4 ITIH5, p.V402I ERBB2, CDK12 ERBB2, CDK12 0 BRIP1 (p.I504M) 0 ZIM3 (p.K389N) 2 SHH (p.A389S) 6 PCMTD1, p.P342S 0 ZNF107 (p.C249Wfs*5) 2 SLC22A23 (p.P156R) 18IDC +8 0 ZNF341 (p.Q105K) 2 TEX15 (p.P1963S) 4 L1CAM, p.R322Q 0 CCNL1 (p.P5T) 0 ZNF653 (p.P409L) 18IDC 6 PEF1, p.L179V CCNE1 CCNE1 2 TMPRSS11D (p.A114V) 0 ZNHIT6 (p.N333K) 18DCIS 2 ZNF445 (p.A307D) 4 MYC, p.V421I 0 FGFRL1 (p.H485Lfs*66) 4 DHX9 (p.N30Tfs*43) 16DCIS 0 COL9A3 (p.G35Afs*53) +8 6 SPEN, p.L2247Cfs*106 0 KIAA1462 (p.Q182R) 4 FREM2 (p.A202T) 14IDC +6 0 MAP3K10 (p.L881Rfs*123) 4 GAK (p.A341T) 16DCIS 4 NCKAP1, p.G442S 0 HMGCS2 (p.L402M) 0 MSH3 (p.P63A) 4 GPATCH8 (p.R1023Q) 14DCIS 4 HEXDC (p.R327C) 6 AKR1C4, p.G298V 22IDC 0 PLEKHG2 (p.E264K) 4 INTS9 (p.M519I) 14DCIS 22DCIS 3 AP5S1 (p.Q82*) 4 SSC5D, p.T1321M 0 KCNH2 (p.Y827H) 4 ITPR2 (p.A445V) 28DCIS 3 DUSP27 (p.G697E) 3 FLG (p.E990K) 4 KCTD14 (p.R157C) 6 ATP8A1, p.I306V 0 KIAA0754 (p.E623D) 3 WEE2 (p.R546P) 4 KIFC2 (p.P771L) 4 TNC, p.R1843C 3 SLC7A9 (p.E244K) 4 MPG (p.R201W) 3 SLC7A9 (p.P248H) 4 NPAT (p.S1200Y) 6 BTRC, p.L389Ffs*5 0 MTOR (p.L219F) 4 PRPF18 (p.E309K) 4 SMO (p.D786N) 4 SKI (p.R282W) 4 SYNE2 (p.M3705I) 4 UCP3 (p.A231S) 6 CLTB, 0 PLA2G4E (p.H392Q) 4 TACC2 (p.V2378I) 4 USP8 (p.A798P) 4 TEX10 (p.H728N) 4 XPC (p.X207_splice) 4 USP9X (p.A479T) 4 ZBTB18 (p.S145G) 6 ERVV−2, p.A464S 0 PVRL4 (p.Q336Rfs*10) 4 SYNGR3 (p.P137T) 4 ZNF561 (p.H415Qfs*22) 4 TMEM26 (p.D253N) 100% 100% 4 AGGF1 (p.V202L) 100% 100% 100% Cancer cell fraction (%) Cancer20% cell40% fraction60% 80% (%) 1 AGGF1 (p.V202L) Cancer20% cell40% fraction60% 80% (%) 4 OR5H15 (p.R143W) 20% 40% 60% 80% 0 RTTN (p.A546D) 20% 40% 60% 80% Cancer cell fraction (%) Cancer20% cell40% fraction60% 80% (%) 0% 1 KCTD7 (p.N334D) 0% 0% 0% 1 LRP1 (p.D4193Rfs*9) 0% 0 SPATA31E1 (p.P288T) 1 SCYL2 (p.L395I) 28DCIS 28IDC 22DCIS 22IDC 1 TFDP2 (p.Q261K) 14DCIS 16DCIS 16IDC 18DCIS 18IDC Cancer CellFraction(%) Cancer CellFraction(%) Cancer CellFraction(%) Cancer CellFraction(%) Cancer CellFraction(%) 80% <CCF≤100% 60% <CCF≤80% 40% <CCF≤60% 20% <CCF≤40% 10% <CCF≤20% 0% <CCF≤10% CCF =0% 80% <CCF≤100% 60% <CCF≤80% 40% <CCF≤60% 20% <CCF≤40% 10% <CCF≤20% 0% <CCF≤10% CCF =0% 80% <CCF≤100% 60% <CCF≤80% 40% <CCF≤60% 20% <CCF≤40% 10% <CCF≤20% 0% <CCF≤10% CCF =0% 80% <CCF≤100% 60% <CCF≤80% 40% <CCF≤60% 20% <CCF≤40% 10% <CCF≤20% 0% <CCF≤10% CCF =0% 80% <CCF≤100% 60% <CCF≤80% 40% <CCF≤60% 20% <CCF≤40% 10% <CCF≤20% 0% <CCF≤10% CCF =0% 14IDC Cluster Cluster Cluster Cluster Cluster 5 4 3 2 1 6 5 4 2 0 3 2 1 0 4 3 1 0 6 5 4 2 1 13IDC 8DCIS 4DCIS 13DCIS 8IDC 4IDC (0.69) G H (0.43) F (0.61) (0.56) J (0.61) I (0) 0 A2ML1, p.A593S 0 A2M, p.V868M 0 AGBL3, p.V400I 0 ADAMTSL4, p.R528C 0 DCAF8L2, p.V587M KMT2A PIK3CA, p.H1047R 0 ANKRD33B, p.A274S 0 APC, p.A1591V 10DCIS 12DCIS 0 DISP2, p.A45T 10IDC 0 C12orf10, p.R253* 0 COL6A2, p.V812L 0 ERRFI1, p.L118Qfs*2 0 CCAR1, p.L106* SS18L1, TSHZ2 HLF, MSI2,CLTC,PPM1D, CD79B,DDX5 0 FANCD2, p.H1320Q 12IDC 0 KIAA1377, p.A763T −4 −2 −4 −2 −4 −2 −4 −2 −4 −2 −4 −2 −4 −2 −4 −2 Log2 Ratio Log2 Ratio −4 −2 Log2 Ratio Log2 Ratio Log2 Ratio Log2 Ratio −4 −2 Log2 Ratio Log2 Ratio Log2 Ratio Log2 Ratio 0 CYP19A1, p.R457* 0 2 4 0 2 4 0 2 4 0 2 4 0 2 4 0 2 4 0 2 4 0 2 4 0 2 4 0 2 4 0 FLYWCH1, p.E19V (0.61) CCND1 CALR(19p13.2-13.11) LYL1, DDIT3,CDK4,MDM2,PTPRB NAB2, STAT6, ETV6, CDKN1B,KRAS,PPFIBP1,H3F3C( KDM5A, ERC1,CCND2,CHD4,ZNF384, (0.28) (0.37) 0 GABRA2, p.R94* +10 0 KMT2A, p.P3515Lfs*36 0 ECT2L, p.I31T MED23 PIK3CA, p.E545D PIK3CA, p.H1047L TP53, p.V73Wfs*50 10DCIS (Ploidy:1.92) 12IDC (Ploidy:2.21) 12DCIS (Ploidy:2.03) 10IDC