Supplementary FigureS1 G E C A Cancer Cell Fraction (%) Cancer Cell Fraction (%) Cancer Cell Fraction (%) 100% 100% 100% 20% 40% 60% 80% Cancer Cell Fraction (%) 20% 40% 60% 80% 20% 40% 60% 80% 100% 0% 0% 0% 20% 40% 60% 80% 0% 1DCIS-A 6ILC 8ILC 3DCIS 8LCIS-A 1DCIS-B 6LCIS-A 1DCIS−A 1DCIS−B 1LCIS−A 1LCIS−B 3IDC Cluster: 3DCIS 3LCIS (0.67) (0.68) 3IDC (0) (0) 8LCIS-B 1LCIS-A 6LCIS−A 6LCIS−B 8LCIS−A 8LCIS−B 6LCIS-B 4 SPAST (p.E602Q) Cluster: 4 4 TRIM63 (p.P120T) (0.69) (0.78) 6ILC 4 TULP1 (p.A114V) 3LCIS (0) 8ILC 4 CYB5R3 (p.P319R) Cluster: 5 5 TBX3 (p.R436Tfs*3) 5 DYSF (p.F205Sfs*35) Cluster: 1LCIS-B 5 DYSF (p.A214Lfs*45) (0.69) 2 ABL1 (p.P810L) (0) (0) (0.57) (0.59) 2 ANP32B (p.G237S) 2 ACKR2 (p.L85V) (0) 2 AHR (p.Q600E) 2 ANKRD34B (p.T302A) 2 C11orf1 (p.Y53C) 2 ART1 (p.R179Q) 4 ZNF484 (p.T708I) 2 ATRNL1 (p.I390V) 2 CBFB (p.X55_splice) 2 B4GALT2 (p.V207I) 1 ABCA3 (p.C1337Y) 4 4 AKT1 (p.L52R) 2 BBS9 (p.Q621*) 2 BBX (p.N563I) 2 BLACE (p.E153K) 1 ACAN (p.V1839L) 4 VPS13A (p.A2948T) 2 2 COPG1 (p.I92V) 2 BLK (p.A71T) 1 CDH1 (p.X571_splice) 4 ZNF426 (p.I297S) 2 C11orf35 (p.C345S) 2 LDB3 (p.R31Q) 2 C11orf35 (p.G207R) 1 EIF4E2 (p.R103C) 2 C2orf62 (p.A382V) 1 ATRX (p.T2295I) 2 C2orf62 (p.S384W) 2 PPAP2B (p.S254N) 2 C3orf35 (p.M1?) 1 FOXK2 (p.H308R) 1 COX8A (p.H61Y) 2 CA2 (p.Q74*) 2 SPEN (p.P677Lfs*132) 2 CCDC154 (p.I612M) 1 HDAC6 (p.T979I) 1 DNAH9 (p.R1533W) 2 CCDC64B (p.E240Q) 2 CEP290 (p.I2134T) 1 ITGAV (p.R152L) 2 CFHR5 (p.V379L) 1 G3BP2 (p.E279K) 2 WIZ (p.R100W) 2 CLIC6 (p.S269G) 1 KRTAP19−4 (p.G40R) 2 DAXX (p.A486G) 1 1 OGDHL (p.V304A) 4 TCF7L2 (p.G308Sfs*16) 2 DISC1 (p.E751Q) 1 LAMA5 (p.R2226Pfs*3) 2 DNAH12 (p.L2346F) 1 PDE10A (p.M460T) 2 DUPD1 (p.E25K) 1 4 GATA3 (p.R366*) 1 LMO7 (p.G1160E) 2 EPC2 (p.R510T) 1 PRR11 (p.E23Rfs*46) 2 ERAP2 (p.R751C) 1 LTBP2 (p.K392T) 4 GLUD2 (p.R76H) 2 FAM161B (p.P688S) 2 FAM47A (p.E507Q) 1 SERPINA3 (p.M290L) 7 2 FNDC3A (p.E360K) 1 RBM10 (p.S622L) 4 BCL11B (p.T435I) 1DCIS−B 2 FUT7 (p.A270T) 1LCIS−B 1 SERPINA3 (p.M290K) 4 2 GATA1 (p.R113H) 1 SLC17A6 (p.E339K) 1LCIS−A 2 GPIHBP1 (p.S144F) 1 SYNM (p.R1092C) 4 FAM149A (p.L332I) 2 GSTO2 (p.M29I) 5 1 SOGA2 (p.N219S) 2 HIST1H4L (p.G10D) 1 TNFRSF8 (p.Q202K) 4 FAM174A (p.A31V) 2 HMCN1 (p.V3540I) 1 WDR3 (p.P804H) 2 HP1BP3 (p.I516L) 2 ICT1 (p.R8L) 1 YY1AP1 (p.G107E) 1 WWP2 (p.N592K) 4 KLHL26 (p.S179L) 7 2 IGLV1−50 (p.N74S) 1 2 KIFC1 (p.R219Q) D 3 CDH1 (p.P127Afs*41) 6 7 2 KIRREL3 (p.I190V) C 1 ZYX (p.Q233L) 2 KRT75 (p.R527Q) 4 MACF1 (p.X4015_splice) L I C 3 ANKRD11 (p.R840Q) S 2 LCE2B (p.I51S) 4 C1orf173 (p.E749K) 2 I 6ILC 2 LEMD3 (p.S164L) 1 S 4 SAG (p.R179C) B 6 2 LRRIQ1 (p.N1702Ifs*20) 3 ARHGAP11A (p.V410I) 4 C2CD5 (p.D67V) B 2 MALRD1 (p.D1091G) L 2 MASP2 (p.D120G) 3 CABIN1 (p.D1749N) 3 BTRC (p.L389Ffs*5) C 4 FRMD3 (p.G200W) 2 MATN4 (p.P508L) I p.X55_splice S 2 MESP2 (p.H241Y) 4 4 HSCB (p.M157T) 3 CASQ1 (p.M87T) 2 MSLNL (p.E702Q) 3 GK2 (p.N92S) A 2 MUC7 (p.L249P) 4 NPFFR2 (p.P214S) 1 3 CEP68 (p.F367Y) 2 MUTYH (p.R171W) 3 3 MAPK8IP2 (p.G227S) 2 NEB (p.E1469D) I 3 DCPS (p.R315H) 2 NID1 (p.R757H) 4 PGBD2 (p.E53*) L 1 2 NOS3 (p.E463D) C 5 3 PEF1 (p.L179V) 2 NRXN3 (p.S184L) 3 DNAJC30 (p.P14L) 4 WEE2 (p.D48V) 6LCIS−B 2 OR5AR1 (p.I225V) 3 SPEN (p.L2247Cfs*106) 2 OR5AS1 (p.D191N) 4 ZNF229 (p.T211S) 3 HLA−DMA (p.G181A) 2 OR6T1 (p.I36T) 3 2 PCDHGA10 (p.E257Q) 2 BCL11A (p.P480L) 3 OR10J3 (p.V205I) 3 TFEC (p.P10S) 2 PCDHGA8 (p.E316Q) 2 PHKB (p.M185I) 2 DNAH17 (p.E2368K) 3 OR52J3 (p.R224C) 2 PIK3C2G (p.A1360V) 3 VKORC1L1 (p.R8S) 2 PKP4 (p.D604G) 3 2 2 PTCH1 (p.T1195S) 2 GAS7 (p.A323V) 3 PGM2 (p.V102M) 3LCIS 2 2 3 AKR1C4 (p.G298V) 2 PTPRC (p.I296L) 8LCIS−B 2 MID1 (p.Y542F) 2 RASGRF1 (p.R478C) 8LCIS−A 3 SCLT1 (p.D104E) 3IDC 2 RNLS (p.M308I) 2 2 RPRM (p.E43K) 2 PYDC2 (p.D48E) 1 3 ATP8A1 (p.I306V) 3 SLC9A5 (p.K642M) 2 SBK1 (p.L32V) 2 5 L 2 SH3RF3 (p.A35T) 2 RREB1 (p.E1498G) C 3 NAP1L5 (p.A22V) 2 SH3TC1 (p.L1016V) L 3 SPEG (p.R1340Q) C 1DCIS−A I 2 SMG1 (p.R1418T) S I 3 ARHGEF12 (p.R705H) 3DCIS 2 SNED1 (p.R129Q) S 6LCIS−A 3 TCP11L2 (p.D261N) 3 SENP6 (p.S606R) 2 SNRNP70 (p.R356Q) 1 B 8 8ILC 3 C11orf35 (p.R141W) NCOR1 2 SORL1 (p.E270K) 3 TMEM108 (p.A255V) 2 SPIC (p.K109R) 1 L 1 1 CBFB (p.X133_splice) 9 2 SPTAN1 (p.D1676H) 3 CASD1 (p.F17L) C 0 1q3 TMEM42gain (p.M96V) 2 ST6GAL2 (p.F30Y) I L 8 S 2 TAF1C (p.G635S) GATA3,HMCN1 C I 3 CXorf66 (p.N244D) 1 CDH1 (p.Y413Ifs*6) D L I A 3 TRBV4−1 (p.Y54*) 2 TBX22 (p.N368H) S C 3 DNAH9 (p.T3487M) C 2 TELO2 (p.A11T) 1q gain, 16q loss I TBX3 1 CEBPA (p.G255E) B S 2 TELO2 (p.A11D) 7 3 TTN (p.P15979L) 3 2 TENM1 (p.G344S) A 3 DTHD1 (p.E725Q) 2 TLX1 (p.G31D) 3 ZNF541 (p.G296W) 1 ELP2 (p.Q500Rfs*7) D 1q gain 2 TNXB (p.T1916A) 3 DYTN (p.F565S) C 2 TRMT10B (p.G186E) I 3 ZNF561 (p.K22T) 1 GATAD2A (p.K367R) S 2 USP29 (p.E400Q) CDH1 p.L731Gfs*38 , 3 EFTUD2 (p.R730H) 2 ZBTB7C (p.V353G) A 2 AP3B1 (p.S855C) 2 ZIM3 (p.K438*) NCOR1 ,CBFB 3 FPR3 (p.C126F) 2 ZNF182 (p.H592Y) 1 1 GNAT2 (p.R105Q) 1 5 2 ATP2B2 (p.D518N) 6 2 ZNF467 (p.E567K) 1q gain, 16q loss 3 COG4 (p.N345T) 3 GUSB (p.A380T) I 3 D L 1q gain 1 GRSF1 (p.I341S) 3 HELZ2 (p.V1034M) C 2 B3GALNT1 (p.G109V) 3 HRH2 (p.A209T) C 3 MYH1 (p.V140L) 3 ZCCHC5 (p.R19W) I 1 HMGCS2 (p.R188H) 3 KIAA1462 (p.A1045V) TBX3 2 CBFB (p.X55_splice) S 3 WFIKKN2 (p.K107R) 3 8 CATSPER1 (p.T628M) 1 3 LSAMP (p.P131Q) 2 CDH1 (p.G690fs) 1 HYAL2 (p.D133N) 8 DFNA5 (p.G59D) 1q gain 8 DNAH8 (p.R1977K) 2 DHX15 (p.E208*) 8 GHRHR (p.I387F) 3 MUC16 (p.S13209N) 1 IGDCC3 (p.M348T) 8 GPR143 (p.C316Y) Cancer CellFraction(%) Cancer CellFraction(%) Cancer CellFraction(%) Cancer CellFraction(%) 8 HS3ST6 (p.K239R) 3 NBPF20 (p.F69C) 2 DVL3 (p.P22R) 8 8 KRT8 (p.S59A) ,GATA3,HMCN1 1 INTS2 (p.Q123H) 8 LMO4 (p.C50G) 80% <CCF100% 60% <CCF<=80% 40% <CCF<=60% 20% <CCF<=40% 10% <CCF<=20% 0% <CCF<=10% CCF =0% 80% <CCF100% 60% <CCF<=80% 40% <CCF<=60% 20% <CCF<=40% 10% <CCF<=20% 0% <CCF<=10% CCF =0% 80% <CCF100% 60% <CCF<=80% 40% <CCF<=60% 20% <CCF<=40% 10% <CCF<=20% 0% <CCF<=10% CCF =0% 3 NUP214 (p.L59F) 2 IDH3G (p.P67S) 80% <CCF100% 60% <CCF<=80% 40% <CCF<=60% 20% <CCF<=40% 10% <CCF<=20% 0% <CCF<=10% CCF =0% 8 SZT2 (p.F1400L) 1q gain, 16q loss 8 TEX13A (p.P150T) 2 1 KDM6A (p.R658*) 3 OR2L2 (p.T105I) 2 MPRIP (p.R67Q) 8 TTN (p.V27187I) 8 EPHB1 (p.I330T) CDH1 p.L731Gfs*38 , ,CBFB 3 PABPC3 (p.F335Lfs*19) 2 MVD (p.G365D) 1 MADD (p.W250C) 8 TSPYL2 (p.R13H) 1 C7orf57 (p.R231*) 1q gain, 16q loss 3 RGMB (p.D103Y) 2 QARS (p.L252P) 1 CDK3 (p.D38N) 1 MRGPRF (p.G63R) 1 DDX11 (p.S561F) 1 FETUB (p.M106I) 3 SPATS2 (p.Y437S) 2 RABGAP1L (p.A306T) 1 FIZ1 (p.S117F) 1 OSGIN1 (p.A11T) 1 1 FREM2 (p.V1876I) 3 TOPBP1 (p.C76Y) 2 SPDEF (p.P321L) 1 HLA−DRB5 (p.R77Q) 1 OVCH1 (p.S688R) 1 LPCAT4 (p.L213I) 3 ZDBF2 (p.R291C) 2 ST5 (p.I889V) 1 NCOR1 (p.L57Afs*23) 1 PRSS1 (p.N246D) 1 TNNT3 (p.R63H) 1 PRSS3 (p.R158Sfs*11) 2 ZNF281 (p.E640G) 1 PRSS3 (p.T160Sfs*4) H F D Cancer Cell Fraction (%) B 100% Cancer Cell Fraction (%) Cancer Cell Fraction (%) 20% 40% 60% 80% 0% 100% 100% Cancer Cell Fraction (%) 20% 40% 60% 80% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 0% 0% 5ILC 9IDC 7DCIS 2ILC CDH1,ELF3, ARID1A,ASXL1,NCOR1,ZNF292 TCF7L2 ,GATA3,CBFB RUNX1p.X118_splice SPENp.P677Lfs*132 1q gain, 16q loss 9LCIS-A p.I1220L p.Q264* 7IDC BTRC, GK2,SPEN p.L2247Cfs*106 1q gain, 16q loss KDM6A ,RUNX1 APC,HMCN1, KDM6A p.W1219C 2LCIS-A 5LCIS 7LCIS−A 7LCIS−B 5ILC 5LCIS 2LCIS−A 2LCIS−B 1q gain 16q loss ,CBFB p.X133_splice7DCIS Cluster: 7ILC 7IDC CDH1,CEBPA,KDM6A 7ILC (0.36) (0.59) 9LCIS-B Cluster: 2ILC ARID1A,ASXL1,NCOR1,ZNF292 Cluster: (0.65) (0.55) (0.69) 2LCIS-B (0.69) (0.65) CDH1,ELF3, ,RUNX1p.X118_splice (0.65) 2 AQPEP (p.E55K) (0.6) p.W1219C p.I1220L p.Q264* 7LCIS-A 1q gain, 16q loss APC,HMCN1, KDM6A ,KDM6A ,RUNX1 1q gain,16q loss ,CBFB p.X133_splice ,CDH1,CEBPA,KDM6A (0) 9LCIS−B 2 BAZ2B (p.Q499*) 9LCIS−A 2 C1orf177 (p.L376Yfs*3) 1 AC002472.13 (p.D116G) 2 CCDC109B (p.Q181*) 9IDC 2 CCDC84 (p.K146N) BTRC, GK2,SPEN p.L2247Cfs*106 2 CDH1 (p.X130_splice) 1 CDH1 (p.L582Cfs*2) TCF7L2 ,GATA3,CBFBp.X55_splice ,SPENp.P677Lfs*132 2 CHADL (p.G539R) 1 CBFB (p.Q67H) Cluster: 2 CHD1 (p.L1358P) 1 GPR39 (p.I15V) 2 CPA3 (p.X328_splice) 7LCIS-B 1q gain, 16q loss 1 2 DDX31 (p.R20W) (0.57) 1 KIAA1429 (p.D395G) 2 ELF3 (p.S133A) 1 CDH1 (p.L731Gfs*38) (0) (0) 2 ERCC2 (p.N238S) 1 MYH9 (p.E929dup) 2 FAM154B (p.P265S) 2 FAT2 (p.V3519I) 1 CENPJ (p.V555I) 1 SOX10 (p.S135G) 2 FBXO11 (p.D908N) 2 FRMPD1 (p.E744K) 1 ZNF473 (p.D76N) 2 GDE1 (p.S52F) 1 DFNA5 (p.S474C) 3 FSCB (p.A181V) 2 GRB10 (p.Q411*) 1 ZNF575 (p.A142T) 2 INSM1 (p.G148R) 2 ITGA10 (p.A633V) 2 AC138647.1 (p.R141C) 2 KIF21B (p.K545R) 1 KY (p.G51E) 2 3 CDH1 (p.X178_splice) 2 KRTAP4−8 (p.C95S) 3 2 ADAMTSL4 (p.L905P) 2 MGST2 (p.S15L) 2 MOXD1 (p.D105Y) 1 MAGEA11 (p.K240*) 2 ARHGAP22 (p.R57C) 2 MROH2B (p.E1109K) 3 CYP4F3 (p.R390W) 2 PGAP1 (p.E461Q) 1 2 CBFB (p.Q134*) 2 PGAP1 (p.E44K) 1 PIK3CA (p.H1047R) 2 PIK3CA (p.E545K) 2 EMILIN2 (p.G934R) 2 PPP6R3 (p.G97E) 3 TCEAL2 (p.R128H) 2 RABEP2 (p.S265L) 1 PLCE1 (p.P698S) 2 GATA3 (p.X308_splice) 2 RIBC2 (p.R132W) 2 2 RNMTL1 (p.Q74L) 2 KLHL36 (p.Q84*) 2 RUNX1 (p.X118_splice) 1 SLC44A4 (p.X377_splice) 1 ADI1 (p.X81_splice) 2 SPINT1 (p.D49N) 2 LDB3 (p.T527N) 2 SYTL4 (p.E286K) 2 TMEM156 (p.I195T) 2 LYN (p.L93Wfs*14) 2 TSPYL2 (p.E93K) 1 TOR1AIP2 (p.V418G) 1 C14orf1 (p.N73S) 2 TXNDC11 (p.M213R) C D 2 NINL (p.A859S) P 2 VPS13D (p.L4009F) H I K 2 ZFYVE26 (p.S1768P) 1 CALCRL (p.X390_splice) 1 P 2 PIK3CA (p.H1047R) 3 2 ZNF341 (p.D25Y) ,CBFB,GATA3,LYN C I P APC 3 ADNP (p.E883Q) p.Q23* A 1 C3orf67 (p.D536E) K I 1q gain,16q loss p.E545K K 3 ANKLE2 (p.S181Rfs*13) 2 TENM4 (p.D1313N) 3 1 ITPRIPL1 (p.V158I) 3 C 3 ARL5C (p.V19L) C 4 FDX1L (p.G87E) A 3 ASXL1 (p.E670Gfs*7) A 1 GDF3 (p.E323Q) ATRX p.E545K 3 ATP10B (p.V1277I) 2 GFM2 (p.D131Y) , C p.H1047R