Supplementary Figure S4

A F K P

Cancer Cell Fraction (%) Cancer Cell Fraction (%) Cancer Cell Fraction (%) Cancer Cell Fraction (%) CCF = 0% CCF = 0% CCF = 0% CCF = 0% 0% < CCF ≤ 10% 0% < CCF ≤ 10% 0% < CCF ≤ 10% 0% < CCF ≤ 10% 1 SERPINA3, p.M290L 1 SERPINA3, p.M290K 6 CLTB, 6 CLTB, 6 GK2, p.N92S 6 MAPK8IP2, p.G227S 6 PCMTD1, p.P342S 6 PEF1, p.L179V 6 AKR1C4, p.G298V p.I306V 6 ATP8A1, 1 BCL11B, p.T435I 1 BCL11B, 1 KLHL26, p.S179L p.X4015_splice 1 MACF1, 5 C11orf1, p.Y53C p.X55_splice 5 CBFB, 5 COPG1, p.I92V 5 LDB3, p.R31Q p.S254N 5 PPAP2B, 5 SPEN, p.P677Lfs*132 5 WIZ, p.R100W 4 TCF7L2, p.G308Sfs*16 6 SPEN, p.L2247Cfs*106 p.L389Ffs*5 6 BTRC, 2 GLUD2, p.R76H p.L332I 1 FAM149A, p.A31V 1 FAM174A, 1 PHF19, p.R217K p.R179C 1 SAG, 6 ERVV−2, p.A464S 5 ANP32B, p.G237S 5 ANP32B, 1 USP8, p.W655R 1 ZNF496, p.K470N 2 LDB3, p.T527N p.L93Wfs*14 2 LYN, p.X3442_splice 4 RYR2, 2 ADAMTSL4, p.L905P 2 ADAMTSL4, p.X308_splice 2 GATA3, 2 KLHL36, p.Q84* 2 NINL, p.A859S 2 PIK3CA, p.H1047R 2 TENM4, p.D1313N p.N406S 0 MAG, 0 SIGIRR, p.M410T 0 ZNF112, p.R791P 4 FDX1L, p.G87E p.A8T 1 BCKDHB, 1 TMED6, p.V72G 1 FGD5, p.E63K p.S201L 1 RAD51B, 1 SMTNL2, p.K340N p.R397* 1 TAF3, 2 ARHGAP22, p.R57C p.Q134* 2 CBFB, 2 EMILIN2, p.G934R 0 NRG3, p.K675N p.A2292D 0 PCNT, 0 PIK3CA, p.E418K 0 PTEN, p.E235* 0 RDH13, p.G16S p.A180P 0 RUNX2, 0 TCTN1, p.G34V p.V450F 0 TMEM132B, 2 HAS2, p.I13T 2 SLC16A2, p.Q301P 2 YPEL2, p.K8N p.R209L 3 FOXA3, p.L670V 3 RTEL1, p.C1008F 3 ADAMTS14, 3 C3orf72, p.S8F 1 TRPM8, p.G913C 4 C17orf67, p.P44H 4 DTX3L, p.V452I 0 GLUD2, p.R50W p.P1443S 0 GPATCH8, p.D86H 0 HIST1H4B, 0 LAMA5, p.C1145S 0 LIFR, p.R75P p.G1614S 0 LTBP2, 0 MAML3, p.S342L 0 MMP2, p.V648A p.A135V 0 MYO18B, 0 SCN4A, p.S682L 0 SELE, p.K107T 0 SMARCA1, p.E500K 0 ST5, p.R312Q 2 CDK16, p.E541D 2 DNAH7, p.M2582I p.A118E 2 FAM184B, 4 PCDHA3, p.Q755* 0 C12orf10, p.R253* 0 CCAR1, p.L106* 0 CYP19A1, p.R457* 0 ECT2L, p.I31T p.P408Afs*99 0 GATA3, p.N253I 0 MCMBP, p.F116L 0 MIF4GD, 0 ADAMTSL4, p.R528C 0 ADAMTSL4, 0 APC, p.A1591V 0 APC,

10% < CCF ≤ 20% 10% < CCF ≤ 20% 10% < CCF ≤ 20% (p.M11I) 1 ACD (p.H513Y) 1 ACSL6 (p.I131V) 1 ADAM17 (p.Y461C) 1 ADNP (p.T1669P) 1 AKAP6 (p.N678Efs*82) 1 ANKRD35 (p.V1684Efs*4) 1 ARID1B (p.Q690Tfs*3) 1 ATG9B (p.G601C) 1ATP1A2 (p.S133F) 1ATP4B (p.Q343K) 1 BAI1 (p.R311G) 1 BRD9 (p.E1325K) 1 C12orf55 1 C6orf203 (p.T132S) 1 CDH24 (p.V140L) 1 CTIF (p.E273D) (p.S2687C) 1 DNAH2 (p.S2687I) 1 DNAH2 1 DSTYK (p.K746N) (p.L599M) 1 EPPK1 (p.E66K) 1 ESR2 1 FAM3A (p.F179I) 1 FOXB2 (p.A253T) (p.N404Y) 1 GCNT3 (p.T66A) 1 GINM1 1 GPR52 (p.L102F) 1 GRIK1 (p.S93L) (p.R226T) 1 HIATL1 1 HIBCH (p.R101T) (p.L187F) 1 IPP (p.L187S) 1 IPP (p.V481I) 1 ITGA7 (p.W1064C) 1 ITGA7 (p.L1114V) 1 ITGAD (p.M379V) 1 KCNG3 (p.A329P) 1 KCNQ5 (p.S572C) 1 KCNT2 (p.R1566G) 1 KIF26A 1 LGI2 (p.A34G) 1 LHCGR (p.L268F) 1 LMTK3 (p.P785Rfs*102) 1 LUZP2 (p.R199W) 1 MAFA (p.H184Q) (p.M1188K) 1 MAGI2 1 MROH2B (p.L525I) 1 NUP50 (p.G75A) 1 NUTM2F (p.P346A) (p.Q296E) 1 PCNT (p.A157T) 1 PEAK1 (p.R166T) 1 PEAK1 (p.Y2024C) 1 PI4KA (p.X185_splice) 1 PLEKHD1 (p.Q17K) 1 PNISR (p.K1638Q) 1 PPL (p.A186V) 1 PRTFDC1 (p.S1197C) 1 PTPRM (p.G365Afs*8) 1 PTPRU 1 QSOX1 (p.S6G) 1 RALGAPA1 (p.S721R) (p.D398H) 1 RBMS3 (p.T141P) 1 RFC3 1 RYR1 (p.K4699M) (p.L728V) 1 SCAPER (p.L328V) 1 SHBG (p.T45P) 1 SNX20 (p.X253_splice)1 SPATA16 (p.Y68Kfs*29) 1 SRPX 1 TDRD6 (p.T693R) (p.V283Afs*6) 1 TMEM132B (p.T391K) 1 TMPRSS3 1 TP53 (p.R306*) 1 TRABD2B (p.A96Cfs*53) 1 TRERF1 (p.Q313E) (p.C502*) 1 TRIP12 1 UQCRC1 (p.R442G) 1 USP34 (p.R2558H) (p.X611_splice) 1 ZSWIM6 (p.D208H) 1 CACNG5 (p.Y4175N) 1 DNAH9 1 DOT1L (p.P1297S) (p.P2358A) 1 EPPK1 1 MAPK10 (p.P416L) 1 MYBBP1A (p.Q914H) (p.L381V) 1 N4BP1 1 OR1L6 (p.L246Rfs*15) 1 RABEP1 (p.E747Kfs*8) (p.P782L) 1 SHROOM1 (p.F146Lfs*26) 1 SLC26A2 (p.Q424P) 1 SNX1 (p.P107T) 1 SPACA7 (p.*417K) 1 TMPRSS11B 1 ZNF473 (p.H509Nfs*15) 1 TIPARP (p.P102A) (p.W545L) 0 ADAMTS12 (p.R291*) 0 AMMECR1L (p.T726K) 0 ATP4A (p.A65D) 0 BBS9 (p.C95G) 0 C17orf77 0 C1orf101 (p.L10V) 0 CAAP1 (p.I191Nfs*6) 0 CBFB (p.G121Afs*14) (p.A281E) 0 CCDC175 0 CIPC (p.S42C) (p.F2738L) 0 DCHS1 (p.T470Qfs*5) 0 EPN2 (p.Q254E) 0 ERCC6 (p.V308I) 0 G6PC 0 GABRA3 (p.L284M) 0 GTF2H1 (p.L127V) 0 HNMT (p.D37H) (p.L381F) 0 HNRNPH1 (p.N382I) 0 HNRNPH1 0 HYDIN (p.L4515R) (p.I76N) 0 IFLTD1 (p.V668E) 0 IGDCC4 (p.S13C) 0 IL16 (p.V64G) 0 KBTBD13 (p.T773K) 0 KCNH3 (p.T106I) 0 KLHL4 (p.K140Lfs*15) 0 KRTAP24−1 0 LENG1 (p.D259N) 0 MNX1 (p.M221L) (p.A467T) 0 MUC20 (p.L483V) 0 NCOA1 0 NLRP6 (p.E595Q) 0 OCIAD1 (p.S93Afs*41) 0 OR13D1 (p.L71I) 0 OR4S1 (p.L142V) 0 OR6N1 (p.G147C) (p.N214D) 0 POU5F1 (p.S519Rfs*20) 0 PRKAA2 0 RASAL2 (p.L964I) (p.L131P) 0 SLC25A24 (p.R488Hfs*26) 0 SLC27A3 (p.S400C) 0 SLC27A3 (p.K417N) 0 SPATS2 (p.E908K) 0 STOX2 0 TRAF7 (p.E324D) 0 TRIO (p.D2835Y) (p.P946A) 0 VWA5B1 (p.W275R) 0 WDR75 0 ZBED3 (p.L133M) 0 ZNF620 (p.L345F) 0 ZNF655 (p.E21K) 10% < CCF ≤ 20% 14DCIS (0.68) 20% < CCF ≤ 40% 4DCIS (0.61) 20% < CCF ≤ 40% 15DCIS (0.89) 20% < CCF ≤ 40% 19DCIS (0) 20% < CCF ≤ 40% 40% < CCF ≤ 60% 40% < CCF ≤ 60% 15IDC (0.69) 40% < CCF ≤ 60% 40% < CCF ≤ 60% 14IDC (0) 4IDC (0.43) (0) 60% < CCF ≤ 80% 60% < CCF ≤ 80% 60% < CCF ≤ 80% 19IDC 60% < CCF ≤ 80% 80% < CCF ≤ 100% 4DCIS 80% < CCF ≤ 100% 80% < CCF ≤ 100% 80% < CCF ≤ 100% +3 +3 15DCIS PIK3CA, p.E418K +11 SPEN, p.L2247Cfs*106 APC ECT2L 14DCIS PTEN, p.E235* +4 +4 100% 100% +118 +4 19DCIS 100% GATA3, p.P408Afs*99 LIFR SMARCA1 PIK3CA, p.H1047R +2 100% +13 +15 GATA3 +35 80% 80% TP53, p.R306* +59 80% CBFB 80% Cluster +9 CBFB CBFB +8 Cluster Cluster ADNP Cluster SPEN, p.P677Lfs*13 TCF7L2 +14 1 0 +13 MNX1 60% 2 60% RAD51B 60% 0 ACSL6 19IDC 60% 0 1 NCOA1 4 15IDC 1 POU5F1 1 BCL11B 5 4IDC 40% 2 40% 2 MACF1 14IDC 40% +10 +1 40% 6 4DCIS 3 15DCIS 3 4 +3 +3 20% +21 20% +2 20% 4 19DCIS 20% 14DCIS Cancer cell fraction (%) Cancer cell fraction (%) Cancer cell fraction (%) HLF, MSI2, CLTC, PPM1D, CD79B, DDX5 (17q22-q23.3)

Cancer cell fraction (%) +41 0% 0% +2 0% +5 +0 SS18L1, TSHZ2 (20q13.2-q13.33) +7 15IDC 0% 4IDC ERCC4, MYH11 (16p13.12-p13.11) 14DCIS 14IDC 4DCIS 4IDC 15DCIS 15IDC SMAD4 (18q21.2) +11 19DCIS 19IDC 14IDC 19IDC

ERCC4, MYH11 SMAD4 4 4 TSHZ2, SS18L1 4 3 19DCIS (Ploidy: 1.8) 14DCIS (Ploidy: 2.9) HLF, MSI2, CLTC 15DCIS (Ploidy: 2.01) 4DCIS (Ploidy: 1.69) PPM1D, CD79B, DDX5 2 2 2 2 1 Ratio 2 Ratio 0 0 0 0 2 -1 Log2 Ratio Log2 Ratio Log Log −2 −2 −2 -2 -3 −4 −4 −4 4 4 4 HLF, MSI2, CLTC 19IDC (Ploidy: 2.05) ERCC4, MYH11 SMAD4 14IDC (Ploidy: 2.01) 4IDC (Ploidy : 1.68) PPM1D, CD79B, DDX5 TSHZ2, SS18L1 15IDC (Ploidy: 2.05) 3 2 2 2 2 1

0 0 Ratio 0 2 Ratio

2 0 Log2 Ratio Log2 Ratio

Log -1 −2 −2 −2 Log -2 −4 −4 −4 -3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X Chromosome 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X Chromosome Chromosome Chromosome

B G L Q

Cancer Cell Fraction (%) CCF = 0% Cancer Cell Fraction (%) Cancer Cell Fraction (%) 0% < CCF ≤ 10% Cancer Cell Fraction (%) CCF = 0% CCF = 0% 10% < CCF ≤ 20% CCF = 0% (p.K532M) 1 ANKRD13C (p.S117I) 1 BTNL8 (p.C287Y) 1 C14orf93 (p.I52T) 1 C16orf3 (p.I52V) 1 C16orf3 1 C3orf62 (p.I266L) 1 CFHR4 (p.S223T) 1 CHEK2 (p.R145W) 1 HIVEP2 (p.C1832Y) (p.E95G) 1 IGF2BP3 (p.K402Gfs*8) 1 KCNN4 (p.D392N) 1 KLHL18 1 MAP2K4 (p.R287G) 1 MAP2K4 (p.S292N) (p.R130S) 1 MUC16 (p.A188V) 1 NOS1 (p.R1317Q) 1 NOTCH4 (p.A1385V) 1 SHANK2 1 TRIOBP (p.A1636D) (p.S97Hfs*99) 1 ZFAND6 1 ZNF597 (p.S261R) 1 CARS (p.M601Ifs*90) (p.A910G) 3 CACNA1F 3 CASS4 (p.T778M) 3 GOLGB1 (p.D2787Cfs*5) (p.W28Mfs*17) 3 KRBA2 3 LCOR (p.A225E) (p.A219E) 3 PRMT8 3 TIE1 (p.R113H) (p.P50S) 0 AHNAK2 0 A TP2B3 (p.A900V) (p.W114Lfs*25) 0 BCAP29 (p.A77V) 0 BCL9L (p.R69C) 0 CA4 0 CDK5R2 (p.G116D) (p.D3870N) 0 CMYA5 (p.A444T) 0 DCHS2 (p.R330Sfs*20) 0 GATA3 (p.A311Vfs*37) 0 GJA1 (p.E108K) 0 GJA3 (p.Q81H) 0 GJA3 (p.A269V) 0 IFLTD1 (p.R770H) 0 KIF17 (p.R172H) 0 MAPK1 0 NUBP2 (p.V184E) (p.W93*) 0 PDPN 0 RDH8 (p.E66K) (p.R2269G) 0 SZT2 (p.Y1229*) 0 SZT2 (p.Y236dup) 0 T P53 (p.X172_splice) 0 TSPAN2 (p.G132S) 0 WNT7B (p.D692Y) 0 XRRA1 (p.Q80E) 2 GIP 2 P ARP15 (p.N108S) 2 RASGRF1 (p.T971P) 2 ZNF287 (p.E182K) (p.P152Q) 2 CCDC71L (p.A369V) 2 PCDHA11 2 RPGR (p.G598*) (p.E1043K) 2 SYNJ1 2 ZNF287 (p.W204*) (p.P115L) 4 C11orf80 (p.D1126A) 4 CLTC 4 LRRK1 (p.E369K) (p.X323_splice) 4 PIPOX 4 UQCRFS1 (p.P208L) (p.V202L) 4 A GGF1 4 A TP9A (p.V112M) (p.P483T) 4 KANK4 4 MRPL16 (p.R192S) 4 NPIPB15 (p.H44Q) 4 O XR1 (p.D538V) 2 GPR101, p.A174V 2 MAPK4, p.H147Y 2 PIK3CA, p.H1047R 2 RREB1, p.P997Rfs*40 2 SPINK5, p.A621T p.V454I 2 SRF, p.G324E 2 SSFA2, 2 ZNF79, p.V156I p.Q104K 3 CCSAP, 3 SCN4A, p.E452K p.R366* 1 GATA3, p.T162Ifs*7 1 HOXD4, 4 CPA1, p.R234C 4 CPA1, 4 EDN3, p.V179I 4 IRS2, p.R871W 4 ITIH5, p.V402I 4 L1CAM, p.R322Q 5 FHAD1, p.E1034V p.E359Afs*44 5 GATA3, 5 S1PR5, p.S104F 5 SERPINI2, p.E341A 4 AMPD1, p.R112W p.D38N 4 ARL14EP, p.V421I 4 MYC, 4 NCKAP1, p.G442S p.T1321M 4 SSC5D, p.R1843C 4 TNC, 0% < CCF ≤ 10% 5 CKAP5, p.R1453C 0% < CCF ≤ 10% 1 PDS5B, p.M875T 1 PDS5B, 3 SCML2, p.R285L p.G481V 2 ACSS3, 0 KMT2A, p.P3515Lfs*36 0 PIK3CA, p.H1047R 1 LAPTM5, p.A20T 2 CHD4, p.R1177C 2 CHD4, p.R957W 1 TEKT3, p.R419H p.K77M 3 ATP6V0D1, 3 GET4, p.A13G 3 NOP2, p.P715R 0 KIAA1377, p.A763T p.K905M 0 STAG1, p.E262V 1 GATA3, p.S311L 1 IL20RB, 2 OR52M1, p.I128M 2 C1orf204, p.P157S p.S441N 2 CACNB4, 2 CHD4, p.I1247T 0 COL6A2, p.V812L 2 DUSP27, p.C782Y 2 EBF1, p.S428L p.L244V 2 GJA8, 2 HRH2, p.R260K 2 KIF5A, p.R808Q 2 LANCL3, p.V130M p.E250* 2 PYROXD1, 2 SBNO2, p.G861Afs*29 2 TBX19, p.S426L 2 TPP1, p.D451H 2 WDR66, p.E670K 2 ZNF527, p.Q229H 0 A2M, p.V868M p.A274S 0 ANKRD33B, 20% < CCF ≤ 40% 2 GPR101, p.A174V 2 MAPK4, p.H147Y 2 PIK3CA, p.H1047R 2 ZNF79, p.V156I p.R366* 1 GATA3, p.T162Ifs*7 1 HOXD4, 2 RREB1, p.P997Rfs*40 2 SPINK5, p.A621T p.V454I 2 SRF, p.G324E 2 SSFA2, p.Q104K 3 CCSAP, 3 SCN4A, p.E452K 4 CPA1, p.R234C 4 CPA1, 4 EDN3, p.V179I 4 IRS2, p.R871W 4 ITIH5, p.V402I 4 L1CAM, p.R322Q 4 AMPD1, p.R112W p.D38N 4 ARL14EP, 5 CKAP5, p.R1453C 5 FHAD1, p.E1034V p.E359Afs*44 5 GATA3, 5 S1PR5, p.S104F 5 SERPINI2, p.E341A p.V421I 4 MYC, 4 NCKAP1, p.G442S p.T1321M 4 SSC5D, p.R1843C 4 TNC, 0% < CCF ≤ 10% 10% < CCF ≤ 20% 24DCIS (0.47) 10% < CCF ≤ 20% 40% < CCF ≤ 60% 10% < CCF ≤ 20% 8DCIS (0.56) 16DCIS (0.89) 20% < CCF ≤ 40% 16DCIS (0.89) 20% < CCF ≤ 40% 24IDC (0.88) 60% < CCF ≤ 80% 20% < CCF ≤ 40% 40% < CCF ≤ 60% 8IDC (0.61) 40% < CCF ≤ 60% 16IDC (0.67) 80% < CCF ≤ 100% 16IDC (0.67) 40% < CCF ≤ 60% 60% < CCF ≤ 80% 60% < CCF ≤ 80% 60% < CCF ≤ 80% 80% < CCF ≤ 100% 80% < CCF ≤ 100% 80% < CCF ≤ 100% +26 +11 24DCIS 16DCIS 16DCIS 8DCIS MAP2K4 MYC, p.V421I +42 MYC, p.V421I GATA3, p.E262V +13 100% +5 100% +12 GATA3 p.R366* 100% GATA3 100% GATA3 p.R366* +13 PDS5B +11 +12 +10 +3 TP53 80% +5 80% PIK3CA, p.H1047R 80% +10 80% Cluster PIK3CA, p.H1047R +3 Cluster PIK3CA, p.H1047R +2 Cluster 24IDC +2 Cluster GATA3, p.E359Afs*44 24DCIS 0 GATA3, p.E359Afs*44 60% 1 KMT2A +23 60% 0 +6 60% 1 60% 1 +6 2 2 1 16IDC FGFR1, WHSC1L1, KAT6A, HOOK3 (8p11.22-p11.21) 2 16IDC 3 CHD4 3 3 40% 4 EBF1 40% 2 40% 4 TCEB1, HEY1 (8q21.13-q21.11); CCND1, NUMA1+24 (11q13.3-q13.4) 40% 3 +2 4 +2 16DCIS 5 16DCIS 5 PRDM1, PDSS2 (6q21); FOXA1, NIN (14q21.1) 20% +4 20% 20% ERBB2, CDK12, LASP1, MLLT6 (17q12); TSHZ2 (20q13.2); ERG (21q22.2) 20% 8DCIS 8IDC +3 +27 Cancer cell fraction (%) Cancer cell fraction (%) Cancer cell fraction (%) +3 +9 Cancer cell fraction (%) 0% 0% 0% 0% +6 16IDC 16DCIS 16IDC 8IDC 8DCIS 8IDC 16IDC 7DCIS 7IDC 24DCIS 24IDC 24IDC WHSC1L1, FGFR1 CCND1, NUMA1 4 4 4 3 24DCIS (Ploidy: 2.05) KAT6A, HOOK3 16DCIS (Ploidy: 2.02) 8DCIS (Ploidy: 1.94) TCEB1, HEY1 16DCIS (Ploidy: 2.02) 2 2 2 2 1

Ratio 0 0 0 0 2 -1 Log2 Ratio Log2 Ratio Log2 Ratio Log −2 −2 −2 -2 -3 −4 −4 −4 4 4 4 24IDC (Ploidy: 2.09) PRDM1, PDSS2 ERBB2, CDK12 TSHZ2 16IDC (Ploidy: 2.01) 8IDC (Ploidy: 1.99) 16IDC (Ploidy: 2.01) 3 LASP1, MLLT6 ERG 2 2 2 2 FOXA1, NIN 1 0 0 0 Ratio

2 0 Log2 Ratio Log2 Ratio Log2 Ratio -1 −2 −2 −2 Log -2 −4 −4 −4 -3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X Chromosome Chromosome Chromosome 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X Chromosome

C H M R p.R203W p.G52V

Cancer Cell Fraction (%) Cancer Cell Fraction (%) Cancer Cell Fraction (%) Cancer Cell Fraction (%) , p.R85G

CCF = 0% CCF = 0% AP21−2, CCF = 0% CCF = 0% .S164*) p.L58F) p.G54R) p.W5*) p.P63A) p.Q528E) AC G3 ( G3 p.S102R) AHA ( p.A392P) AHA A2( T2L6 ( p.E289K) T2L6 0% < CCF ≤ 10% 0% < CCF ≤ 10% 0% < CCF ≤ 10% A2( 0% < CCF ≤ 10% XA13 ( XA13 0 ADAMTS12 (p.E1469K) 0 ADAMTS12 (p.E67K) 0 ADAMTS16 0 ARHGEF38 (p.P179Hfs*29) (p.P823S) 0 ATG9B (p.P152H) 0 CATSPER1 0 CCDC88C (p.X1371_splice) 0 CCNF (p.D637N) (p.Y353Lfs*5) 0 CDYL 0 COL27A1 (p.G646E) 0 DDX11 (p.E78K) 0 DMGDH (p.W606C) 0 FMN2 (p.G941A) 0 GALNT18 (p.F92L) 0 GALNTL6 (p.E236K) 0 HCFC1 (p.S2025C) 0 IGFN1 (p.D1166N) 0 INO80E (p.K86Sfs*45) 0 IRF4 (p.Q395H) 0 ITGA9 (p.E967K) 0 KCTD3 (p.H403Y) 0 KDM5B (p.G576R) 0 KIAA1462 (p.Q893R) (p.R419T) 0 MAATS1 0 NELL1 (p.P628S) 0 NOC2L (p.R213K) 0 NUP210L (p.G612R) (p.V193L) 0 OR10AG1 0 PCSK2 (p.E90K) 0 PLCH2 (p.F717L) 0 PRRC2A (p.G1682E) 0 PTPN20B (p.L193F) 0 SEC24B (p.Q496K) 0 SLC4A3 (p.L747R) 0 SLC6A13 (p.Q341E) 0 SLFN14 (p.S83C) 0 SNX13 (p.E515K) 0 SRCRB4D (p.E459Q) 0 TIAM2 (p.P579S) 0 TNFRSF1A (p.A357V) 0 TP53 (p.R273C) 0 TRIM13 (p.E387K) (p.G364D) 0 TSTD2 0 TTN (p.I21107L) 0 ZFYVE27 (p.E148Q) 0 ZNF407 (p.S586C) 0 HSPA13 (p.S10L) 0 HSPA13 5 PDCD7 (p.A2T) 5 SPTBN4 (p.A2141V) 6 ERBB2 (p.D769H) 6 ERBB2 (p.D904N) 6 HYDIN (p.Q3905Rfs*5) 6 OR4K2 (p.D175G) 2 GPR119 (p.S6L) 2 SLITRK5 (p.R208W) (p.Q430K) 2 ADAMTS3 (p.R516C) 2 ADAMTS5 2 BMP10 (p.W198R) 2 CDH26 (p.E267K) 2 CDK5R1 (p.R153C) 2 CPXM2 (p.A118V) 2 GTPBP4 (p.N5T) 2 HIC1 (p.P265S) 2 HSPG2 (p.D3515N) 2 KCNH8 (p.V1034L) 2 KIF13A (p.A211V) (p.R202C) 2 KRT15 (p.P23T) 2 NR2F1 2 OIT3 (p.G428S) 2 PARS2 (p.P444R) (p.R60H) 2 PTGS1 2 RREB1 (p.L163Q) 2 SERPINA11 (p.A15D) 2 SERPINB13 (p.F201L) 2 SHH (p.A389S) 2 SLC22A23 (p.P156R) 2 TEX15 (p.P1963S) 2 TMPRSS11D (p.A114V) 2 ZNF445 (p.A307D) 4 DHX9 (p.N30Tfs*43) 4 FREM2 (p.A202T) 4 GAK (p.A341T) (p.R1023Q) 4 GPATCH8 4 HEXDC (p.R327C) 4 INTS9 (p.M519I) 4 ITPR2 (p.A445V) 4 KCTD14 (p.R157C) 4 KIFC2 (p.P771L) 4 MPG (p.R201W) (p.S1200Y) 4 NPAT 4 SMO (p.D786N) 4 SYNE2 (p.M3705I) 4 UCP3 (p.A231S) 4 USP8 (p.A798P) 4 XPC (p.X207_splice) (p.S145G) 4 ZBTB18 4 ZNF561 (p.H415Qfs*22) (p.V202L) 4 A GGF1 4 OR5H15 (p.R143W) 1 ADAMTS17, p.V831A 1 ADAMTS17, 1 ARHGEF25, p.A8T p.R165H 1 FAM47B, 1 GIMAP1, p.A244V 1 GPRIN3, p.A378V p.R34H 1 GSDMC, 1 HYDIN, p.H2700N p.R417* 1 KRT4, 1 MED23, p.L338P 1 MED23, p.Q337P 1 PER2, p.G256A 1 PIK3CA, p.E545D 1 PIK3CA, p.H1047L 1 PLXNB1, p.M954L p.R78Q 1 SCN3B, p.L16V 2 ADAM30, 2 CCDC83, p.E139Q 2 EXOC3L1, p.S70L p.R1281* 2 HEATR5B, p.A49del 2 ZNF286B, 0 CC2D2A (p.L377R) 0 CC2D2A (p.X329_splice) 0 CCDC146 0 CCT4 (p.S173*) 0 CDKN2C (p.G162A) (p.S658P) 0 CEACAM5 0 CGNL1 (p.E71K) (p.P319L) 0 CHRNA2 (p.E526D) 0 CNNM4 0 COL4A3 (p.R1390T) 0 COQ7 (p.R28T) 0 ABCC5 (p.P671S) 0 A CAN (p.P2064H) 0 ADIPOQ (p.E220Q) 0 AK9 (p.D421H) 0 ALDH9A1 (p.N493Rfs*20) 0 AP1AR (p.E105Q) 0 APLP1 (p.P439S) 0 APOL5 (p.R199K) 0 ARHGEF18 (p.S477F) 0 ASIC1 (p.R514Q) (p.P130A) 0 A TOH7 (p.R73C) 0 B3GALT5 1 PTEN (p.D326H) 0 BPIF 0 BRCA1 (p.L1154Mfs*4) 0 BSG (p.G18E) 0 BTBD7 (p.G971R) 0 BTN3A1 (p.Y396Sfs*6) 0 B UB1B (p.R597T) 0 C2ORF15 (p.Q45E) 0 C2orf44 (p.S438*) 0 CADM4 (p.G362S) 0 CAMK2B (p.C657S) (p.R8L) 0 COX16 0 CREB3L3 (p.D182N) (p.K187N) 0 CRYBG3 0 CSMD3 (p.N1892H) 0 CTTNBP2 (p.E200Q) 0 CYP46A1 (p.S307Y) 0 DGA 0 DLG5 (p.K1577N) 0 DMD (p.Q2569*) 0 DNAH3 (p.S1099L) 0 DOC2A (p.R264W) 0 DPH6 (p.D148Y) (p.*280Sext*6) 0 ELOVL1 0 EZH2 (p.V626L) (p.V2178F) 0 F AT2 0 FGFR4 (p.E94D) 0 FSHR (p.Y626S) 0 GALNT12 (p.V209L) 0 G AT 0 GDI2 (p.M66I) 2 OR2AT4 (p.T80K) 2 OR2AT4 (p.D277V) 2 PRRT4 2 REXO1 (p.D609E) 2 RFX7 (p.M1281I) 2 RNF123 (p.P1023A) 2 RNF128 (p.P315T) 2 SAMD3 (p.Q241K) 2 SERPINB12 (p.D316E) 2 SOW (p.E110*) 2 ST6GALNAC1 (p.Q232E) 2 ST6GALNAC1 2 STRIP1 (p.E767K) 2 TCP1 (p.R310T) 2 THOC2 (p.S1230*) 2 TLL1 (p.D947E) 2 TNN (p.S567C) 2 TUBA3E (p.E433*) 2 ZBTB24 (p.L607Ffs*16) 2 ZBTB37 (p.E191Q) 2 ZBTB37 (p.R185T) 2 ZFC3H1 (p.E1975K) 2 CEBPZ (p.D477Mfs*11) 2 MCOLN3 (p.M47Hfs*5) 1 BRD1 (p.H342L) (p.R247H) 1 F AM47C 0 GJA10 (p.D132H) 0 GJA10 0 GLRA4 (p.L13F) (p.D227H) 0 GPANK1 0 GPR75−ASB3 ( p.Q194*) 0 GRHL1 (p.T143Dfs*35) 0 GRID2IP (p.E208K) (p.E1076Q) 0 HDAC4 0 HIP1R (p.S913Gfs*27) 0 HIST1H2BA (p.E115Q) 0 HO 0 MCM8 ( 0 MEMO1 (p 0 MLIP (p.K14N) 0 MSN (p.R408Q) (p.Q9401E) 0 MUC16 (p.A666T) 0 MUC17 0 MYH6 (p.E380K) (p.N149S) 0 MYO3B (p.E448Q) 0 MYO5C (p.H60Y) 0 NHLH1 0 NLRP5 (p.R456H) (p.I13T) 0 NNAT 0 NT5C3A (p.D322G) 0 OR2A12 (p.R234K) 0 OR2B11 (p.R175P) 0 PDIA2 (p.L223F) 0 PEAR1 (p.S915R) 0 PER2 (p.D224N) 0 PER2 (p.G520S) 0 PER2 (p.L826F) 0 PHF21B (p.G368S) 0 PIGA (p.G335E) 0 PIGG (p.E238D) 0 PPP1R26 (p.R1047T) 0 PPP1R3D (p.G45R) 0 PRAMEF22 (p.R237C) 0 PRKCG (p.E135D) 0 QRSL1 (p.Y285S) 0 RAPGEF4 (p.E40Q) 0 RASGRP3 (p.L343V) 0 RGS22 (p.A398V) ( 0 R YK 0 R YR1 (p.N918S) 0 SERINC3 (p.T38S) 0 SERPINA4 (p.D330H) 0 SIGLEC7 (p.N105Ifs*4) 0 SKAP1 (p.E179Q) 0 SLC22A1 (p.S552*) 0 SLC25A38 (p.I144M) 0 SLC2A14 (p.T340A) 0 SLC2A6 (p.A346P) 0 SLC35F5 (p.C248Afs*22) 0 SLITRK6 (p.H794D) 0 SMTNL1 (p.V507L) 0 SP4 (p.R665P) 0 SPTBN4 (p.R2368W) 0 STXBP5L (p.D750H) 0 SUSD4 (p.C274Y) 0 SYCP1 (p.L968Tfs*5) 0 T AF5 (p.Q618E) 0 TEK (p.S164*) 0 TF (p.D652G) 0 THRAP3 (p.S171C) 0 TMEM209 (p.G100*) 0 TMEM37 (p.G83R) 0 TMEM65 (p.D132Lfs*31) 0 TP53 (p.R175H) 0 TRIP13 (p.A122Lfs*7) 0 UBAP2L (p.S454F) 0 USP13 (p.I690M) 0 WDR17 (p.W529C) 0 WDR48 (p.P197S) 0 WDR65 (p.A566T) 0 WDR87 (p.L2562V) 0 WWC1 (p.X667_splice) 0 XKRX (p.K342Q) 0 ZFPM1 (p.S552Rfs*242) 0 ZNF566 (p.E4*) 0 ZNF609 (p.L995M) 0 ABI3BP (p.L445P) 0 AMZ2 (p.L97V) 0 GPS1 (p.S12*) 0 KIAA1407 (p.E148Q) 0 LONRF1 (p.D555Y) 0 PODXL2 (p.G579C) 0 PRH2 (p.P103A) 0 ZFPM1 (p.P759Afs*318) 2 A CO2 (p.E677Q) 2 A TG4D (p.E205G) 2 BHLHB9 (p.Q431K) (p.E4*) 2 BSPRY (p.M1583I) 2 CACNA1A (p.K261Q) 2 CDC27 2 CEP192 (p.K1870Q) 2 CUX1 (p.M621I) 2 DLG1 (p.M745I) 2 DUSP7 (p.S15L) 2 EIF4ENIF1 (p.V260L) 2 ENPP4 (p.L349V) 2 ITGAL (p.R1020S) 2 ITPR3 (p.R1682W) 2 KLHL18 (p.P509H) 2 MRPL19 (p.P29L) 2 MYT1L (p.S568I) 2 NLRP7 (p.Q959E) 2 OR1L4 (p.K81N) 1 PRKA 1 SLC5A9 (p.Y187H) (p.G2530V) 1 TNRC18 1 CELSR2 (p.L17P) 0 HOXD13 (p.Y243*) 0 HOXD13 0 HSPD1 (p.E347D) 0 KCNJ14 (p.D418H) 0 KIAA0391 (p.I251M) 0 KIAA0556 (p.K465Rfs*3) 0 KIAA1524 (p.D655N) 0 LRRK2 (p.E2503K) 0 L TN1 (p.N582Mfs*33) (p.A651V) 0 MALRD1 0 MAP2 (p.Q318*) 0 MAP3K8 (p.Q276E) 0 CACNA1A, p.S428T 0 CACNA1A, 1 DPYSL4, p.R552* 1 FEZ1, p.Q166H 1 FRMPD4, p.R179C 1 GPR114, p.R210H p.G291E 1 IFT80, 1 LRP8, p.T744M 1 MED15, p.G114D 1 MICALL1, p.S447N p.A643S 1 MLXIP, 1 MUC5 AC , p.R476H p.V338M 1 MYPOP, p.P154S 1 PAQR6, p.G573A 1 RIN1, 1 SAMHD1, p.A441S 1 SAP25, p.R126C 1 SH3TC2, p.R753W 1 SLC34A2, p.A651V 1 SMARCD3, p.Q262Hfs*8 p.A4T 1 TNFSF11, 3 ZFPM1, p.A842V 0 OR2H2, p.W221* 0 RP11−503N18.3, 1 CTDSPL, p.R38K 1 DEF8, p.V17I p.W174C 1 UCP1, 1 USP9X, p.R2429I 1 YY1AP1, p.E801Nfs*41 p.R476C 1 ZNF280D, 1 ZNF808, p.R494H 2 DNAH2, p.R1448H 1 ADAM15, p.R596Q 1 ADAM15, 1 AK9, p.Q901H 1 ARHGEF16, p.S627N p.G68Efs*37 1 ATXN7L3B, 2 ZNF354B, p.I207M 2 ZNF354B, 2 CAPNS2, p.G118S 2 CYP11A1, p.R151W 3 NCOR1, p.T1566M 3 OR10A6, p.R293* 3 REXO1, p.D57N 0 NBEAL2, p.H875Y 2 NPHP1, p.F351L p.G694E 2 COPA, 2 F9, p.T205P 2 H2BFM, p.Q118H 0 KRT 2 W 0 AQP9, p.A163P 0 AQP9, 2 EHMT1, p.G1239R p.P254L 2 FLNB, 2 FOLR4, p.R198Q 3 ARFGEF1, p.F1614C 3 C10orf71, p.V1247M p.S426Ifs*81 3 GATA3, 10% < CCF ≤ 20% 10% < CCF ≤ 20% 2 FREM3, p.P112L 2 GDPD4, p.S276L 2 LGALS12, p.A94T p.R1510* 2 PHIP, 2 POLG, p.R42Q 2 RSPO3, p.Q254H 2 SYT8, p.C120Y p.Q1057* 2 TAF1, 2 TINF2, p.F14Gfs*2 p.N500K 2 VASN, 2 XRRA1, p.R190C 2 ZNF157, p.R433Q 10% < CCF ≤ 20% 10% < CCF ≤ 20% 18DCIS (0.78) 20% < CCF ≤ 40% (0.28) 20% < CCF ≤ 40% 20% < CCF ≤ 40% 20% < CCF ≤ 40% 10DCIS 17DCIS (0.47) 25DCIS (0) 40% < CCF ≤ 60% (0.61) 40% < CCF ≤ 60% 40% < CCF ≤ 60% 40% < CCF ≤ 60% 18IDC (0.77) 10IDC 25IDC (0.08) 60% < CCF ≤ 80% 60% < CCF ≤ 80% 17IDC (0.62) 60% < CCF ≤ 80% 60% < CCF ≤ 80% 80% < CCF ≤ 100% 80% < CCF ≤ 100% 80% < CCF ≤ 100% 80% < CCF ≤ 100%

+34 18DCIS 17DCIS SLC34A2 +200 +51 25DCIS +61 +2 10DCIS +4 +7 100% +23 100% USP9X 100% +14 100% +45 TP53, p.R175H TP53, p.R273C +26 PIK3CA, p.H1047L PTEN 25IDC 80% BRCA1 Cluster 80% PIK3CA, p.E545D +10 80% 80% SMO Cluster +10 EZH2 0 18IDC MED23 Cluster Cluster 60% 0 10IDC 60% GATA3 +8 60% GATA2 60% 1 +25 2 1 NCOR1 RSPO3 0 18IDC 10DCIS CACNA1A 1 2 WGD 4 40% 2 TAF1 40% 40% 2 +3 40% +38 5 4 25DCIS 6 +0 +40 17IDC 3 20% +12 20% BCL9, FLG, NUP21OL, TPM3, TDRD10, RIT1, LMNA, PRCC, NTRK1 +23 20% 20% CD1D, B4GALT3, SDHC, FCGR2B, PBX1, TPR (1q21.2-q31.1) 17DCIS +32 Cancer cell fraction (%) Cancer cell fraction Cancer cell fraction (%) Cancer cell fraction +4 Cancer cell fraction (%) Cancer cell fraction NUTM2B (10q22.3) +5 0% 0% ERBB2, RARA (17q12-q21.2) (%) Cancer cell fraction CCNE1 (19q12) 18D 10IDC WGD+34 0% 0% ERBB2, LASP1, CDK12 (17q12) 18DCIS 18IDC 10DCIS 10IDC NOTCH1, FAM166A (9q34.3) 17DCIS 17IDC +29 25DCIS 25IDC +64 WGD 25IDC CCND1 (11q13.3); JAK3, ELL (19p13.11) 17IDC NUTM2B ERBB2, LASP1 CCNE1 BCL2, KD5R (18q21.33-q22.1) 3 18DCIS (Ploidy: 2.3) CDK12 4 4 25DCIS (Ploidy: 1.89) NOTCH1, FAM166A ERBB2, RARA 3 BCL9, FLG, NUP21OL, TPM3, TDRD10, RIT1 10DCIS (Ploidy: 1.92) 17DCIS (Ploidy: 3.16) 2 LMNA, PRCC, NTRK1, CD1D, B4GALT3, 2 SDHC, FCGR2B, PBX1, TPR 2 2 1 1

Ratio 0 Ratio

2 0

0 0 2 -1 -1 Log Log2Ratio Log2 Ratio Log -2 −2 −2 -2 -3 -3 −4 −4 4 4 18IDC (Ploidy: 3.9) NUTM2B ERBB2, LASP1 CCNE1 NOTCH1, FAM166A CCND1 BCL2, KDSR 3 CDK12 10IDC (Ploidy: 1.91) 17IDC (Ploidy: 2.99) JAK3, ELL 3 25IDC (Ploidy: 3.66) BCL9, FLG, NUP21OL, TPM3, TDRD10, RIT1 2 LMNA, PRCC, NTRK1, CD1D, B4GALT3, 2 2 2 SDHC, FCGR2B, PBX1, TPR 1 1 0 0 Ratio Ratio 2 0 2 0 Log2 Ratio -1 Log2 Ratio -1 Log −2 −2 Log -2 -2 -3 −4 −4 -3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X Chromosome Chromosome 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X Chromosome Chromosome

D I N S

p.Y799C) Cancer Cell Fraction (%) Cancer Cell Fraction (%) Cancer Cell Fraction (%) Cancer Cell Fraction (%) p.T1421S) .S4W) A ( A p.E955K) CCF = 0% CCF = 0% CCF = 0% p.G40V) CCF = 0% p.A305G) .H1508L) .K134Q) p.Y101*) p.S119F) T1 ( p.E370K) p.E50K) T3 ( VELD1 ( p.A142E)

0% < CCF ≤ 10% 0% < CCF ≤ 10% 0% < CCF ≤ 10% ( Q 0% < CCF ≤ 10% AMTS18 ( AMTS18 T31 ( T4 ( p.S38C) CT3 ( p.R286H) CT3 T8 ( p.R140C) OP1MT (p.D300H) OP1MT ELQ (p.R1023*) AM181A ( p.V270I) OM1L1 ( p.T245K) 10% < CCF ≤ 20% 10% < CCF ≤ 20% 10% < CCF ≤ 20% ARP2 (p.S925R) (p.S64R) AT3 10% < CCF ≤ 20% 1 RBMXL3, p.Y504* 1 SLC9A8, p.F182C p.D204V 1 TAF1A, 1 USP8, p.G664R p.Y341F 1 ZNF862, p.S443I 1 ZNF862, 2 ANKRD28, p.N663T 2 MYH6, p.R1151W 1 AKT1, p.E17K p.I444N 1 ASB18, p.M1235I 1 COL14A1, p.R1135* 1 CPAMD8, p.S11F 1 HIF1AN, p.F1149Kfs*3 1 MAP3K1, p.A64S 1 MMGT1, p.Q264Hfs*11 1 NR1H4, p.L98* 1 PDE11A, p.H2402Q 1 PRRC2C, 1 POLR2E, p.E134K 1 A CTR3C (p.G30R) 1 XXYL 1 ZNF275 (p.T50N) 1 ZNF727 (p.E337Q) 1 ZNF860 (p.E330Q) 1 ZNF99 ( p.E808D) 1 ZSCAN5B (p.D397N) 3 AAMP (p.X41_splice) 3 ANTXR2 (p.A359Cfs*13) 3 CASP14 ( p.R121Q) 3 HERC2 (p.R2762L) 3 HS3ST4 (p.Y47C) 3 LRRIQ4 (p.E406D) (p.D1512H) 3 R TTN 3 ZNF212 (p (p.T1862M) 2 NAV2 (p.S959L) 2 T ACC2 2 APOBR (p.G364W) 2 NFKBIE (p.R133L) 0 FMN1 (p.M968I) 0 GBX1 (p.R351Q) 0 GPR116 ( p.T236N) 0 IGF2 (p.E230Rfs*50) 0 IRAK2 (p.F210L) 0 KR 0 LRRC23 (p.S99F) 0 MAP3K12 (p.G566A) 0 MAR 0 NFXL1 (p.Q600E) 0 OR1L1 (p.S239C) 0 OR4S2 (p.S240C) 0 OR6C75 (p.E109G) O XA1L (p.R394W) 0 0 PPM1A (p.D111G) 0 RB1 (p.C489*) 0 SMAP1 (p.K172Rfs*48) 0 SPINK5 (p.K824Efs*4) 0 TIE1 (p.S489I) 0 TREML2 (p.A152D) 0 TRIM63 (p.S256Y) 0 UBQLN2 (p.S193R) 0 ZNF107 (p.N21K) 0 CCDC129 (p.S1036F) 1 PTPRG ( PTPRG 1 1 RP1 (p.R2005T) 1 RSF1 (p.X1188_splice) (p.R195C) 1 R TF1 (p.E767Q) 1 SKIDA1 1 SLC12A6 (p.L233F) 1 SLC30A3 (p.R306W) 1 SQRDL (p.I85M) 1 SYNE1 (p.H1363Y) 1 TIE1 (p.E243*) 1 TLL2 (p.E822Q) 1 TLR3 (p.P602T) 1 TNK2 (p.D1038H) T 1 1 TP53 (p.G266V) 1 TP63 (p.S153R) (p.G255R) 1 TPO 1 TRIM45 (p.K461Gfs*96) 1 TTLL10 (p.R17W) 1 TTN (p.D29960H) 1 WDR49 (p.L200F) (p.F349L) 2 NOX3 0 ANKRD44 ( p.H565Yfs*8) 0 ABCC5 (p.A241P) (p.V781I) 0 ADAMTS16 (p.X91_splice) 0 ADK 0 ANKRD12 ( p.R904T) 0 ASXL1 (p.S989C) 0 CCNDBP1 (p.G128A) 0 CHD2 (p.E133A) (p.D999G) 0 CLTCL1 0 CRH (p.V114G) 0 CTNND2 (p.E59K) 0 DIRAS1 (p.E134K) 0 EVX2 (p.E198K) 0 F5 (p.W152C) 0 FLG2 (p.E222A) 1 AHNAK2 (p.V4568I) 1 ARHGEF28 ( p.S773F) 1 AR 1 A TP10A (p.S186F) 1 BIRC6 (p.T3567I) 1 C19orf44 (p.V562M) 1 CCDC54 (p.E161Q) 1 DCST1 (p.S691C) 1 DNAJC13 (p.A236V) 1 NOS1 (p.L830F) 1 NUFIP1 (p.E254K) (p.E1017Q) 1 OGT 1 P APD4 (p.R73*) 1 PCNA (p.E25Q) 1 PKHD1L1 (p.I3928T) 1 PRDM15 (p.A90V) 1 PRRC2A (p.G1674V) 1 DUOX1 (p.D135H) 1 DUOX1 1 EXT1 (p.W445*) 1 GNB4 (p.I229N) 1 GPR17 (p.S44Pfs*31) 1 GPR84 (p.Y198C) 1 HTR3C (p.E197Q) 1 J AK3 (p.S826*) 1 KA 1 KCTD1 (p.D35N) 1 KIF4A (p.S507F) 1 KLC1 (p.E401Q) 1 KLK5 (p.S39C) 1 LAMB4 (p.E554K) 1 LILRA4 (p.D261N) 1 LIMK2 (p.I508M) 1 MCTP2 (p.K329R) 1 MEI1 (p.T40I) 1 MESP2 (p.T266A) 1 MMP1 (p.I253T) 1 MVP (p.E412K) (p.S462L) 1 MYO16 (p.E125K) 1 MZF1 1 NEB (p.D4229H) 1 F 1 FCGR2A (p.P262R) (p.Q451*) 1 FGB 3 ZFP92 (p.Y22*) 3 COL11A1 (p.G607S) 3 CYFIP2 (p.E30D) 3 LRRC4B (p.E191D) 3 NHSL1 (p.R260S) (p.R216H) 3 ST3GAL3 1 TMC6 (p.L473M) 1 TTBK2 (p.R340Q) 1 UNC5B (p.E718*) 1 USP28 (p.L267I) 1 VSIG10 (p.G416A) 1 VSIG10L (p.A73V) 1 WDR93 (p.E85K) 1 ZNF257 (p.H108D) 1 ZNF335 (p.R602C) 1 GNA 1 ZNF714 (p.N513S) 4 H 4 ARAP3 (p.G588C) 4 EML5 (p.S614C) 3 T ARBP1 (p.X1330_splice) 3 TMEM255B ( p.Y231C) 3 UBE2L3 (p.E112K) (p.D127*) 3 XPOT 1 CSMD1 (p.P3272S) 1 TDRD9 (p.R43C) 1 ABCA6 (p.L1174Wfs*3) 1 A CTR1B (p.P259S) (p.X121_splice) 1 ADA (p.G773V) 1 ADAMTS4 1 ADCY5 (p.L937Q) 1 ALX4 (p.R126Q) 1 ANKRD13B (p.T556M) 1 T AF7L (p.D48N) AG1 (p.E164G) 3 P AG1 3 PCDHA2 (p.T223M) 3 SALL3 (p.L1020S) 3 SELE (p 3 SFR1 (p.K193N) (p.S521C) 1 CACHD1 (p.E1326Q) 1 CACNA1E 1 CNTLN (p.A72Gfs*51) 1 CRLS1 (p.H290D) (p.S516L) 1 CRTC2 1 CUL5 (p.Q391H) 1 CYP3A7 ( p.S284C) 1 DGKB (p.H366Q) 1 DNAH11 (p.G867V) 1 DNAH17−AS1 ( p.A105T) 1 ELF5 (p.Y226*) 1 F 1 F 1 FGFRL1 (p.W204C) (p.F380C) 1 FOXRED2 1 FRG1 (p.S26N) 1 GPR113 ( p.G671R) (p.R21M) 1 IMPA1 1 KIAA0232 (p.S182F) 1 KIAA2013 (p.S38Pfs*72) 1 LCMT2 (p.R256C) 1 LLGL1 (p.S611R) 1 NBEAL1 ( p.A1322D) 1 NBN (p.A241S) 1 OR4L1 (p.S230*) 1 PCDHB12 ( p.A515S) 1 PDC (p.D244Y) 1 PKD1 (p.A21E) 1 PKHD1L1 (p.T3630A) 1 PLEKHM1 (p.E308Q) (p.M36I) 1 PPARG (p.R1681Q) 1 PRPF8 1 RBBP8 (p.X647_splice) 1 SHANK1 (p.G1316S) 1 SHKBP1 (p.L241P) 1 SLC13A3 (p.A203V) 1 SLC22A11 (p.V384A) 1 SLC22A24 (p.G119D) 1 SNAP91 ( p.T434N) 1 ( p.A1656V) SOGA1 1 ( p.Q80L) SOGA3 1 SYS1 (p.R42Q) 3 KRAS (p.G13D) 4 KIF14 (p 4 PIK3CA (p.P539R) (p.D2088Y) 4 PTPRB 4 TP53 (p.P177_C182del) 4 ZNF317 (p.H208Y) (p.V162I) 0 NEUROD6 0 PHYH (p.Q42E) 0 RP1 (p.K800E) (p.E120K) 0 SNTG1 0 TEC (p.R99M) T 0 0 ZNF585A (p.S704P) 3 ADCY4 (p.P782L) 3 AKAP9 (p.R1654Gfs*23) 3 AMBRA1 ( p.X949_splice) 3 BMPER (p.H435Y) 3 C1orf68 (p.C219Y) 3 C5orf60 (p.G26S) ( DISP2 3 3 FXR2 (p.D9Mfs*22) 3 GLMN (p.Q19E) 3 KIF1C (p.I549T) 0 A CTR 0 ARHGEF18 ( p.P665R) 0 CSPG5 (p.A83S) 0 IGSF10 ( p.V493I) 0 IL1RAPL2 (p.M556I) 0 ITIH2 (p.D539N) 0 KIF1A (p.R1395C) 0 PCDHGC3 ( p.N330K) (p.Y24Vfs*34) 0 PCGF2 0 PKHD1 (p.Q430R) (p.S2185T) 0 SACS 0 SELL (p.M381I) 0 SYNJ1 (p.S1074T) 0 TFR2 (p.G655R) 0 ZNF510 (p.T52S) 0 ZNF536 (p.I503F) ( BTC 0 0 CDC42BP 0 ITIH2 (p.R581S) 0 LRP6 (p.L248S) 0 NR1H3 (p.V218I) 0 NUP188 (p.S1126Cfs*9) 0 OPRM1 (p.A19V) 0 OR2A14 (p.R219H) 0 OR2B11 (p.A48T) 4 SKI (p.R282W) (p.V2378I) 4 T ACC2 4 TEX10 (p.H728N) 4 USP9X (p.A479T) 4 SYNGR3 (p.P137T) 4 TMEM26 (p.D253N) 1 A GGF1 (p.V202L) 1 KCTD7 (p.N334D) 1 LRP1 (p.D4193Rfs*9) 1 SCYL2 (p.L395I) 1 TFDP2 (p.Q261K) 0 ABRACL (p.R35H) 0 ABRACL 0 AD 0 ADRA1A (p.P327L) 0 AKAP4 (p.G454A) 0 ARID2 (p.R1068H) 0 ARPP21 (p.P791L) 0 ARPP21 (p.P791T) 0 ASPM (p.S222T) 0 A TRX (p.L1276I) 0 A TRX (p.R1401W) 0 A TXN7L2 (p.X453_splice) (p.E209K) 0 CCDC60 0 CLIP2 (p.R448H) (p.D381H) 0 CRY2 0 D A (p.C96R) 0 DPPA2 0 FLNA (p.I1620F) 0 FLNA (p.K1621E) 0 FYCO1 (p.E734Q) 0 GRK5 (p.R190Q) 0 GUF1 (p.P457S) 0 HEG1 (p.S722Y) 0 IGF1R (p.E1037K) 0 IL17RA (p.V127L) 0 KHDRBS2 (p.P202S) 0 KIAA1524 (p.N67S) 0 KIAA1731 (p.P1682Qfs*5) 0 KLRB1 (p.L12V) 0 KPNA7 (p.T51M) 0 LUZP4 (p.R5W) 0 MAMLD1 (p.W303C) 0 MED12L (p.A1237S) 0 MUC16 (p.V3336F) 0 NKAPL (p.R321K) 0 O TUD3 (p.E172Vfs*19) 0 P ARP14 (p.L223F) 0 PCGF6 (p.Y340*) 0 PEX14 (p.G110S) 0 RAPGEF6 (p.F742Y) (p.Q194*) 0 RRAGB 0 RSRC2 (p.R253Q) 0 SETDB2 (p.K563*) 0 SI (p.T279I) 0 SIGLEC5 (p.A464P) 0 SLC46A2 (p.P273Lfs*31) 0 SLC7A5 (p.L349H) 0 SNCAIP (p.D257N) 0 SORCS3 (p.R794Q) 0 SP8 (p.D237N) 0 ST6GAL2 (p.D191N) 0 SYNCRIP (p.N285Tfs*22) (p.X179_splice) 0 TFAP2D 0 THRAP3 (p.N110D) 0 TP53 (p.Q192*) 0 TRIM4 (p.G465R) 0 USP29 (p.N188K) 0 UTP20 (p.X1014_splice) 0 VPS4B (p.S248Kfs*2) 0 WDFY3 (p.E928*) 0 WRN (p.F763Lfs*14) 0 ZBTB33 (p.S297*) 0 ZIM3 (p.K389N) 0 ZNF107 (p.C249Wfs*5) 0 ZNF341 (p.Q105K) 0 ZNF653 (p.P409L) 0 ZNHIT6 (p.N333K) 0 FGFRL1 (p.H485Lfs*66) 0 KIAA1462 (p.Q182R) 0 MAP3K10 (p.L881Rfs*123) 0 MSH3 (p.P63A) 0 PLEKHG2 (p.E264K) 3 AP5S1 (p.Q82*) 3 DUSP27 (p.G697E) 3 FLG (p.E990K) 3 WEE2 (p.R546P) 3 SLC7A9 (p.E244K) 3 SLC7A9 (p.P248H) 4 PRPF18 (p.E309K) 20% < CCF ≤ 40% 20% < CCF ≤ 40% 20% < CCF ≤ 40% 20% < CCF ≤ 40% (0.37) 22DCIS (0.49) 40% < CCF ≤ 60% 12DCIS 40% < CCF ≤ 60% 21DCIS (0.20) 40% < CCF ≤ 60% 26DCIS (0.97) 40% < CCF ≤ 60% 12IDC (0) 21IDC (0.62) 22IDC (0.43) 12DCIS (0.37) 60% < CCF ≤ 80% 60% < CCF ≤ 80% 60% < CCF ≤ 80% 26IDC (0.33) 60% < CCF ≤ 80% 80% < CCF ≤ 100% 80% < CCF ≤ 100% 80% < CCF ≤ 100% 80% < CCF ≤ 100%

+7 +3 12DCIS +12 21DCIS +36 26DCIS 100% +22 100% +101 100% +30 100% +93 +8 +8 22DCIS +13 KRAS, p.G13D AKT1, p.E17K 12IDC TP53, p.G266V +44 80% TP53, p.Q192* +6 80% 80% PIK3CA, pP539R +74 80% 22IDC ASXL1 RB1 Cluster ATRX Cluster +2 Cluster EXT1 21IDC 60% Cluster GNAQ NBN 26IDC 0 60% 12DCIS 60% 0 TP53 GNAQ 60% ARID2 0 1 JAK3 1 FLGN +7 +13 1 KDM5A, ERC1 (12p13.33) 3 +9 40% 1 40% 2 21DCIS 40% GATA3, MLLT10 (10p12.31-10p14) 40% 22IDC 3 2 MYC, COX6C, UBR5, EXT (8q22.2-q24.2) 4 +9 +36 3 20% 4 12IDC 20% 20% 26DCIS 20% IRF4, FOXQ1 (6p25.3) +16

MYC, COX6C, UBR5, EXT (8q22.2-q24.2) (%) Cancer cell fraction Cancer cell fraction (%) Cancer cell fraction (%) Cancer cell fraction WGD +27 (%) Cancer cell fraction 0% 0% ERBB2, CDK12, MLLT6, LASP1 (17q12) 21IDC 0% +25 0% EGFR (7p11); BRAF, CREB3L2, TRIM24 (7q33-q34) +6 ARID5B, CCDC6 (10q21.2); CDK4 (12q14.1) TERT (5p15.33) 22DCIS 22IDC 12DCIS 12IDC 21DCIS 21IDC ERBB2, CDK12, LASP1, MLLT6 (17q12) 26DCIS 26IDC RECQL4 EPPK1 (8q24.3) CCNE1, TSHZ3, CEP89 (19q12-q13.11) 22DCIS WGD +25 +26 26IDC NIN (14q22.1) RECQL4 EPPK1 ARID5B, CCDC6 CCNE1, TSHZ3 ERBB2, CDK12 3 22DCIS (Ploidy: 4.1) 4 3 21DCIS (Ploidy: 2.4) MYC, COX6C 3 26DCIS (Ploidy: 2.46) MYC, COX6C GATA3, MLLT10 ERBB2, CDK12 BRAF, CREB3L2, TRIM24, EGFR CEP89 UBR5, EXT MLLT6, LASP1 UBR5, EXT1 CDK4 12DCIS (Ploidy: 2.03) IRF4, FOXQ1 KDM5A, ERC1 LASP1, MLLT6 2 TERT 2 2 2 1 1 1 Ratio Ratio Ratio 2 0 0 0

0 2 2 -1 -1 -1 Log Log2 Ratio Log Log -2 −2 -2 -2 -3 -3 -3 −4 4 ARID5B, CCDC6 CCNE1, TSHZ3 22IDC (Ploidy: 3.7) 21IDC (Ploidy: 2.5) MYC, COX6C ERBB2, CDK12 26IDC (Ploidy: 3.5) ERBB2, CDK12 3 CEP89 12IDC (Ploidy: 2.21) 3 UBR5, EXT MLLT6, LASP1 3 NIN BRAF, CREB3L2, TRIM24, EGFR CDK4 LASP1, MLLT6 2 2 2 IRF4, FOXQ1 2 1 1 1 0 Ratio Ratio Ratio 2 0 0 2 0 2

-1 Log2 Ratio -1 -1 Log Log

Log −2 -2 -2 -2 -3 −4 -3 -3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X Chromosome Chromosome Chromosome Chromosome

E J O T p.W305C) .E61K) p.D536H) .E31Q) .S .E85K) .E26Q) .E26V) p.L60V) p.P302L) p.L629Sfs*20) p.G29R) p.S219*) .V315I) .S10F) .S107Y) .S112Y) .S80F) p.G397E) .E56Q) .E42Q) p 74F) p.Q235E) .Q88E) p.E1221K) p.R191T) p.Q446E) .E79K) p.S293F) p.Q1193H) p.S1008F) p.E142K) .E80K) p.Q193H) .E97K) p.E398K) .S21W) p p.P337Hfs*58) p.M4391I) p .A39G) p.S1365C) p p.D1151N) p .E23V) p.E372K) p.G127R) p.E966Q) .R6K) p.E133K) p.E466K) p.E515K) p.D379H) p.E340Q) p.E236K) p.Q126E) p.R86C) p.L1447V) p.Q354E) p.D42N) .A86E) p.P212A) p.P37L) .E746K) .E173K) .E24Q) .E46K) .E48Q) p.D4627Y) p.I217M) .E49V) .E29K) p.M298I) .S82F) .P983A) .D4N) p.S346L) p.I29M) p.Q112K) p p.R593T) p.S111C) p.Q153*) p.R479Q) p.Q166H) p.D631N) p.D363N) p.D2781N) p.E8316K) p.Q105E) p.D605N) p.E390*) p.Q62*) p.D1241H) p.S143F) .Q53E) p.Q569E) p.S468L) p.S106F) p.L653F) p p.G88R) p.X99_splice) p.E1805K) p p.L588V) p.P297S) .E34K) p.Y69*) p.G367E) p.S169W) .E12K) p.L163I) p.E232Q) p.M321I) .E90K) p.K538E) p.D1566H) p.Q607*) p.E139*) p.L32F) .G549A) p.D288N) p.R463K) p.D152H) p.I168M) p.D1738H) p.E273K) p.K298N) p.S816F) p.R1473Q) p.E69*) p.E221K) p.S407L) p.E446K) p.E1019*) p.E977Q) p p.E195*) p.E114Q) p.S36C) p.G459R) p.E296K) p.S155L) p p.E187K) p.D159H) p.E327K) p.H322Nfs*10) p.C642G) p.F127L) p.S422*) p.E219Q) p.E1973K) p.E419K) .S85W) .X8_splice) OD2( p.G603R) p.R74K) p.E184K) p.I332M) p.E259K) AF1 ( p.Q324E) A ( AF1 ( A ( p.E658D) p.Q1052*) p.E808Q) A4 ( p.L7572F) p.E9992Q) p.E24502Q) C1 ( p.E521K) p.D18N) p.D2528Y) p.E2632*) p.P1592T) AHB( p.H2203D) A7( XF1( R J D T ( p.E333K) T X5 ( p.E505Q) CB( T1 ( AD2A ( A1 ( A2B ( TCH1 ( TCH1 TCH2 ( TCH2 XB13( XO1 ( O16 ( p.E1433K) TC1 ( p.S272F) .H8Q) CNA1I( CNG3 ( CNG3 CNA1I( XA2 ( A33 ( p.S101F) A33 VER1( O ( O A1 ( p.R374T) CH2( TPR ( ARD9 ( ARD9 AF1 ( TPR ( T3( p.L67F) GE2 ( p.Q64E) OK2 ( p.G1000E) J AT P 5orf42 ( p.L1593P) T T OW PAT OS1 ( p.L17F) OPN1B ( L O R CA CA CO1( AM135A ( p.S543*) AM135A ( p.Q701*) AM208B AM47B ( p.D89N) AM47B AM161B ( p.E583D) AM161B AM171B ( p.S716*) AM171B AM169A ( p.E496Q) AM169A .A3V) AD A ANC1( TN1 ( p.N582Mfs*33) 4 BAI1 ( p.N246K) 2 C 2 A TR( ( BCKDHA 2 0 S UBC ( 0 0 USP40 ( p.D227N) 0 ZZEF1 ( 4 ABCF3 ( 4 D A 4 D ALRD3 ( p.S113L) 4 DDX43 ( p.R375K) 4 EARS2 ( 4 ESYT3 ( 4 F 4 F 3 A 3 R126Q) 4 G 4 GTF2IRD1 ( p.E632K) ( HNRNPL 4 4 IGSF21 ( p.D51H) 4 KCNH1 ( 4 MAP3K9 ( p.E1078K) 4 POLR1A ( p.E1615Q) 4 POU2F1 ( p.S164F) 4 PTK7 ( 4 STK10 ( p.Q573H) 4 TNRC6B ( p.D1493N) 4 TSPYL2 ( p 4 ZFP41 ( p.E38D) 4 ZFP41 ( p.E55Q) 4 ZNF592 ( p.Q292*) 4 ZNF609 ( p.S959L) 4 ZNF703 ( p.S285L) 3 ALX4 ( p. 1 NDU F 1 1 IGSF5 ( p.L283F) 1 IP6K2 ( p.E151Q) 1 ISLR2 ( p.D389N) 1 KCNJ4 ( p.E384*) 1 KCNN2 ( 1 KCNQ5 ( p.R427K) 1 KLHL13 ( p.S648L) 1 LENG8 ( p.F800L) 1 LRRFIP1 ( p.Q180*) 1 MALRD1 ( p.A392V) 1 MAP3K12 ( p 1 MKL1 ( p.S257L) 1 MUC5B ( p.S48L) 1 M Y 2 AHNAK ( AHNAK 2 2 ARHGAP31 ( p.R323*) 2 ARHGAP31 ( p.R323K) 3 CR A 3 CYP20A1 ( p.M173I) 0 CCND1 ( CCND1 0 0 CELF2 ( p.D449E) 0 COG2 ( p.R442C) 0 CTGF ( 0 FGF8 ( p.R244L) 0 GAB P 0 GNL3 ( p.E198Q) 0 HINT2 ( p.E125*) 0 ITIH6 ( p.S636L) 0 KIAA0232 ( p.Q632E) 0 KIAA0232 ( p.S646C) 0 KIAA1109 ( p.A4245D) 0 LRP2 ( p.N3893K) 0 LRRC16A ( 0 MYCBP2 ( 0 NKAP ( 0 PCDHA1 ( p.S379*) 0 PHF13 ( p 0 PRDM15 ( p.E733*) 0 PRR14L ( p.E1960Q) 0 RNF213 ( p.L2020V) 0 RNF43 ( p.S607L) 0 SEC16B ( p.D78N) 0 SOBP ( p.R869T) 3 G ( HERC1 3 3 HMCN1 ( p.T2183N) 3 KIAA1024 ( p.I620M) 3 KIAA1429 ( p.P1677L) 3 LSM5 ( p 3 MUC16 ( 3 PEX6 ( 3 PVRL4 ( p.E389K) 3 RRBP1 ( p.E939*) 4 ABCC8 ( p 1 F ( FURIN 1 1 FUT1 ( p.L157F) 1 GRM4 ( p.D442H) 1 HES6 ( p.E106K) 2 ADH1B ( p.D361H) 3 C A 0 A TG9B( 1 DIP2B ( 1 DLEC1 ( p.R81C) 1 DNAJC13 ( p.D2195N) 1 DNAJC30 ( p.R146W) 1 DNASE2B ( 1 DNMT3A ( p.F752L) 1 EPOR ( 1 F 0 HNRNPUL2 ( HNRNPUL2 0 0 IRF8 ( p.P407A) 0 OR2M4 ( p.S148F) 0 TMC2 ( p.E741Q) 0 TTN ( 3 TET2 ( ( TICRR 3 3 TMEM27 ( p.E187K) 3 TPR ( 3 TRPC3 ( p.E214K) 3 TRPC4 ( p.E649K) 3 TTN ( 3 ZBTB18 ( p.D14N) ( ZCCHC3 3 3 ZNF276 ( p 3 ZNF584 ( p.L398F) 3 ZNF880 ( p.R448T) 3 B 3 C12orf55 ( p.Q48*) 0 A 0 0 AL O 2 TUBGCP4 ( 2 USP9X ( 2 VPREB1 ( 2 WDR19 ( p.E1262K) 2 WEE1 ( 2 XPNPEP2 ( 2 ZNF304 ( p.E588Q) 2 ZNF37A ( p.R548T) 2 ZNF681 ( p.*646Yext*15) 2 RGS21 ( p 2 SLC29A4 ( p.M212V) 2 SSH2 ( p.D464N) 2 TRIM64B ( p.D372Y) 1 ABCA8 ( A 1 1 AMDHD1 ( p.X398_splice) 1 ARHGAP42 ( p.E213Q) 1 C11orf53 ( p.S21*) 1 C12orf40 ( p.I66Ffs*5) 1 C12orf40 ( p.M33I) 1 C3orf52 ( p.L15R) 1 C5orf38 ( p.R30L) 1 CD86 ( p.M214I) 1 CDC42BPB ( p.E844K) 1 COL11A1 ( p.G1096R) ( DHCR24 1 1 DHX36 ( p.D400N) 1 SCAF4 ( 1 SELP ( 1 SLC18B1 ( p.Q190*) 1 THA 1 TPR ( 1 TRPM6 ( p.E270K) TSHR( 1 ZNF3 ( p.E161*) 0 GABPB2 ( STXBP2( 1 S 1 SUPT6H ( p.D522H) 2 TET1 ( 2 TMIGD1 ( p.M26I) 2 TMPRSS11D ( p.Q314E) 1 R 1 RPN2 ( p.Q166H) 3 PSAPL1 ( 3 RASGRP2 ( 3 RIC8A ( p.E438K) 3 SCN1A ( p.E526Q) 3 SCN2A ( p.E206Q) ( SENP1 SH3BP5 ( SHISA7 ( SPEN ( SPEN ( 2 SRCAP ( SRCAP 2 2 SSH2 ( p.H1023Y) 2 SSH2 ( p.P1006S) 2 T 2 T 1 R L 3 PPFIA1 ( p.E106K) 2 SETD1B ( 2 SLC37A3 ( p.E242K) 2 S 1 H O 1 INTS3 ( 1 INTS3 ( 1 INTS7 ( 1 LAMC1 ( p.K802N) 1 MED1 ( p.L946V) 1 MED1 ( p.P381T) 3 PNN ( 3 POLR3B ( p.L664V) 3 P A 3 PCDH15 ( 3 PLXNB2 ( p.E717*) 2 R A 2 RINT1 ( p.H400Y) 2 RINT1 ( p.L397V) 2 SCEL ( p.D489Efs*8) 1 GSK3A ( ( HDGF 1 3 N O 3 NR1H3 ( p.P193S) 3 OLFM2 ( p.R58G) 3 OR4C16 ( p.F166L) 3 OSER1 ( 2 N O 2 NUPL1 ( p.A576G) 2 OR12D3 ( p.Q314E) 2 OR6N2 ( p 2 P AMR1( 2 P ARP9 ( 2 PCDH20 ( 2 PCDHA6 ( p.P130Q) 2 PCDHGA12 ( p 2 PDE5A ( p.E837K) 2 PLEKHD1 ( p.R289P) 2 POLR3F ( p.E301D) 2 PPL ( p.E1407Q) 2 PPP1R10 ( p.R846C) 2 PPP2R5C ( p 2 PSMG1 ( p 2 RAB44 ( p.L378F) 2 RALGPS1 ( p.N136Y) 2 L 2 MAN2A1 ( p.S21L) 2 MAPKBP1 ( 2 MEX3A ( p 2 MTMR14 ( p.F392L) ( NALCN 2 2 NCKAP1 ( 2 F 2 FRMD4A ( p.D617H) 1 CNTLN ( CNTLN 1 1 CPVL ( p.M461I) 1 DNAJC7 ( p.E154Q) 1 EPM2AIP1 ( p.S562*) 1 F 1 GRK4 ( p.D368N) 3 NEU 3 NLRX1 ( p.S293C) 3 IQCA1 ( 3 ITIH5 ( p.F319L) 3 KIAA1024 ( p.S684C) 3 KIAA1429 ( p.Q1703*) 3 KLRC1 ( p.D158N) 3 KMT2D ( p.E107K) 3 KSR2 ( p.Q825H) 3 LAMC1 ( p.Q176*) 3 MYH7B ( p.Q1120*) 2 HPN HPN ( 2 2 IFNGR1 ( p.E323K) 2 IL4I1 ( p.D535H) 2 IM P 2 IPO13 ( p.P762T) ( IQCH 2 2 KDELC1 ( p 2 KDM2B ( p.M151I) 2 LAMA1 ( p.E2601K) 2 LRRK2 ( p.T1048S) 2 C RTA 2 C R 2 CUX2 ( p.E1016Q) 2 DLL3 ( p.S536*) ( DPCR1 2 2 F 2 FMN2 ( p.G941A) 2 G 2 HMCN1 ( p 1 CDHR3 ( CDHR3 1 ( CENPC 1 3 IFNW1 ( p.R190K) 3 IFT122 ( p 2 C A ( CCDC36 2 2 CDT1 ( p.L415V) 1 CADPS ( p.R732T) 1 CAMK1G ( 1 CCDC107 ( p.E209Q) 1 CD69 ( p.S75*) 1 CDC73 ( p.R156H) 3 D YRK4 ( 3 EGFL6 ( p.S551C) 3 EHMT2 ( p.E204Q) 3 ENG ( 3 F 3 FBXL20 ( p.Q311*) 3 FBXO17 ( p.E172*) 3 FBXW11 ( p 3 GPR176 ( p.E443K) 3 GTF2F1 ( p.Q488H) 3 HECTD4 ( p.G1490A) 1 T 1 TTN ( 1 WDR72 ( p.G403E) 1 WDR81 ( p.E433Q) 1 ZBTB46 ( p.I133M) 1 ZNF229 ( p.S613F) 1 ZSCAN25 ( p 1 ZSCAN25 ( p 1 APC ( ( p 1 BUB1 3 DNA 3 1 TPM2 ( 3 CIC ( 3 CLK3 ( p.X453) 3 CWF19L1 ( p.V375M) 3 DMTF1 ( p.D710Y) 1 TPM2 ( 3 C A ( CCAR1 3 ( CCDC13 3 ( CCDC13 3 3 CCDC181 ( p.H281D) ( CCDC38 3 ( CCDC38 3 ( CCDC67 3 3 CDK8 ( p ( CHPF 3 1 T 1 TERF2IP ( 3 ANAPC2 ( p.S567F) 3 ANKRD11 ( p.K793N) 3 APOBR ( 3 ARFRP1 ( p.X116_splice) 3 ARHGAP22 ( p.S314*) 3 ARL5C ( p 3 C12orf55 ( p 3 C1orf170 ( p 3 C1orf170 ( p 1 R 1 RPS6KA2 ( 1 RPUSD4 ( p.D291H) 1 SCN3A ( p 1 SDK1 ( p.E1518Q) 1 SGK223 ( p.Q933*) 1 SH3TC1 ( p.E618K) 1 SHH ( 1 SLC12A4 ( p.E748K) 1 SLC1A7 ( p.M64I) 1 SP8 ( p 1 ST7 ( p.*500Sext*48) 1 R L ( RNH1 1 1 PTPRS ( 1 RBBP8 ( ( RCN2 1 1 RH O 1 RILPL1 ( p 1 PIK3IP1 ( p 1 PLXND1 ( p.E501D) 1 PPP1R13B ( p.E650Q) 1 PPP1R13B ( p.E664D) 1 PPP1R13B ( p.Q686H) 1 PRLR ( p.D346Y) 1 PRSS33 ( p.R141G) 1 PICK1 ( 1 N O 1 OPLAH ( 1 PCLO ( p.P836S) 1 NDU F 1 ( NEDD1 1 1 NKIRAS1 (

Cancer Cell Fraction (%) Cancer Cell Fraction (%) p.L131I) Cancer Cell Fraction (%) Cancer Cell Fraction (%) p.G332S) p.P324R)

CCF = 0% CCF = 0% p.R201Q) CCF = 0% CCF = 0% T5 ( p.X20_splice)

TA31E1 (p.P288T) TA31E1 30DCIS (0.97) AM208A ( p.G1097Qfs*3) 0% < CCF ≤ 10% 0% < CCF ≤ 10% AM47E−STBD1 ( 0% < CCF ≤ 10% 0% < CCF ≤ 10% 1 AKNA (p.N355D) (p.L27I) 1 BACH2 1 BIRC6 (p.A3738E) 1 BIRC6 (p.A3738T) 1 BRINP2 (p.L393V) 1 CDC27 (p.R266*) 1 CENPF (p.F522V) 1 DHX57 (p.Y749H) 1 DNAAF2 (p.E694*) (p.T489N) 1 PDGFRA (p.D811E) 1 PRPF40A (p.D444H) 1 PTPRK 1 RGPD3 (p.L812R) 1 RNF17 (p.X1483_splice) 1 RNF32 (p.C70*) (p.H119Pfs*54) 1 ST6GALNAC2 1 TLN2 (p.L739M) 1 TNC (p.Q1198H) 1 V ARS2 ( p.P741Lfs*6) 1 ZNF835 (p.D310E) 2 CCNG2 (p.E240D) 2 SERPINB4 (p.Q211H) 2 CR1 (p.P1791T) 2 DPH7 ( p.P249T) (p.R536K) 2 ITGA6 2 LRRC55 (p.D105Y) 2 NDUFC2 (p.F69Lfs*7) 2 ZNF174 (p.E351Q) 0 KLHDC7B (p.C414*) 0 RBM45 (p.A382Lfs*7) 0 TMEM181 (p.G598Afs*13) 0 ZC3H13 (p.S224G) 0 ZNF443 (p.E216V) 0 APOL6 (p.P37L) 0 METTL3 (p.R536Q) 0 DKK1 (p.D88H) 1 ADRA2C (p.S213Y) 1 AHI1 (p.T253N) 1 F (p.P30Rfs*3) 1 FLT4 1 KBTBD13 (p.D234E) 1 KDM7A (p.L739M) 1 MYH7B (p.S214C) 1 NCBP2 (p.Y89F) 1 NUMB ( p.P437T) 1 OR4D10 (p.I135V) 0 PTBP1 ( PTBP1 0 ( PTGS2 0 0 PYGL (p.M351I) (p.V277F) 0 RAVER2 R UNDC10 (p.F56C) 0 SENP6 (p.N375H) 0 SH2D6 (p 0 SIGLEC5 ( p.S294C) 0 SLC12A5 (p.H618D) 0 SLX4 (p.D1218A) (p.K223*) 0 STXBP5L 0 SYNRG (p.E273Q) (p.R469*) 0 TET3 0 TP53 (p.C238G) 0 TPD52L3 (p.K78E) 0 UFL1 (p.H92Q) 0 UIMC1 (p.H398Y) 0 WRN (p.Y413*) (p.R397C) 0 WTIP 0 WWP2 (p.G314*) 0 ZFYVE1 (p.E166V) 0 ZNF573 (p 0 ZNF687 (p.S1123Pfs*43) (p 0 HMBOX1 0 GRK1 (p.S5F) 0 GRM8 (p.T349A) 0 GTF3C5 (p.R467C) 0 GUCY2C (p.D623G) (p.A299T) 0 HDAC7 0 IFNGR1 (p.P328A) 0 IFNGR1 (p.S306L) 0 IGF1 (p.X134_splice) (p.T380A) 0 ITGA8 0 KDM5A (p.F298L) 0 KIAA1239 (p.R621W) 0 KIAA2026 (p.T1058P) 0 KRIT1 (p.L557Q) 0 L3MBTL1 (p.K680T) 0 LARP4 (p.E257Sfs*2) 0 L TN1 (p.N582Mfs*33) 0 MAST1 (p.M476L) 0 MUC16 (p.E11386D) 0 NALCN (p.I1679V) 0 OR51I2 (p.R305H) 0 OR52L1 (p.G111R) 0 P AM (p.H362D) (p.D364Y) 0 PFKL (p.N332K) 0 PGBD4 0 PIK3CA (p.N1068Kfs*5) 0 POM121 (p.S647G) 0 PPL ( p.E1247Afs*19) 0 PRR16 (p.N141D) 0 EPRS (p.R1209T) 0 F 0 FCHSD1 (p.L130H) 0 GPR111 ( p.N362H) 0 GPR125 ( p.S1280Y) 0 GPR162 ( p.V337M) 0 DOK7 (p.G16R) 0 2−Mar ( p.V335L) 0 2−Mar 0 A CSM4 (p.A277T) (p.E1145D) 0 ADAMTS19 (p.D766H) 0 AMOTL1 0 ARRDC1 (p.X74_splice) 0 AR 0 ASCC3 (p.K1556N) (p.H660D) 0 A TF6 0 BAIAP2 (p.R476Q) 0 C10orf76 (p.Q649H) 0 CBLB (p.D427N) 0 CC2D2A (p.V1229L) 0 CCM2L (p.P38S) ( CIC 0 0 CWC25 (p.K184R) 0 DDX58 (p.T260Nfs*19) 0 DIS3L2 (p.T731N) 0 DKK2 (p.S79I) 30IDC (0.43) 0 TMTC1, p.D867N 0 TP53, p.V73Wfs*50 0 TRIM3, p.R28Q 0 ZNF541,p.Y78F 2 DCST1, p.W671R 2 HNRNPR, p.G189R p.R417Q 2 KRT4, p.V19M 2 LGALS3BP, 2 LZTS2, p.S639I 2 OR4C16, p.L13F p.N477S 2 PREP, 0 GABRA2, p.R94* 0 HCN1, p.E2V 0 HIC2, p.G402S p.G559S 0 HSPA1L, p.G96A 0 IMPAD1, 0 KIFC3, p.E359K 0 PCSK1,p.R80Q p.R58* 0 TAF3, p.D110N 2 PTOV1, 0 DISP2, p.A45T 0 ERRFI1, p.L118Qfs*2 p.H1320Q 0 FANCD2, p.E19V 0 FLYWCH1, 2 SBK2, p.A317S 2 SLC26A11, p.R498W 2 SYNE1, p.L1321M 2 TECPR1, p.V1003M 2 TSPYL1, p.E151A p.S168I 2 TUBB, 0 A2ML1, p.A593S p.V400I 0 AGBL3, 0 DCAF8L2, p.V587M 2 ZNF500,p.E82Q 1 DNAJC18, p.P155S 1 PTEN, p.Y27C 1 SENP1, p.D37Y 1 SLC6A9, p.C293Y p.R131* 1 STAG1, p.E2068K 1 WNK1, p.P88R 1 ACACA, 1 C2CD2, p.E87V 1 C4orf3, p.H120R 1 CDKAL1, p.R241K 1 DNAH10, p.M116I p.R733C 1 EMILIN3, 1 FBXO47, p.T238M 1 INTS8, p.S268L p.E201* 1 PSD, 1 PTPRF, p.R808G 1 PTPRF, 10% < CCF ≤ 20% p.Q364H 1 RAPGEF5, p.S393R 1 RTL1, 1 ZNF281,p.S841L p.G81V 1 ZNF585B, 1 ZNF829,p.E486V 10% < CCF ≤ 20% 10% < CCF ≤ 20% 10% < CCF ≤ 20% 0 CCNL1 (p.P5T) 0 CCNL1 0 COL9A3 (p.G35Afs*53) 0 HMGCS2 (p.L402M) 0 KCNH2 (p.Y827H) 0 KIAA0754 (p.E623D) (p.L219F) 0 MTOR 0 PLA2G4E (p.H392Q) 0 PVRL4 (p.Q336Rfs*10) 0 R TTN (p.A546D) 0 PIBF1 (p.T757N) 0 TUBGCP3 (p.E884K) 0 ABCA13 (p.S3457R) 0 ALDH1L2 (p.A848E) 0 BRINP1 (p.D701E) 0 BRIP1 (p.I504M) 0 S PA 1 CDC27 (p.N486H) 1 CDC27 1 KNOP1 (p.I218Sfs*41) 1 TBC1D16 (p.D210Y) 1 TBC1D16 (p.E214*) (p.R147S) 0 GSTO1 ASF3 ( 2 W ASF3 2 ZC3H12B (p.E316K) 3 ATR (p.T1798A) 3 USP24 (p.S581N) 2 EDRF1 (p.E521K) 2 ERBB3 (p.D297Y) 2 LCMT1 (p.S34A) 2 MYH1 (p.Y353C) 2 PIK3CA (p.H1047R) 2 PTPRZ1 (p.M710I) (p.S3505*) 2 SACS 2 SLC17A8 (p.N435H) 2 TBX3 (p.F133V) 2 TP53 (p.R249T) 20% < CCF ≤ 40% 20% < CCF ≤ 40% 23DCIS (0.58) 20% < CCF ≤ 40% 20% < CCF ≤ 40% (1.0) 13DCIS (0) 28DCIS 40% < CCF ≤ 60% 40% < CCF ≤ 60% 23IDC (0.31) 40% < CCF ≤ 60% 40% < CCF ≤ 60% 28IDC (0.54) 60% < CCF ≤ 80% 13IDC (0.69) 60% < CCF ≤ 80% 60% < CCF ≤ 80% 60% < CCF ≤ 80% 80% < CCF ≤ 100% 80% < CCF ≤ 100% 80% < CCF ≤ 100% 80% < CCF ≤ 100% +168 +44 +20 13DCIS +44 23DCIS +128 30DCIS 100% +30 100% +93 100% APC CCND1 100% +20 28DCIS +12 PDGFRA ATR DNMT3A +18 +3 +4 TP53, p.C238G BRIP1 80% TP53, p.V73Wfs*50 +31 80% 23IDC 80% NOTCH1 +138 80% PIK3CA, p.H1047R +2 28IDC PIK3CA SPEN MTOR Cluster Cluster Cluster KMT2D Cluster TP53, p.R249T 60% PTEN, p.Y27C 13IDC CBLB +45 60% 0 60% 0 60% 0 TET2 0 TBX3 1 CIC 30IDC 1 KDM5A 1 40% 1 +4 40% 2 40% 2 40% 2 2 28DCIS +5 3 +44 23DCIS +2 3 20% 13DCIS 20% 20% 30DCIS 20% +32 +30 4

WGD +67 +26 (%) Cancer cell fraction Cancer cell fraction (%) Cancer cell fraction (%) Cancer cell fraction ERBB2, CDK12 (17q12) (%) Cancer cell fraction 0% 0% PIK3CA, SOX2, TBL1XR1, MECOM (3q26.33-q26.2) 0% 0% +4 KDM5A, ERC1, CCND2, CHD4, ZNF384, +57 EGFR (7p11.2); FGFR1, WHSC1L1, KAT6A, HOOK3 (8p11.22-p11.21) ERBB2, CDK12 (17q12-q21.2) ETV6, CDKN1B, KRAS, PPFIBP1, H3F3C (12p.13.33-p.11.1) 13IDC 28IDC EIF2S2, SDC4, ADNP, NFATC2, TSHZ2 (20q11.22-q13.2) MYCL1, MPL (1p34.2) 28DCIS 28IDC NAB2, STAT6, DDIT3, CDK4, MDM2, PTPRB (12q13.3-q.15) 13DCIS 13IDC 23IDC 23DCIS 23IDC 30DCIS 30IDC LYL1, CALR (19p13.2-13.11) ATP1A1 (1p13.1) +5 30IDC NUTM2B (10q22.3) CCND1 (11q13.2-q13.4) +16 FGFR1, WHSC1L1 ERBB2, CDK12 28DCIS (Ploidy: 2.0) 4 23DCIS (Ploidy: 2.6) EGFR 30DCIS (Ploidy: 2.02) 3 ERBB2, CDK12 KDM5A, ERC1, CCND2, CHD4, ZNF384, LYL1, CALR 3 PIK3CA, SOX2 KAT6A, HOOK3 3 RARA 13DCIS (Ploidy: 3.76) ETV6, CDKN1B, KRAS, PPFIBP1, H3F3C KDM5A, ERC1, CCND2, CHD4, ZNF384, LYL1, CALR TBL1XR1, MECOM ETV6, CDKN1B, KRAS, PPFIBP1, H3F3C 2 CCND1 NAB2, STAT6, DDIT3 2 13DCIS (Ploidy: 3.76) 2 2 CDK4, MDM2, PTPRB CCND1 NAB2, STAT6, DDIT3 1 1 CDK4, MDM2, PTPRB 1 Ratio Ratio 0 0 Ratio 0 2 0 2 2 -1 -1 -1 Log2Ratio Log Log Log -2 −2 -2 -2 -3 -3 -3 −4 4 KDM5A, ERC1, CCND2, CHD4, ZNF384, LYL1, CALR EIF2S2, SDC4, FGFR1, WHSC1L1 ERBB2, CDK12 28IDC (Ploidy: 2.0) ERBB2, CDK12 23IDC (Ploidy: 2.3) EGFR 30IDC (Ploidy: 1.98) 3 13IDC (Ploidy: 2.8) ETV6, CDKN1B, KRAS, PPFIBP1, H3F3C ADNP, NFATC2, 3 KDM5A, ERC1, CCND2,KAT6A, HOOK3CHD4, ZNF384, LYL1, CALR 3 RARA MYCL1, MPL NUTM2B ATP1A1 NAB2, STAT6, DDIT3 TSHZ2 13IDCPIK3CA, SOX2 (Ploidy: 2.8) ETV6, CDKN1B, KRAS, PPFIBP1, H3F3C 2 2 CCND1 CDK4, MDM2, PTPRB 2 TBL1XR1, MECOMATP1A1 NAB2, STAT6, DDIT3 CCND1 CDK4, MDM2, PTPRB 2 1 1 1 0 Ratio Ratio Ratio 2 0 2 0 2 0

-1 Log2Ratio -1 -1 Log Log −2 Log -2 -2 -2 -3 −4 -3 -3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 21 X Chromosome Chromosome Chromosome Chromosome Supplementary Figure S4. Clonal relatedness, clonal decomposition and phylogenetic analysis of synchronously diagnosed ductal carcinoma in situ and invasive breast cancers (A-T) Clonal decomposition and phylogenetic analysis of (A) Case 14, (B) Case 16, (C) Case 18, (D) Case 22, (E) Case 28, (F) Case 4, (G) Case 8, (H) Case 10, (I) Case 12, (J) Case 13, (K) Case 15, (L) Case 16, (M) Case 17, (N) Case 21, (O) Case 23, (P) Case 19, (Q) Case 24, (R) Case 25, (S) Case 26 and (T) Case 30. Clonal frequency heatmaps of mutations in the DCIS and synchronous IDC-NST of a given case are shown (top), grouped by their clonal/subclonal structure (clusters) as inferred by PyClone. Cancer cell fractions are color- coded according to the legend. Shannon index of intratumor heterogeneity is shown in parentheses to the left. PyClone parallel coordinates plots are shown (middle right). Copy number plots depicting segmented Log2 ratios (y-axis) according to genomic position (x-axis) of DCIS and IDC-NSTs are depicted (bottom). Genes included in amplifications are shown in red. PyClone-derived phylogenetic trees of synchronous DCIS and IDC- NST (middle center) are shown. Trunk and branches are colored according to clusters as per PyClone, and the number of somatic mutations that result in the divergence of a clone/subclone from its ancestor are shown. Cancer genes (blue) and hotspot mutations (orange) that define a given clone are depicted. Phylogenetic trees based on copy number alterations is shown (middle center). The numbers alongside the branches represent the total number of copy number alterations. Genes included in amplifications are shown in red.