1 Supplementary Note Choice of Names for the Consensus

Supplementary Note

Choice of names for the consensus molecular classes Differentiation states, as assessed by transcriptomic markers, were key determinants in choosing consensus class names, and the first part of each name indicates the differentiation signature that a class is associated with: Luminal, Basal, or Neuroendocrine. The one exception to this, the Stroma-rich class, is discussed below. We discussed numbering each consensus class (1 to 6), or each luminal class (i.e. Lum 1 to 3), but chose names rather than numbers, and preferred simpler names over longer names that could be more precise. We declined to name classes using tumour aggressiveness, as our understanding or aggressiveness may change with future studies involving larger cohorts, and with new treatments.

Luminal Papillary (LumP) We named the LumP class from the papillary morphology that was frequent (~60%) in this class’ tumours, though we note that this morphological pattern was also observed in LumNS (42%) and LumU (31%) tumours. Although LumP muscle-invasive (MI) tumours may have arisen as a progression from superficial papillary tumours, we caution that the LumP MIBC class name should not be confused with non-muscle invasive (NMI) papillary tumours. Because more than 50% of these tumours activate FGFR3 through either mutation, fusion, or genomic amplification, we also considered “Luminal FGFR3”. However, FGFR3 may not be an oncogenic driver for all tumours of this class, and mutated-FGFR3 tumours are also found in other consensus classes.

Luminal Non-Specified (LumNS) This class represents only 8% of the 1750 MIBC tumours analysed. Although it is enriched with micropapillary histological variants, and is significantly associated with carcinoma in situ, we had too few LumNS cases to confidently base a consensus class name on either association. Future data

1 and studies may support associating this consensus class with genomic or histological properties; until then, we use “Non-Specified”. We note that this subtype corresponds well with the Lund UroC subtype, which has very distinct genomic properties1. We considered, but did not retain, the name “Luminal”, since we use this to refer to all tumours with luminal differentiation: LumP, LumNS, LumU, and a subset of stroma-rich tumours.

Luminal Unstable (LumU) The name “unstable” refers to the “genomically unstable” class name in the Lund molecular taxonomy, and our LumU consensus class includes all tumours classified as “genomically unstable” by the Lund classifier. LumU tumours display several features of genomic instability, such as higher overall and APOBEC mutation burdens, and more somatic copy number alterations. We preferred the shorter “Luminal Unstable” over the longer, more precise, “Luminal Genomically Unstable”. We considered “Luminal GU”, but did not retain it, because “GU” could be mistaken as an abbreviation for Genitourinary.

Stroma-rich While we prefer class names that relate to tumour cell properties, this consensus class includes tumours that have diverse differentiation states and tumour cell phenotypes. It includes both luminal and non-luminal tumours. Given this, instead of using a name that indicates a differentiation state, we used a name that reflects the microenvironment: “Stroma-rich”. On a case-by-case basis, a tumour from this class may actually be phenotypically identical to “LumP”, “LumNS”, “LumU”, “Basal”, or “NE-like”, but will be in a “stromainfiltrated” context, in which the infiltrating stromal cells are principally smooth muscle, then fibroblasts and myofibroblasts. Because this class strongly overlapped with “Infiltrated” subtypes from TCGA and Lund classifications, we considered the name “Infiltrated”, but did not retain it, to prevent confusion between immune (lymphocytes) and stromal infiltration.

2 We also considered “Desmoplastic”, but judged “Stroma-rich” to be more accurate and easily understandable.

Basal/Squamous (Ba/Sq) “Basal/Squamous” reflects the molecular and histological characteristics of the corresponding tumours, notably high levels of KRT14, KRT5/6, and a lack of GATA3 and FOXA1. The denomination “Basal/Squamous-like” was recommended accordingly by this present group of expert in 20152. The “-like” extension was left out to reflect the true squamous differentiation that characterized a subgroup of these tumours. Although only 42% of histologically reviewed tumours within this class show squamous differentiation, this feature is very specific to these tumours since 79% of tumours with squamous differentiation are classified within this group. We discussed using the shorter names “Basal” or “Basal-like”, but suggest that these be used only informally.

Neuroendocrine-like (NE-like) This consensus class is strongly associated with neuroendocrine histological variants: 75% of histologically reviewed tumours within this consensus class show neuroendocrine differentiation, and virtually all tumours with such histological features fall into this consensus class. Although the TCGA “Neuronal” subtype is associated with this consensus class, we did not use this name because: 1) the NE-like consensus class is more strongly associated with neuroendocrine histology than TCGA Neuronal subtype, and 2) bladder tumours are in any case unrelated to neural cells.

3 Supplementary Figure 1: MCL clustering results. (a) Measure of clustering performance by calculating the mean silhouette width of the resulting network clustering for each inflation factor I tested. The number plotted above each point gives the number of resulting classes. All clustering results had a very high silhouette width. We selected the inflation factor maximizing the mean weighted silhouette width among the 6-classes solutions, which corresponds to a local maximum of the plotted function (I = 11.4, red dot). (b) Consensus clustering matrices for best 4-classes (I = 3), 5- classes (I = 4.8) and 6-classes (I = 11.4) solutions (related to bold dots on (a)).

4 a 4 4 1.00

5 6 6 6 6 6 6 6 6 6 0.96 6 6 6 6 6 6 4 5 6 6 6 6 6 6 6 6 6 5 6 6 6 6 6 6 6

0.92 4 5

4 Mean Weighted Silhouette Width Mean Weighted 0.88

4 6 8 10 12 14

Inflation factor b K = 4 (I = 3) K = 5 (I = 4.8)

K = 6 (I = 11.4)

5 Supplementary Figure 2 : Relationships between consensus classes and the six original classification systems, and comparison with pan-cancer classification system (a) Consensus predictions within each subtype of the six original classification systems. (b) Enrichment of MIBC tumours from consensus classes in each of the TCGA PanCanAtlas integrative clusters. Enrichment was evaluated using the 406 MIBC tumours from TCGA BLCA dataset. Only the 15 (over 33) PanCanAtlas iCluster groups including bladder tumours were kept for the analysis.

6 Baylor UNC MDA a 100% 100% 100%

75% 75% 75%

50% 50% 50%

25% 25% 25%

0% 0% 0% like − basal Basal Basal luminal Luminal p53 Differentiated

BSQ_like (n=147) CIT−Curie Lund Luminal_1 (n=126) TCGA 100% 100% Infiltrated (n=45) 100% 75% 75% Luminal_2 (n=21) 75% Luminal_3 (n=53) 50% 50% 50% NE_like (n=6) 25% 25% 25%

0% 0% 0% % Cluster Inf Inf Inf like like GU − − − C8:UCEC Membership by row C12:THCA − − C14:LUAD MC1 MC2 MC3 MC5 MC4 MC7 MC6 Prog C22:TGCT UroB UroC − Ba/Sq GU Uro Luminal C10:Pan-SCC Mes Neuronal Ba/Sq 0% 100% Sc/NE UroA C18:Pan-GI (MSI) C5:CNS/Endocrine C7:Mixed (Chr9 del) C27:PanSCC (HPV) C13:Mixed (Chr 8 del) C2:BRCA(HER2 amp) Basal_squamous Luminal_papillary Luminal_infiltrated C17:BRCA (Chr 8q amp) C3:Mesencymal (Immune) C25:Pan-SCC (Chr 11 amp)

LumP Stroma C20:Mixed (Stromal/Immune) −rich TCGA PanCanAtlasLumNS iClusterBa/Sq Classification LumU NE−like

Ba/BSQ_likeSq (n=147) (n=147) LumPLuminal_1(n=126) (n=126) StromaInfiltrated-rich (n=45)(n=45) LumNSLuminal_2(n=21) (n=21) LumULuminal_3(n=53) (n=53) NENE_like-like (n=6)(n=6)

Cluster membership

C8:UCEC enrichment by row C12:THCA C14:LUAD C22:TGCT C10:Pan-SCC 0 1 C18:Pan-GI (MSI) C5:CNS/Endocrine C7:Mixed (Chr9 del) C27:PanSCC (HPV) Row Normalized C13:Mixed (Chr 8 del) C2:BRCA(HER2 amp) sum of squares =1 C17:BRCA (Chr 8q amp) C3:Mesencymal (Immune) C25:Pan-SCC (Chr 11 amp) C20:Mixed (Stromal/Immune) TCGA PanCanAtlas iCluster Classification

7 Supplementary Figure 3 : The three histological features most associated with consensus classes. Illustrations of the three histological features that are most significantly associated with one of the consensus classes, along with their frequency within each class : Squamous differentiation (a), Micropapillary variants (b), and Neuroendocrine differentiation (c). For each feature, the barplot on the left shows the percentage of histologically reviewed tumours from each class presenting this histological characteristic. Fisher’s exact tests were performed to assess the strength of enrichment within each group and are given below the barplots for the most significant associations (indicated with an asterisk). The total number of cases that were reviewed for each feature are given between parenthesis under each barplot.

8 a

Squamous differentiation

100% 75% 50% * 25% 0% P(Fisher) = 3.6 x 10-32 (n = 789) b

Micropapillary variant

100% 75% 50% * 25% 0% P(Fisher) = 0.001 (n = 240) c

Neuroendocrine differentiation

100% 75% * 50% 25% 0% P(Fisher) = 9.7 x 10-22 (n = 770)

9 Consensus call CS1 CS2 CS5 Supplementary Figure 4 : Differentiation status (Luminal vs non-luminal) CS4of CS6 Stroma-rich tumours and associated overall survival CS3 ConsensusBaylor.subtype call CS1Differentiated Differentiation status of Stroma-rich tumours (n=263) CS2Basal a CS5 UNCChapelHill.subtype CS4 UNC subtypes ChapelHillCS6Luminal LuminalBasal Baylor subtypes (Tumour differentiation) BasalCS3 BaylorBaylor.subtypeBaylorMDA.subtype Urothelial differentiation signature (Lund) Differentiatedluminal BasalDifferentiated Basalp53−like Scaled mean expression basal −2 −1 0 1 ChapelHill.subtype CIT.subtype Luminal BasalMC1 MC2 MDA.subtypeMC3 luminalMC4 Overall survival of patients with Stroma-rich tumours p53MC5−like b basalMC6 CIT.subtypeMC7 TCGA2017.subtypeMC1 UNC classification Baylor classification MC2Luminal Chapel Hill classification (TumourBaylordifferentiation classification ) MC3Luminal_infiltrated MC4Basal_squamous MC5 1 1 Neuronal MC6Luminal_papillary MC7 Lund2017.subtype TCGA2017.subtype 0.8 0.8 UroA−Prog LuminalUroC Luminal_infiltratedUro−Inf Basal_squamousUroB 0.6 0.6 NeuronalGU Luminal_papillaryGU−Inf Lund2017.subtypeBa/Sq−Inf

frequency 0.4 frequency 0.4 UroABa/Sq−Prog UroCMes−like % patients alivepatients% UroSc/NE−Inf−like 0.2 0.2 UroB GU GU−Inf Basal (n=98) logrank test Basal (n=65) logrankBa/Sq test−Inf 0 Luminal (n=39) p−value = 0.78 0 Differentiated (n=72) p−valueBa/Sq = 1 Mes−like 0 10 20 30 40 50 60 0 10 20 30 40 50 Sc/NE60−like Months Months

10 Supplementary Figure 5 : Classifier performance metrics. A single sample classifier was built on a subset of 403 core consensus samples (129 samples from Sjodahl2017 dataset and 274 samples from TCGA dataset) and tested on the remaining 681 core consensus samples from the 16 other datasets. Balanced accuracy, specificity, and sensitivity were measured regarding prediction of the 6 consensus classes on validation samples only (a) and on the whole set of core consensus samples (b). Performance metrics relatively to each type of profiling techniques (Affymetrix, Illumina, RNA-seq) are given on panel (c).

a Performance over validation samples (n=681)

Balanced accuracy Specificity Sensitivity 100%1.0 80%0.8 60%0.6 40%0.4 20%0.2 0%0.0 like like like like like like rich rich rich − − − − − − − − − LumP LumP LumP LumU LumU LumU LumNS LumNS LumNS Mean balancedNE accuracy : 0.97NE NE

Overall accuracyBASQ : BASQ 0.96 [0.94, 0.97] BASQ Stroma Stroma Stroma No Information Rate (NIR) : 0.45 P-value(Acc > NIR) : < 2.2 x 10-16 LumP LumNS LumU b Performance over all core samples (n=1084) Stroma−rich Ba/Sq Balanced accuracy Specificity Sensitivity NE−like 100%1.0 80%0.8 60%0.6 40%0.4 20%0.2 0%0.0 like like like like like like rich rich rich − − − − − − − − − LumP LumP LumP LumU LumU LumU

MeanLumNS balanced accuracyLumNS : 0.97 LumNS NE NE NE

Overall accuracyBASQ : BASQ 0.96 [0.95, 0.97] BASQ Stroma Stroma Stroma No Information Rate (NIR) : 0.44 P-value(Acc > NIR) : < 2.2 x 10-16

c Performance for each profiling technique (n=1084)

− Mean balanced− accuracy / Overall− accuracy (number− of core samples− ) − Illumina Illumina Illumina Illumina Illumina Illumina RNA RNA RNA RNA RNA RNA Affymetrix AffymetrixAffymetrix 0.98 / 0.97Affymetrix (n=504) Affymetrix Affymetrix Affymetrix Illumina 0.97 / 0.95 (n=242) RNA−seq LumP LumNS 0.94 / 0.95LumU (n=338) Stroma−rich Ba/Sq NE−like 1.0 1.0 1.0 1.0 1.0 1.0 0.8 0.8 0.8 0.8 0.8 0.8 0.6 0.6 0.6 0.6 0.6 0.6 0.4 0.4 0.4 0.4 0.4 0.4 0.2 0.2 0.2 0.2 0.2 0.2 11 0.0 0.0 0.0 0.0 0.0 0.0 seq seq seq seq seq seq − − − − − − Illumina Illumina Illumina Illumina Illumina Illumina RNA RNA RNA RNA RNA RNA Affymetrix Affymetrix Affymetrix Affymetrix Affymetrix Affymetrix

LumP LumNS LumU Stroma−rich Ba/Sq NE−like 1.0 1.0 1.0 1.0 1.0 1.0 0.8 0.8 0.8 0.8 0.8 0.8 0.6 0.6 0.6 0.6 0.6 0.6 0.4 0.4 0.4 0.4 0.4 0.4 0.2 0.2 0.2 0.2 0.2 0.2 0.0 0.0 0.0 0.0 0.0 0.0 seq seq seq seq seq seq − − − − − − Illumina Illumina Illumina Illumina Illumina Illumina RNA RNA RNA RNA RNA RNA Affymetrix Affymetrix Affymetrix Affymetrix Affymetrix Affymetrix Supplementary Table 1 : Description of the 18 mRNA datasets and MIBC tumours included for the consensus discovery. 16 datasets are publicly available using the information in "Data accession column". The number of muscle-invasive samples used from each dataset is given in the "MIBC samples" column. Samples originating from post-treatment tumour samples were excluded. Available clinical characteristics associated to the included samples are summarized in the four last columns.

MIBC Stage Available Dataset Publication Data accession mRNA profiling Normalisation %Male Age (mean) samples (T2/T3/T4) OS data Dyrskjot Cancer Res. 2004 GSE3167 Affy U133A RMA 31 80% 61 3/12/15 31 Sanchez J. Clin. Oncol. 2006 PMID:16432078 (supTab10) Affy U133A log2(MAS5) 53 74% 67 9/34/10 0 Stransky Nat. Genet. 2006 E-TABM-147 Affy U95 RMA 39 83% 63 9/19/11 37 Kim Mol. Med. 2011 GSE13507 Illumina Human 6 v2 QN BeadStudio 61 82% 67 31/19/11 61 Riester Clin. Cancer Res. 2012 GSE31684 Affy U133p2 RMA 78 73% 69 17/42/19 78 Sjödahl2012 Clin. Cancer Res. 2012 GSE32894 Illumina HT12v3 QN log2 93 74% 72 85/7/1 51 Iyer J. Clin. Oncol. 2013 cBioPortal Illumina HT12 QN 58 na na na 25 Choi MDA discovery Cancer Cell 2014 GSE48075 Illumina HT12v3 QN GenomeStudio 73 75% 69 42/23/8 73 Choi MDA MVAC Cancer Cell 2014 GSE52219 WG-DASL HT12v4 QN LIMMA 23 na na 15/7/1 22 Choi MDA validation Cancer Cell 2014 GSE48276 WG-DASL HT12v4 QN LIMMA 46 81% 66 39/7/0 46 Choi Philadelphia NAC Cancer Cell 2014 GSE48276 WG-DASL HT12v4 QN LIMMA 42 na na 16/19/7 0 CIT Sci. Transl. Med. 2014 E-MTAB-1803 Affy U133p2 RMA 87 84% 68 31/37/19 75 Hedegaard Cancer Cell 2016 EMTAB4321 RNA seq log2(FPKM + 1) 16 77% 71 na 2 Seiler Eur. Urol. 2017 GSE87304 Affy HumanExon 1.0 ST SCAN 305 70% 62 143/109/49 296 Sjödahl2017 J. Pathol. 2017 GSE83586 Affy HumanGene 1.0 ST RMA 243 78% na 241/1/1 0 TCGA Cell 2017 Firehose 2016_01_28 RNA seq log2(RSEM + 1) 406 74% 68 122/194/58 404 Aarhus.1 unpublished - RNA seq log2(TPM + 1) 28 90% 63 10/10/8 28 Aarhus.2 unpublished - 3'RNA seq log2(TPM + 1) 68 74% 65 27/20/21 68 Supplementary Table 2: Gene signatures associated with bladder cancer summarized in Figure 2.

Signature Genes Source Gene lists derived from Biton et al independent component analysis TMEM163, FMO9P, EPB41, IDH1, GCLC, POF1B, TBC1D1, TRAK1, BAMBI, PLCE1, SCNN1B, BHMT, DHRS2, CYB5A, PPARG, SLC9A2, TOP2B, TMEM97, NTAN1, Urothelial differentiation PMID:25456126 SEMA5A, KRT20, MYCL, UPK1A, TOX3, RNF128, DAB1, ZNF436, LYPD6, ACOX1, KSR2, DMGDH, GRHL3, NIPAL1, RALGAPA2, SCNN1G, SNX31 LYNX1, SCEL, S100A8, SLPI, S100A9, PI3, CEACAM6, VSNL1, SERPINB2, CSTA, FGFBP1, SPRR1B, DSG3, KRT1, S100A7, CLCA2, SPRR2B, KRT6A, KRT6B, SFN, Basal differentiation PMID:25456126 SERPINB3, KRT16, SERPINB13, SERPINB4, KRT4, SPRR1A, ABCA12, SPRR3, TMEM45A, RHCG, IL36G, IL20RB, DENND2C, KRTDAP, HES2, SBSN ZDHHC15, FAM184A, EML5, SNAP25, CACNA2D2, DCX, PSIP1, ST18, RGS7, INSM1, SLC4A8, CAMK2B, ASCL1, RTN1, SCN3A, ADAM22, FAM105A, DPY19L2P2, Neuroendocrine differentiation PMID:25456126 ASRGL1, SLC1A2, MAP6, NRXN1, TTLL7, CNKSR2, RAB39B, KCNC1, GKAP1, TMEM170B, PPM1E, ELAVL4, STXBP5L, GPR137C, HEPACAM2, KIAA2022 PLCD3, BTBD16, ANKRD20A5P, PROM2, SPOCD1, IGBP1, ST3GAL5, DGKA, AQP3, MAP3K5, FABP4, HNMT, MGST2, KCNQ1, IRS1, HSD17B2, ALDH1L1, SMAD3, MST1R, TCN1, CYP3A5, CTSE, HOXD1, PLCH2, SLC24A1, ID3, ABCC3, PDLIM1, AGR2, NSG1, ANXA10, MR1, BTF3, CAST, VWA8, UNC5B, HIBCH, ARAP3, TMPRSS4, Ta Pathway PMID:25456126 OBFC1, IL20RA, SSH3, TMC7, CLCA4, CRTAC1, KLHL3, MECOM, AIG1, CAPNS2, FAM213A, ANKRD50, FAM110C, SYTL1, CDC42EP5, C1orf132, MCTP2, GPR39, RASSF6, STK32A, SLITRK6, SEMA4B, SHH, TRERF1, TMEM51-AS1 ANLN, CASC5, FIGNL1, RECQL4, KIAA1524, DTYMK, CENPL, TK1, SUV39H2, TYMS, MAD2L1, RBL1, RSRC1, CDKN3, CDC25A, BIRC5, FANCB, LOC100288637, TROAP, PSMB2, STMN1, H2AFZ, PAICS, KPNA2, TUBA1B, CSE1L, PCNA, TOP2A, DDX39A, SMC4, DNMT1, MYBL2, MCM5, MTHFD2, NCAPD2, RRM2, PSRC1, CKS1B, MCM6, GNL2, NASP, MCM2, PLK1, H2AFV, KIAA0101, SNRPB2, FOXM1, CTPS1, TOPBP1, ACTL6A, SNRPD1, CCNB2, LIG1, UBE2S, CDC20, UBE2C, RNASEH2A, TIMELESS, SPAG5, RFC5, CDK1, LMNB1, EZH2, CCNA2, TMPO, PTTG1, GGH, SKP2, RFC2, HMGB3, BUB1B, DLGAP5, FANCA, VRK1, CDC6, CHAF1A, RFC4, ZWINT, TRIP13, AURKA, CDC45, RFC3, RAD51AP1, NDC80, CKS2, SMC2, DBF4, GTSE1, TTF2, POLA2, KIF11, CSTF2, ARHGAP11A, CDC7, BRCA1, RAD54L, EXO1, NEK2, KIF23, WDHD1, NUDT1, FEN1, CHAF1B, ESPL1, TTK, MELK, POLA1, PLK4, RAD51, CCNE2, CENPE, PRIM1, ORC1, CDC25C, KIF20B, GPSM2, STIL, CHEK1, H2AFX, SAC3D1, BLM, POLE2, PSMC3IP, SNRPA1, GINS1, KNTC1, KIF14, NUP155, APOBEC3B, HMMR, TFRC, CENPI, POLQ, CENPF, ANP32E, BRCA2, PTTG3P, CCT5, MCM7, HMGB2, Cell cycle activity WHSC1, SQLE, KIF2C, MSH2, PPAT, AURKB, BUB1, KIFC1, CDT1, SPC25, TPX2, CHEK2, CENPA, MCAM, MKI67, MCM4, XPOT, NUP205, TTI1, NCAPH, FANCI, DNAJC9, PMID:25456126 TEX30, CCNE1, OIP5, DNA2, TBC1D31, GMPS, CCNB1, HMGB3P1, SKA1, HN1, PRC1, NUP85, NUSAP1, NDC1, ASF1B, GTPBP4, CKAP2, TACC3, ZWILCH, KIF4A, CDCA4, CEP55, DTL, NCAPG, HJURP, CENPM, KIF20A, SMC6, ATAD2, FBXO5, CENPU, MAGOHB, DSCC1, MIS18A, ORC6, PBK, BRIX1, TIPIN, CENPQ, KIF15, DCLRE1B, SHCBP1, NEIL3, DSN1, CEP72, BORA, CENPN, C16orf59, NCAPG2, ERCC6L, ECT2, ASPM, AUNIP, PARPBP, HELLS, ATAD5, KLHL7, FANCE, DEPDC1, MCM10, C1orf112, PDSS1, CENPJ, KIF18A, CDCA3, CDCA8, GINS2, FAM64A, DONSON, SPDL1, BRIP1, KIF18B, RACGAP1, CENPK, UBE2T, TCF19, NUF2, MND1, GSG2, RAD18, MCM8, CDCA7, CCDC77, CMSS1, CDCA5, FBXO45, KNSTRN, UHRF1, FAM83D, BRI3BP, SAPCD2, CCSAP, CENPO, HAUS8, POC1A, CBX2, CDCA2, CENPW, DEPDC1B, SKA3, TNFAIP8L1, TMPO-AS1, CEP85, E2F7, MTFR2, PIF1, PRR11, DDIAS, GEN1, MASTL, ZGRF1, DIAPH3, C18orf54, IQGAP3, ZNF367, CKAP2L, C5orf34, TICRR, SGOL2, CENPH, SASS6, SGOL1, CCDC150, EME1, LIN9, C4orf46, LRR1, ESCO2, SPC24, LOC442075, CEP152, FANCD2, CLSPN NEXN, PRUNE2, PDE5A, NEGR1, ITIH5, MSRB3, MOXD1, FILIP1L, PTGFR, FGF7, C1S, RHOJ, TAGLN, FILIP1, ADAMTS9-AS2, LRRN4CL, NR2F1-AS1, RBPMS, PTRF, LOC100127983, PDE1A, MEIS1, PELO, MYLK, ACTA2-AS1, MYH11, PDLIM7, CSGALNACT1, GAS6, CSRP1, GSN, SPARCL1, FLNA, PALLD, VCL, ACTA2, ANXA6, DSTN, MYL9, MMP2, MBNL1, IGFBP7, ITGA5, VIM, DPYSL3, COL6A3, FHL1, CALD1, EGR1, AEBP1, EFEMP1, DCN, PPP1R12B, SFRP1, WWTR1, CELF2, GAS7, DES, PDGFRB, ACTG2, SERPINF1, MGP, NR4A1, RGS2, PCOLCE, SVIL, FMOD, LTBP1, PKIG, FBN1, SYNPO, LPP, ANK2, BIN1, GYPC, C7, FBLN1, FBLN5, MAP1A, ATP1A2, COL15A1, RCAN2, ZEB2, TMOD1, CXCL12, TCF4, LMOD1, LRRC32, DMD, FBLN2, HEPH, CNN1, MAOB, TPM2, PDE2A, EMILIN1, PRELP, EDNRB, COL16A1, REEP1, SLCO2A1, FGF2, LMO3, GAS1, EDNRA, GEM, CLDN5, COX7A1, S1PR1, HLF, GPRASP1, AOC3, RAMP1, TCF21, PLN, SRPX, AOX1, LAMA2, PTGS1, ACTC1, DDR2, SOD3, KCNJ8, RAMP3, AGTR1, ACOX2, FXYD1,RECK, SCRG1, GHR, CMAHP, RUNX1T1, PCP4, PYGM, ROR2, MMRN1, CPA3, TPSAB1, HSD17B6, OMD, PLCL1, FOXF1, SELP, EPHA3, ECM2, TPM1, CILP, GNAL, LDB2, EFEMP2, TEK, CH25H, HDC, PRKG1, TPSB2, CDH11, ISLR, CASQ2, SMTN, MEIS2, MS4A2, AQP1, FLNC, COL21A1, PTGIS, ACKR1, DTNA, PGM5, MCAM, COL6A2, MEF2C, FERMT2, CRYAB, BAG2, SPON1, SYNE1, ENTPD1, RARRES2, NR2F1, IGF1, CD200, ADH1B, PDLIM3, TGFB1I1, ITGA7, TGFB3, CHRDL1, SLIT2, KCNMB1, HGF, ABCB1, GATA6, P2RX1, MEG3, FGFR1, CNTN1, PTGDS, SORBS1, C1R, COL6A1, PPAP2B, MAP1B, FNBP1, CLIP3, ZCCHC24, TENC1, MXRA7, SPARC, ELN, MFAP4, SYNM, DAAM2, JAM3, NCAM1, COL14A1, PDZRN3, ANGPTL2, DPT, STARD13, OLFM1, FBXL7, KIAA1462, PTPRD, LDB3, VSTM4, STON1, Smooth muscle PMID:25456126 MXRA8, NFASC, SNED1, SGCD, OSR2, PARVA, CACNB2, C1orf95, PTGER3, ADAMTSL3, RYR2, ITGA8, HSPA12A, ITGA1, DIXDC1, HSPB6, PLA2G5, OLFML1, A2M, FXYD6, FAM129A, OLFML3, KANK2, LMCD1, LHFP, SDPR, OGN, TNS1, PLSCR4, HSPB7, SOBP, CD248, SLC24A3, PID1, KLHL41, RASL12, DACT1, JAM2, NRP2, FAT4, EMCN, WFDC1, POPDC2, TMEM35, MYOT, ZFPM2, HAND2-AS1, CYTL1, BHMT2, ADAMTS5, LINC00312, BNC2, ADAMTS9, PDZRN4, FAXDC2, LIMS2, RAB23, ARHGAP24, SYNC, GLT8D2, CRISPLD2, KCNMA1, GPR124, COL8A2, KIAA1644, CLU, DCHS1, ADAMTS1, KCNE4, CYBRD1, RAB9B, SLMAP, SFRP2, SMOC2, CCDC3, GLIS2, TSHZ3, ABI3BP, ZAK, C2orf40, SCARA3, CHRDL2, BOC, ANGPTL1, CFL2, PLCD4, MRVI1, TIMP2, MYADM, CCDC80, FBXO32, PKDCC, MIR100HG, SYNPO2, JAZF1, CGNL1, PRICKLE2, PCDH18, SELM, COL8A1, NFIC, PODN, ZNF521, CCDC50, CNRIP1, ATP8B2, NFIA, CPXM2, PPP1R14A, GPC6, C11orf96, STARD9, TSPAN2, ITGA9, TMEM119, TSPAN18, NFIX, MAGI2-AS3, EBF1, RNF150, LRCH2, MRGPRF, RERG, UNC5C, NDE1, ASB2, ADCY5, ZNF25, RSPO3, LSAMP, DACT3, ARHGAP20, SH3RF3, SCN7A, PDE3A, RAP1A, PGR, PREX2, CPED1, CYS1, RBPMS2, HDAC4, MAMDC2, COL1A2, ANKRD29, MYOCD, TWIST2, JPH2, SHE, HIC1, PRDM6, PGM5- AS1, LRFN5, FSTL1, ADCY4, SOX17, KGFLP2, FKBP7, GPR155, MYCT1, MIR143HG, DNM3OS, GPR133, MBNL1-AS1, COL3A1, MGC24103, ADAM33, LOC100507073, LOC283075, RBM24, GXYLT2, RBFOX3, ASB5, RBMS3, ADAMTS8, TSLP, HMCN1, ST7L, NFATC4, DOK6, LOC100507165, GATA5, MICU3, CACNA1C, C1QTNF7, MKX, MIR99AHG, FBXL22, RNF180, FENDRR, KCNQ4, LOC100507311, IFFO1, MRC2, ACACB FCER1G, FILIP1L, FGD6, C1S, ITGB2, SAMSN1, POSTN, COL1A1, BTBD19, PTRF, MSN, SPARC, CALU, DPYSL2, CTSB, PALLD, ANXA6, STOM, MMP2, LGALS1, BGN, IFITM2, VIM, COL6A3, TGFBI, CLIC4, TNC, LAPTM5, CD14, LUM, AEBP1, COL3A1, DCN, NID1, SEC14L1, LAMA4, ARL4C, NNMT, PDGFRB, SERPINF1, TRAM2, COL1A2, CTSK, PCOLCE, ICAM1, WIPF1, AXL, FBN1, CD93, SIRPA, ADAM12, MPP1, LOXL2, PAPSS2, CAV1, CHST15, CSF1R, PDGFRA, TIMP2, SH2B3, COL5A1, MMD, COL15A1, FCGR2A, ZEB2, CD163, EMP3, ADCY7, TCF4, LRRC32, VCAM1, HEPH, CYBB, NID2, TYROBP, TPST1, ALOX5AP, RUNX3, GLIPR1, FLI1, COL16A1, PLEKHO2, MRC1, GAS1, EDNRA, MYO5A, NUAK1, VCAN, PDPN, GFPT2, CSF2RB, DDR2, LCP2, GPR183, CALD1, BMP1, OSMR, ITGAM, IL7R, PRRX1, TNFAIP6, CDH11, ISLR, PTPRC, Myofibroblasts THEMIS2, ENTPD1, THY1, COL6A2, TUBB6, TSPAN4, CHI3L1, SPON1, RARRES2, ADAM19, NCF2, FAP, FYN, FN1, INHBA, LAIR1, SLC43A3, CD86, FCGR2C, PXDN, C1R, PMID:25456126 COL6A1, MT2A, IFITM3, SULF1, HEG1, PRKCDBP, PLXNC1, SACS, TMEM158, ITGA4, MXRA8, RNASE6, PCSK5, MYO1F, IFITM1, COL8A1, LOX, CCL2, TMEM176A, GREM1, LMCD1, LHFP, PDGFC, DSE, CSGALNACT2, CD248, DACT1, DOCK10, MS4A4A, MS4A6A, PLXDC1, C5AR1, TMEM176B, LEPRE1, GLT8D2, CRISPLD2, LEF1, CLEC7A, COL5A2, COL8A2, CYBRD1, SFRP2, FERMT3, LRRC8A, SULF2, PAPPA, GNG2, EDIL3, BCAT1, KIRREL, C1QC, RASA3, NRP2, ITPRIP, COL12A1, MYADM, CTHRC1, GNB4, TRIM47, KLHL5, PRICKLE1, FMNL2, ADAMTS2, CHST11, ZNF521, FAM20C, SLFN11, MPEG1, DOCK11, FAM101B, SGMS2, GPC6, FYB, GPX8, SOCS3, CLMP, ALPK2, C10orf128, LOC100132891, PRDM1, WISP1, BNC2, FPR3, GXYLT2, IFFO1, MRC2, KIAA0226L CCL5, GIMAP1, SLAMF6, IL12RB1, P2RY10, ITGAL, STAP1, CELF2, ZAP70, ZC3H12D, NEDD9, SCML4, HLA-DPB1, SPOCK2, CD53, SLA, HLA-DMB, IRF8, IL2RG, CD48, CD37, RUNX3, PIM2, IRF4, CD52, PTPN7, ARHGAP25, LCK, IL10RA, SASH3, IKZF1, CD79A, ACAP1, CXCL13, POU2AF1, IL2RB, CD3E, BTK, CR2, AOAH, HLA-DOB, CD8A, TRAF3IP3, CD2, CD27, SLAMF1, CD19, KIAA0125, TNFRSF17, GZMK, CCR2, CCR5, PTPRC, LTB, TNFRSF9, GPR171, CXCR3, LAX1, SP140, CORO1A, IGHM, Lymphocytes B&T CYTIP, TRAC, PRKCB, NCKAP1L, BTN3A1, IL16, SELPLG, CD247, CCL19, CST7, GZMB, GPR18, MS4A1, TRBC1, ITK, EVI2B, IGLJ3, YME1L1, IGJ, PPP1R16B, HMHA1, PMID:25456126 DOCK2, GUSBP11, CD3D, NKG7, CD6, IGKC, IGHD, IGLL3P, LY9, TRAT1, IGLV1-44, IGLL5, ARHGAP15, BIN2, GIMAP4, PVRIG, PLA2G2D, GVINP1, DENND1C, MZB1, SLAMF7, IL18BP, PARVG, TLR10, LOC96610, FCRL5, ARHGAP9, RCSD1, RASSF4, NLRC5, FAM46C, HLA-DOA, TMC8, JAK3, NAPSB, GIMAP7, KLHL6, TBC1D10C, RASAL3, SNX20, P2RY8, CD84, C5orf56, MIR142, FCRL3, SLA2, TAGAP, BTLA, RHOH, NLRC3, CTLA4, SAMD3, IL21R, LOC100506776, TIGIT, PYHIN1, MYO1G, WAS CTSB, UBE2L6, OPTN, MX1, CFB, PLSCR1, ICAM1, FCGR2A, IFIT5, CYBB, ALOX5AP, IFI44L, IFIT3, TLR2, OASL, IL15, XAF1, SP110, IFI35, NCF2, FCGR2C, CEBPB, Interferon response PMID:25456126 RSAD2, IFI44, LAP3, DDX60, IFIH1, HERC6, SAMD9, HERC5, CLEC4A, PARP9, DTX3L, SAMD9L, IFIT2, LOC100505702 ALG14, SAR1B, PSMD10, TIMM10, PPA2, HNRNPC, ERH, DAD1, C1D, ATP6V0B, HINT1, DYNLL1, RAN, RPS15A, PSMB1, COX6A1, HSBP1, SERP1, EIF2S1, CAPZA2, COX7A2L, PSMA5, PSMA2, UBE2D2, VBP1, SUPT4H1, UBE2N, ZNHIT1, UQCRQ, NME1, COX7A2, COPS5, CNIH1, PSMA1, NDUFS3, NEDD8, NDUFAB1, COX7B, TAF9, LAMTOR5, POLR2G, COX5B, PPIE, EAPP, POLR2K, SDHB, GTF2A2, BET1, LSM4, RFXANK, NDUFB7, POP4, LSM5, NDUFV2, ATP5J2, TXNDC9, MRPL40, NDUFB3, RPP30, TRAPPC3, NDUFB6, NDUFB5, PNO1, TBCA, HCCS, MRPL33, HSPB11, CCNH, MED7, MRPL57, LSM6, XRCC4, PFDN4, SNRPG, BUD31, ANAPC10, CLIC1, ATP6V1G1, GLRX3, CETN2, NDUFA2, EMG1, GPN1, POP7, RPA3, PTS, TMED6, PCMT1, PEX2, ATP5L, C14orf2, PDCD10, MRPS11, ZNHIT3, SUB1, ACP1, PSMA7, Mitochondria CHCHD2, MTCH2, NDUFA4, MRPL18, MRPL42, UBL5, COA3, MRPL15, MRPS16, MRPL13, DCTPP1, FAM96B, RBX1, MCTS1, NDUFB2, MRPL44, UTP11L, MRPL48, PMID:25456126 RNF7, THOC7, MRPL22, COMMD8, TIMM8B, MED28, MRPL39, NUP37, CRIPT, MRPS33, CNIH4, RPL26L1, ACN9, ALG13, TPRKB, MRPL11, MRPS22, C1GALT1C1, CHMP5, TMEM70, GEMIN6, MRPS28, GLRX2, C11orf73, SF3B5, ISCA1, SLIRP, MRPS15, TMEM14B, TMEM208, TMEM126B, MRPL17, NDUFB9, OSTC, PDZD11, FUNDC2, EMC4, SDHAF2, RNF181, SELK, TMEM14C, ZCCHC17, MRPL1, MRPS23, COX16, NDUFA12, TRMT10C, C14orf142, TMEM126A, TMEM60, SF3B6, MRPL47, GTPBP8, DPY30, MRPL27, MRPL36, C11orf31, FAM96A, TMEM261, SARNP, TOMM5, MRPL14, MRPL32, MRPL21, DNAJC19, SMIM12, USMG5, MPLKIP, MRPL50, COA6, NCBP2- AS2, COX14, C19orf70, TRAPPC5, ISCA2, TMEM167A, NSMCE2, NUDCD2, CISD2, MYEOV2, CHCHD1, MED30, CMC1, UQCC3, IMMP1L, CDKN2AIPNL Gene lists extracted from Eriksson et al and Sjödahl et al (Lund signatures) FBP1, ACER2, PKHD1, CAPN5, S100P, TMEM51, DHRS2, CYP4F22, SPINK1, ACSL5, ST3GAL5, TBX3, HPGD, TGFBR3, FAM3B, ATP8B1, RNF128, SNCG, SLC44A3, Urothelial differentiation GATA3, LARGE, PPARG, BQ441651, ICA1, GGT6, RAB11A, TRAK1, VSIG2, BCAS1, RAB15, FAM174B, SLC29A3, FOXA1, GOLT1A, PPFIBP2, DENND2D, AK024898, PMID:26008846 ACAA1, DNAJA4, HMGCS2, C10orf116, CYP2J2 VSNL1, KRT14, TGM1, SERPINB4, GSDMC, KRT6A, LGALS7, SFN, SPRR2A, BG205162, C12orf54, SPRR2D, HOXD11, KRT6C, KRT5, DSG3, KRT6B, HOXD10, IL20RB, Keratinization PMID:26008846 RHCG, AHNAK2, SPRR2F, FGFBP1 PRIM1, WDR34, CCNB1, SLFN11, SGOL1, FAM83D, MCM2, CHAF1B, MCM4, MCM5, POLA2, NDC80, KNTC1, CDCA8, CBX2, hNp95, UBE2C, HMMR, BIRC5, CTPS, TYMS, AURKA, SNRPB, TUBA1A, ANLN, FOXM1, CDCA5, CDKN3, BUB1, CENPL, CCNB2, ECT2, UBE2T, LMNB1, C1orf135, MCM6, LOC146880, CTSL2, CKAP2L, CENPM, ASF1B, GMPS, PAQR4, PRR11, POLE2, TK1, C17orf53, RPA3, EZH2, KIF18A, C16orf59, CCNE2, H2AFZ, CDCA3, MELK, CDCA7, NUF2, CKS2, KIAA1524, SNX8, AURKB, Late cell-cycle SPC25, NEK2, KIF20A, CHEK1, GINS2, TOP2A, GPSM2, CENPE, MSH6, ATAD2, CDC20, TPX2, C17orf79, STIL, CDC45, FAM72D, KIF14, CDC7, CCDC109B, MCM10, PMID:26008846 CENPW, FAM72A, CEP55, FAM64A, KIF11, TROAP, E2F2, FADS1, TUBA1C, NCAPG, BLM, TTK, HMGB2, CENPA, TRIP13, POC1A, CDC25B, KIF2C, DTL, FANCI, RFC4, HJURP, RFC5, ZWINT, DLGAP5, PTTG3, PRC1, PLK4, NUSAP1, MNS1, RNASEH2A, CCNA2, FEN1, KIF4A, MMD, BRCA1, DNMT1, KIFC1, C1orf112, KIF15, TIMELESS, PTTG1, SLC25A19, NCAPG2, POLQ, OIP5, ASPM, MAD2L2 C3orf54, CAPNS2, SEMA4B, WNT7B, DUOXA1, C16orf74, ZNF385A, SMAD3, SLC2A9, D4S234E, TP63, CLCA4, IRS1, SYTL1, PLCH2, SSH3, FGFR3, PTPN13, DUOX1, FGFR3-coexpressed genes PMID:22553347 TMPRSS4 Supplementary Table 3 : Association of the consensus molecular classification with exome data from TCGA (n=388). We used processed exome TCGA data to analyse the mutation profiles relatively to each consensus class. Only genes with MutsigCV Q-values < 0.02 (computed by TCGA) are listed in the table. Chi-squared tests were performed for each gene to test if the gene mutations were differentially enriched within the consensus classes. For each class, Fisher's exact tests were performed to measure specific enrichment in the class.

Maximal Fisher P val Fisher P val Fisher P val Fisher P val Fisher P val Nb Nb of Chisq P val Mutation mutation (association (association (association Fisher P val (association (association patients unique (association frequency frequency Enrichment Nb of %of with this Nb of with this Nb of %of with this Nb of (association with Nb of %of with this Nb of with this with mutation MutsigCV P MutsigCV with in all in a within a specific mutated mutated consensus mutated %of mutated consensus mutated mutated consensus mutated %of mutated this consensus mutated mutated consensus mutated %of mutated consensus mutation site val Q val consensus) tumours subtype subtype ? tumours tumours class) tumours tumours class) tumours tumours class) tumours tumours class) tumours tumours class) tumours tumours class) Gene npat nsite p q Chisq.pval freq.all freq.max subtype.spe LumP LumP.prop LumP.Pfish LumNS LumNS.prop LumNS.Pfish LumU LumU.prop LumU.Pfish Stroma-rich Stroma-rich.prop Stroma-rich.Pfish Ba/Sq Ba/Sq.prop Ba/Sq.Pfish NE-like NE-like.prop NE-like.Pfish TP53 196 118 0,00E+00 <1.64e-12 5,55E-10 50% 100% TRUE 38 32% 1,00E+00 9 45% 7,54E-01 39 76% 3,40E-05 12 28% 9,99E-01 90 61% 5,81E-04 6 100% 1,50E-02 FGFR3 56 18 0,00E+00 <1.64e-12 6,18E-10 14% 33% TRUE 40 33% 1,37E-11 1 5% 9,59E-01 1 2% 1,00E+00 2 5% 9,93E-01 12 8% 9,99E-01 0 0% 1,00E+00 RB1 70 66 3,22E-15 4.85e-12 6,33E-06 18% 67% TRUE 6 5% 1,00E+00 1 5% 9,81E-01 11 22% 2,62E-01 9 21% 3,30E-01 37 25% 2,05E-03 4 67% 9,87E-03 RUNX1 13 12 0,00000194 0.00121 7,85E-04 3% 33% TRUE 1 1% 9,93E-01 0 0% 1,00E+00 3 6% 2,37E-01 1 2% 7,88E-01 6 4% 3,70E-01 2 33% 1,44E-02 ELF3 46 48 4,84E-14 5.15e-11 4,77E-03 12% 35% TRUE 17 14% 1,87E-01 7 35% 4,29E-03 7 14% 3,76E-01 5 12% 5,78E-01 9 6% 9,98E-01 0 0% 1,00E+00 KDM6A 103 91 0 <5.25e-12 1,36E-02 27% 50% TRUE 45 38% 2,19E-03 6 30% 4,78E-01 15 29% 4,17E-01 7 16% 9,76E-01 30 20% 9,95E-01 3 50% 2,06E-01 ERCC2 38 22 0 0.000 1,59E-02 10% 22% TRUE 10 8% 8,25E-01 0 0% 1,00E+00 11 22% 6,55E-03 1 2% 9,92E-01 17 11% 2,84E-01 0 0% 1,00E+00 NFE2L2 24 16 0 <1.64e-12 3,26E-02 6% 11% TRUE 2 2% 9,98E-01 1 5% 7,15E-01 1 2% 9,65E-01 3 7% 4,80E-01 16 11% 1,68E-03 0 0% 1,00E+00 STAG2 56 53 1,89E-14 2.13e-11 7,60E-02 16% 23% TRUE 27 23% 1,19E-02 2 10% 8,53E-01 4 8% 9,77E-01 9 21% 2,15E-01 19 13% 9,16E-01 0 0% 1,00E+00 TBC1D12 49 4 0 <1.64e-12 8,61E-02 13% 20% TRUE 23 19% 1,20E-02 4 20% 2,49E-01 7 14% 4,96E-01 4 9% 8,38E-01 11 7% 9,97E-01 1 17% 5,65E-01 FOXQ1 14 9 0,000000491 0.000317 1,33E-01 5% 15% FALSE 7 6% 3,05E-01 3 15% 5,82E-02 1 2% 9,26E-01 0 0% 1,00E+00 7 5% 5,65E-01 0 0% 1,00E+00 KRAS 13 5 0 <1.64e-12 1,45E-01 3% 17% FALSE 4 3% 5,37E-01 0 0% 1,00E+00 0 0% 1,00E+00 3 7% 1,37E-01 4 3% 7,37E-01 1 17% 1,73E-01 ZFP36L1 25 27 1,88E-14 2.13e-11 1,79E-01 6% 14% TRUE 9 8% 3,58E-01 0 0% 1,00E+00 4 8% 4,22E-01 6 14% 4,56E-02 6 4% 9,61E-01 0 0% 1,00E+00 PSIP1 20 20 0,00000266 0.00155 1,85E-01 5% 17% FALSE 8 7% 3,06E-01 2 10% 2,96E-01 5 10% 1,26E-01 1 2% 9,21E-01 4 3% 9,85E-01 1 17% 2,85E-01 ARID1A 97 107 1,68E-13 1.69e-10 2,20E-01 26% 67% TRUE 29 24% 7,01E-01 7 35% 2,26E-01 14 27% 4,25E-01 11 26% 5,60E-01 34 23% 8,47E-01 4 67% 3,91E-02 RXRA 24 12 4,42E-09 3.33e-06 2,55E-01 7% 16% TRUE 9 8% 5,69E-01 1 5% 7,97E-01 8 16% 2,45E-02 3 7% 6,47E-01 8 5% 9,24E-01 0 0% 1,00E+00 PTEN 14 15 0,0000351 0.0172 2,69E-01 4% 17% FALSE 2 2% 9,47E-01 0 0% 1,00E+00 3 6% 2,37E-01 1 2% 7,88E-01 6 4% 3,70E-01 1 17% 1,86E-01 METTL3 18 20 0,00000255 0.00154 2,71E-01 5% 8% FALSE 8 7% 1,56E-01 0 0% 1,00E+00 4 8% 2,00E-01 3 7% 3,21E-01 3 2% 9,89E-01 0 0% 1,00E+00 CDKN2A 26 22 0 <1.64e-12 2,90E-01 7% 9% FALSE 9 8% 4,11E-01 1 5% 7,59E-01 2 4% 8,82E-01 0 0% 1,00E+00 14 9% 6,87E-02 0 0% 1,00E+00 HRAS 16 10 5,66E-13 5.12e-10 3,26E-01 4% 8% TRUE 9 8% 4,48E-02 1 5% 6,01E-01 1 2% 9,14E-01 0 0% 1,00E+00 6 4% 6,87E-01 0 0% 1,00E+00 ERBB2 48 25 0,0000289 0.0145 3,40E-01 14% 18% FALSE 16 13% 7,12E-01 0 0% 1,00E+00 9 18% 3,03E-01 6 14% 6,12E-01 25 17% 1,75E-01 0 0% 1,00E+00 RHOA 18 15 1,93E-13 1.83e-10 3,57E-01 5% 10% FALSE 8 7% 1,56E-01 2 10% 2,36E-01 3 6% 4,30E-01 0 0% 1,00E+00 5 3% 8,82E-01 0 0% 1,00E+00 PIK3CA 86 35 0 <1.64e-12 3,85E-01 22% 29% FALSE 25 21% 7,35E-01 2 10% 9,61E-01 15 29% 1,36E-01 10 23% 5,11E-01 35 24% 3,69E-01 0 0% 1,00E+00 NHLRC1 9 10 0,00000889 0.00487 3,99E-01 3% 17% FALSE 3 3% 7,14E-01 0 0% 1,00E+00 1 2% 7,92E-01 1 2% 7,30E-01 5 3% 4,15E-01 1 17% 1,59E-01 TSC1 33 30 0,000000348 0.000233 3,99E-01 9% 15% FALSE 14 12% 1,84E-01 3 15% 2,80E-01 3 6% 8,81E-01 6 14% 1,95E-01 10 7% 9,39E-01 0 0% 1,00E+00 FBXW7 30 25 0 <1.64e-12 4,18E-01 8% 11% FALSE 7 6% 8,75E-01 2 10% 4,69E-01 4 8% 5,76E-01 1 2% 9,75E-01 16 11% 5,78E-02 0 0% 1,00E+00 HIST1H3B 12 9 2,82E-08 1.96e-05 4,82E-01 3% 10% FALSE 4 3% 6,11E-01 2 10% 1,40E-01 2 4% 5,28E-01 0 0% 1,00E+00 5 3% 5,96E-01 0 0% 1,00E+00 SF1 10 13 0,0000127 0.00674 5,03E-01 3% 17% FALSE 4 3% 5,37E-01 1 5% 4,75E-01 1 2% 8,20E-01 1 2% 7,61E-01 4 3% 7,37E-01 1 17% 1,73E-01 EP300 61 73 1,09E-12 9.35e-10 6,14E-01 15% 33% FALSE 15 13% 9,08E-01 2 10% 8,53E-01 8 16% 5,71E-01 7 16% 5,30E-01 27 18% 1,76E-01 2 33% 2,40E-01 CDKN1A 35 30 1,11E-16 1.00e-12 6,54E-01 9% 12% FALSE 14 12% 1,24E-01 2 10% 5,39E-01 5 10% 4,71E-01 4 9% 5,36E-01 9 6% 9,54E-01 0 0% 1,00E+00 CREBBP 48 47 0,0000381 0.0181 7,41E-01 13% 17% FALSE 13 11% 8,34E-01 3 15% 4,89E-01 4 8% 9,23E-01 6 14% 4,89E-01 23 16% 1,43E-01 1 17% 5,65E-01 ZBTB7B 11 8 0,00000325 0.00183 7,82E-01 3% 5% FALSE 5 4% 2,99E-01 1 5% 4,75E-01 2 4% 4,83E-01 0 0% 1,00E+00 4 3% 7,37E-01 0 0% 1,00E+00 RHOB 26 18 1,89E-14 2.13e-11 7,92E-01 7% 10% FALSE 9 8% 4,11E-01 2 10% 3,94E-01 4 8% 4,54E-01 4 9% 3,22E-01 7 5% 9,26E-01 0 0% 1,00E+00 KLF5 23 21 1,09E-09 8.92e-07 8,25E-01 6% 17% FALSE 9 8% 3,05E-01 1 5% 7,30E-01 2 4% 8,51E-01 2 5% 7,71E-01 9 6% 6,06E-01 1 17% 3,20E-01 SF3B1 24 19 0,0000174 0.00898 8,40E-01 6% 7% FALSE 8 7% 4,19E-01 0 0% 1,00E+00 3 6% 6,05E-01 2 5% 7,50E-01 10 7% 3,69E-01 0 0% 1,00E+00 ASXL2 36 39 3,04E-09 2.39e-06 8,51E-01 10% 17% FALSE 11 9% 6,31E-01 1 5% 8,72E-01 7 14% 1,97E-01 4 9% 6,08E-01 13 9% 7,14E-01 1 17% 4,54E-01 PTTG1IP 3 3 0 <1.64e-12 9,03E-01 1% 1% FALSE 1 1% 6,72E-01 0 0% 1,00E+00 0 0% 1,00E+00 0 0% 1,00E+00 2 1% 3,25E-01 0 0% 1,00E+00 C3orf70 17 10 6,19E-09 4.48e-06 9,48E-01 4% 5% FALSE 6 5% 4,36E-01 1 5% 6,01E-01 1 2% 9,14E-01 2 5% 5,82E-01 7 5% 4,89E-01 0 0% 1,00E+00 Supplementary Table 4 : Regions of amplification or deletion identified by GISTIC2 algorithm and significantly associated with one of the consensus classes. We analysed 600 segmented CNV profiles from 5 datasets (TCGA, CIT, Stransky, Sjödahl, Iyer). GISTIC2 was used to identify significantly altered regions within each consensus class (GISTIC residual q-value < 0.05) and Fisher exact tests were performed to test the specific association of the regions with each consensus class compared to the others. For each regions we computed the gene expression vs copy number correlation of all encompassed genes and marked as candidate genes those whose Pearson correlation was at least 0.4 in one of the 5 datasets analysed. The best observed correlation among all genes within the region is reported here, alongside with the name of corresponding gene. For each consensus class, we highlighted in bold the region whose copy number alterations were the most significantly associated with the class.

Candidate genes Gene with Highest High level Amplification : GISTIC frequency Deletion : Deep deletion : GISTIC (max correlation highest correlation CNV- amplification : Association Event Cytoband Wide_Peak_Boundaries residual within genes in region Association with Association with q_value with expression > correlation CNV- expression (max Association with with class q_value subtype class (Fisher P) class (Fisher P) 0.4) expression over 4 datasets) class (Fisher P) (Fisher P) Luminal Papillary (n=174) Amplification 3p25.2 chr3:11952019-12503638 1,00E-07 1,00E-07 47% PPARG;SYN2;TIMP4 PPARG;TIMP4 TIMP4 0,65 8,98E-01 3,26E-01 Amplification 4p16.3 chr4:1719188-1787852 2,69E-08 2,69E-08 25% TACC3;TMEM129 TMEM129 TMEM129 0,50 8,92E-03 4,13E-03 Amplification 6p22.3 chr6:21457951-21655358 1,60E-07 1,60E-07 27% SOX4 SOX4 0,38 1,00E+00 1,00E+00 ADAM3A;FGFR1;ADAM2;IDO1;TACC1;ADAM18;ADAM9;PLEK HA2;TM2D2;LETM2;IDO2;HTRA4;ADAM32;ADAM5P;RNF5P1; TACC1;ADAM9;PLEK Amplification 8p11.23 chr8:38260816-39893269 5,38E-05 5,38E-05 28% C8orf86;LOC100130964 HA2;TM2D2;LETM2 TM2D2 0,61 2,00E-01 5,28E-01 Amplification 8q22.3 chr8:101710215-102008872 2,55E-18 2,55E-18 55% YWHAZ;PABPC1 YWHAZ YWHAZ 0,46 7,22E-01 9,97E-01 hsa-mir-548k;CCND1;DHCR7;CTTN;FGF3;FGF4;KRTAP5- 9;PPFIA1;FADD;FGF19;SHANK2;ANO1;NADSYN1;FAM86C1;K CCND1;DHCR7;CTTN; RTAP5-8;ORAOV1;DEFB108B;KRTAP5-10;FLJ42102;KRTAP5- PPFIA1;FADD;ANO1; Amplification 11q13.3 chr11:69435628-71582733 1,77E-33 1,77E-33 34% 7;KRTAP5-11;LOC100133315;MIR548K;MIR3664 ORAOV1 CTTN 0,86 2,92E-02 3,35E-01 hsa-mir- 1279;LYZ;CNOT2;PTPRB;PTPRR;TSPAN8;YEATS4;LGR5;CC T2;FRS2;CPSF6;RAB21;KCNMB4;TRHDE;TMEM19;TBC1D15; THAP2;RAB3IP;TPH2;BEST3;ZFC3H1;LOC283392;LRRC10;M LYZ;CNOT2;CCT2;RA Amplification 12q15 chr12:69599247-74433391 3,64E-19 9,27E-17 35% RS2P2;MIR1279;MIR3913-2;MIR3913-1 B21;TMEM19 RAB21 0,60 4,94E-02 5,42E-04

Amplification 20q11.21 chr20:30629351-30927566 7,78E-04 7,78E-04 61% hsa-mir-3133;hsa-mir-149;hsa-mir-4269;hsa-mir-562;hsa-mir-hsa-mir-1825;HCK;PLAGL2;KIF3B;TM9SF4;POFUT1;TSPY26P KIF3B;POFUT1 POFUT1 0,44 6,63E-01 8,44E-01 1471;hsa-mir-1244- 1;AGXT;ALPI;ALPP;ALPPL2;KIF1A;BOK;CHRND;CHRNG;COL 6A3;DTYMK;GBX2;GPC1;GPR35;HDLBP;HTR2B;SP110;INPP 5D;KCNJ13;NCL;NDUFA10;SEPT2;NEU2;NPPC;PDCD1;PDE6 D;PPP1R7;PSMD1;PTMA;SNORD20;SAG;SP100;SPP2;DGKD; PER2;LRRFIP1;GPR55;TRIP12;ECEL1;EIF4E2;HDAC4;FARP2 ;ARL4C;RAMP1;NMUR1;STK25;COPS8;CAPN10;SP140;PASK ;ATG4B;SH3BP4;NGEF;SNORD82;SNED1;GIGYF2;TRAF3IP1; ANO7;PRLH;THAP4;ANKMY1;SCLY;ASB1;CAB39;UGT1A10;U GT1A8;UGT1A7;UGT1A6;UGT1A5;UGT1A9;UGT1A4;UGT1A1; UGT1A3;ATG16L1;USP40;HJURP;HES6;CXCR7;RNPEPL1;GA GPC1;HDLBP;NCL;ND L3ST2;RAB17;COPS7B;TRPM8;MLPH;IQCA1;C2orf54;ARMC9; UFA10;SEPT2;PPP1R EFHD1;ILKAP;ITM2C;ING5;MGC16025;B3GNT7;SP140L;AGA 7;PSMD1;PTMA;SP10 P1;TWIST2;DIS3L2;NEU4;SPATA3;FBXO36;MTERFD2;UBE2F 0;DGKD;TRIP12;EIF4 ;OTOS;MYEOV2;OR6B3;LOC150935;LOC151171;LOC151174 E2;RAMP1;STK25;CO ;SLC16A14;LOC151475;LINC00471;LOC151484;MSL3P1;C2o PS8;GIGYF2;TRAF3IP rf57;TIGD1;LOC200772;C2orf72;CXXC11;DUSP28;ESPNL;EC 1;THAP4;SCLY;ASB1; EL1P2;LOC348761;RBM44;AQP12A;KLHL30;C2orf82;OR6B2; CAB39;ATG16L1;USP ASB18;FLJ43879;MIR149;DNAJB3;LOC643387;PRR21;PRSS 40;RNPEPL1;COPS7B 56;AQP12B;SNORA75;SCARNA6;SCARNA5;D2HGDH;LOC72 ;MLPH;ILKAP;AGAP1; 8323;PP14571;LOC100286922;MIR1471;MIR1244-1;BOK- DIS3L2;MTERFD2;UB AS1;MIR1244-3;MIR1244-2;MIR4269;UBE2F- E2F;MYEOV2;SLC16A Deletion 2q37.1 chr2:230566343-243199373 2,81E-17 2,65E-08 53% SCLY;MIR4777;MIR2467;MIR4440;MIR4786;MIR4441 14;PP14571 NCL 0,68 1,89E-01 5,96E-02 Deletion 4q22.1 chr4:90132769-93230133 2,70E-05 7,64E-05 24% SNCA;MMRN1;GPRIN3;FAM190A;LOC644248 SNCA 0,26 1,00E+00 1,00E+00

AGA;GPM6A;VEGFC;NEIL3;SPCS3;WDR17;SPATA4;ASB5;L Deletion 4q34.3 chr4:175896011-182083197 5,10E-05 3,05E-04 28% OC285501;LINC00290 AGA;SPCS3 SPCS3 0,54 1,00E+00 7,29E-01 Deletion 5q12.1 chr5:58249079-59795032 2,42E-12 2,44E-12 40% hsa-mir-582;PDE4D;PART1 PDE4D PDE4D 0,43 9,99E-01 3,06E-01 CDKN2A;CDKN2B;C9o Deletion 9p21.3 chr9:21855688-22514916 5,61E-142 5,61E-142 68% CDKN2A;CDKN2B;C9orf53;DMRTA1;CDKN2B-AS1 rf53;DMRTA1 CDKN2A 0,71 2,21E-07 7,81E-04 Deletion 10q26.3 chr10:131976693-133943438 8,68E-05 8,86E-04 37% hsa-mir-378c;BNIP3;PPP2R2D;TCERG1L;FLJ46300;MIR378C PPP2R2D PPP2R2D 0,48 9,55E-01 2,49E-01 Deletion 11q23.3 chr11:119360546-119984555 1,14E-04 1,15E-04 40% PVRL1 PVRL1 0,11 4,40E-01 6,50E-01 hsa-mir-15a; RCBTB2;KPNA3;RB1; RCBTB2;MLNR;GUCY1B2;KPNA3;RB1;DLEU2;ITM2B;LPAR6; DLEU2;ITM2B;TRIM13 TRIM13;DLEU1;FNDC3A;INTS6;PHF11;RCBTB1;CYSLTR2;SP ;DLEU1;FNDC3A;INTS RYD7;RNASEH2B;DHRS12;CDADC1;CAB39L;SETDB2;EBPL; 6;PHF11;RCBTB1;RN ARL11;WDFY2;ST13P4;DLEU7;FAM124A;CTAGE10P;KCNRG; ASEH2B;DHRS12;CA Deletion 13q14.2 chr13:48806861-52387891 3,32E-12 1,04E-10 27% MIR15A;MIR16-1;SERPINE3;MIR3613;MIR4703 B39L;SETDB2;EBPL; FNDC3A 0,75 1,00E+00 8,45E-01 ADCY9;CREBBP;DNASE1;SRL;TFAP4;DNAJA3;TRAP1;PAM1 6;NMRAL1;CORO7;SLX4;GLIS2;VASN;LOC100507501;CORO CREBBP;TFAP4;DNAJ Deletion 16p13.3 chr16:3616295-4551070 1,43E-06 1,43E-06 36% 7-PAM16 A3;TRAP1;NMRAL1 TFAP4 0,72 9,75E-01 2,47E-01 Deletion 20p13 chr20:1468401-1615958 1,62E-05 1,57E-05 16% SIRPB1;SIRPD SIRPB1 0,31 5,83E-01 Inf Luminal Non-Specified (n=35) hsa-mir- 556;APOA2;CD48;FCER1G;FCGR2A;FCGR2B;FCGR3A;FCGR 3B;HSPA6;HSPA7;LY9;MPZ;NDUFS2;NIT1;PFDN2;PPOX;SDH NDUFS2;NIT1;PFDN2; C;SLAMF1;USF1;B4GALT3;CD84;FCGR2C;DEDD;ADAMTS4;N PPOX;SDHC;USF1;B4 OS1AP;NR1I3;DUSP12;ATF6;OLFML2B;USP21;F11R;UFC1;C GALT3;DEDD;NOS1A D244;ITLN1;SLAMF7;PVRL4;TOMM40L;FCRLA;SH2D1B;KLHD P;DUSP12;ATF6;USP C9;FCRLB;ITLN2;ARHGAP30;C1orf192;C1orf111;C1orf226;RP 21;F11R;UFC1;PVRL4 Amplification 1q23.3 chr1:160495354-162446706 2,06E-04 2,06E-04 71% L31P11;PCP4L1;MIR556;TSTD1;MIR4654 ;TOMM40L;C1orf226 NDUFS2 0,77 3,73E-01 4,86E-02 Amplification 3p25.2 chr3:12437701-12491536 2,63E-06 2,63E-06 71% PPARG PPARG PPARG 0,51 2,13E-01 1,05E-03 hsa-mir-548a-3;hsa-mir-3151;hsa-mir- 1273;ANGPT1;ATP6V1C1;COX6C;DPYS;EIF3E;ODF1;POLR2 K;SPAG1;KLF10;TRHR;YWHAZ;FZD6;TTC35;RIMS2;ZFPM2;D ATP6V1C1;COX6C;EI CAF13;RNF19A;RGS22;PABPC1;LRP12;RRM2B;ZNF706;UBR F3E;POLR2K;KLF10;Y 5;AZIN1;OXR1;ENY2;BAALC;GRHL2;SLC25A32;TM7SF4;NAC WHAZ;TTC35;DCAF13 AP1;NCALD;NUDCD1;PKHD1L1;CTHRC1;ABRA;C8orf56;ANKR ;ZNF706;UBR5;AZIN1; D46;VPS13B;TMEM74;SNX31;FBXO43;RSPO2;FLJ42969;MIR ENY2;SLC25A32;NUD Amplification 8q22.2 chr8:100791157-110430427 7,37E-04 7,37E-04 66% 3151;LOC100499183;MIR4471 CD1 ENY2 0,78 6,70E-01 2,23E-01 hsa-mir-548k;CCND1;DHCR7;CTTN;FGF3;FGF4;KRTAP5- 9;PPFIA1;FADD;FGF19;SHANK2;ANO1;NADSYN1;FAM86C1;K CCND1;DHCR7;CTTN; RTAP5-8;ORAOV1;DEFB108B;KRTAP5-10;FLJ42102;KRTAP5- PPFIA1;FADD;ANO1; Amplification 11q13.3 chr11:69434304-71582733 1,11E-06 1,11E-06 43% 7;KRTAP5-11;LOC100133315;MIR548K;MIR3664 ORAOV1 CTTN 0,86 4,00E-01 1,53E-01 hsa-mir- 1279;CPM;LYZ;MDM2;CNOT2;RAP1B;YEATS4;CCT2;FRS2;CP SF6;KCNMB4;SLC35E3;NUP107;RAB3IP;BEST3;LRRC10;MIR Amplification 12q15 chr12:68904948-70771660 7,66E-07 7,66E-07 37% 1279;SNORA70G;MIR3913-2;MIR3913-1;LOC100507250 LYZ;CNOT2;CCT2 LYZ 0,54 3,84E-01 2,14E-01 CDKN2A;CDKN2B;C9o Deletion 9p21.3 chr9:21865498-22447986 1,96E-11 1,96E-11 74% CDKN2A;CDKN2B;C9orf53;CDKN2B-AS1 rf53 CDKN2A 0,71 2,37E-02 9,78E-01 Luminal Unstable (n=80) BMP8B;MYCL1;PPT1;PABPC4;PPIE;CAP1;HEYL;HPCAL4;TRI PPT1;PABPC4;PPIE;C Amplification 1p34.2 chr1:40039708-40605877 5,63E-05 5,63E-05 41% T1;OXCT2;NT5C1A;MFSD2A AP1;HPCAL4;TRIT1 PPIE 0,60 2,42E-03 6,19E-04 hsa-mir- 4257;ARNT;CTSK;CTSS;ECM1;ENSA;MCL1;RPRD2;ADAMTSL ARNT;ENSA;RPRD2;G Amplification 1q21.3 chr1:150340410-150865163 1,77E-19 3,05E-08 83% 4;GOLPH3L;TARS2;HORMAD1;MIR4257 OLPH3L;TARS2 TARS2 0,67 1,44E-06 2,14E-07 hsa-mir-556; APOA2;CD48;FCER1G;FCGR2A;FCGR2B;FCGR3A;FCGR3B;H NDUFS2;NIT1;PFDN2; SPA6;HSPA7;LY9;MPZ;NDUFS2;NIT1;PFDN2;PPOX;SDHC;SL PPOX;SDHC;USF1;B4 AMF1;USF1;B4GALT3;CD84;FCGR2C;DEDD;ADAMTS4;NOS1 GALT3;DEDD;NOS1A AP;NR1I3;DUSP12;ATF6;OLFML2B;USP21;F11R;UFC1;CD244 P;DUSP12;ATF6;USP ;ITLN1;SLAMF7;PVRL4;TOMM40L;FCRLA;SLAMF6;SH2D1B;K 21;F11R;UFC1;PVRL4 LHDC9;UHMK1;FCRLB;ITLN2;ARHGAP30;C1orf192;C1orf111; ;TOMM40L;UHMK1;C1 Amplification 1q23.3 chr1:160476230-162467608 3,29E-23 1,94E-15 86% C1orf226;RPL31P11;PCP4L1;MIR556;TSTD1;MIR4654 orf226 NDUFS2 0,77 2,88E-07 1,46E-09 Amplification 3p25.2 chr3:12478818-12531178 1,37E-16 1,37E-16 80% TSEN2 TSEN2 TSEN2 0,65 1,44E-06 1,35E-14 Amplification 6p22.3 chr6:20328722-21795751 1,21E-52 1,21E-52 78% E2F3;SOX4;CDKAL1;LINC00340 E2F3;CDKAL1 E2F3 0,74 3,01E-12 7,63E-11 Amplification 6q21 chr6:107096807-107459080 5,16E-04 5,16E-04 20% hsa-mir-587;C6orf203;QRSL1;BEND3;LOC100422737 C6orf203 C6orf203 0,65 4,37E-01 3,39E-03 hsa-mir-1302- 6;AHR;HDAC9;AGR2;SNX13;TSPAN13;BZW2;ANKMY2;AGR3; SNX13;TSPAN13;BZW Amplification 7p21.1 chr7:16667770-18739132 2,21E-06 2,21E-06 71% PRPS1L1 2;ANKMY2 ANKMY2 0,58 3,01E-05 1,11E-07 hsa-mir-486;ANK1;IKBKB;PLAT;KAT6A;AP3M2;NKX6- Amplification 8p11.21 chr8:41501040-42133127 6,37E-05 8,02E-04 50% 3;MIR486 PLAT;KAT6A;AP3M2 PLAT 0,50 9,02E-03 3,19E-02 YWHAZ;PABPC1;ZNF706;ANKRD46;SNX31;FLJ42969; Amplification 8q22.3 chr8:101337944-102360137 2,86E-19 2,86E-19 74% MIR4471 YWHAZ;ZNF706 YWHAZ 0,46 1,39E-02 3,36E-02 Amplification 10p14 chr10:7958318-8275516 8,55E-10 8,55E-10 76% GATA3;TAF3;FLJ45983 TAF3 TAF3 0,54 1,65E-04 7,92E-11 ABAT;PMM2;USP7;CA ABAT;PMM2;USP7;CARHSP1;TMEM186;C16orf72;RBFOX1;M RHSP1;TMEM186;C16 Amplification 16p13.2 chr16:7419224-9600143 7,00E-12 7,00E-12 49% ETTL22;TMEM114;MIR548X orf72 USP7 0,82 4,23E-04 4,47E-04 Amplification 19q12 chr19:30287570-30651320 4,78E-08 4,78E-08 64% CCNE1;URI1 URI1 0,39 9,51E-02 6,61E-05 COL4A3;COL4A4;AGFG1;SP110;IRS1;CCL20;TRIP12;SP140; PID1;DOCK10;C2orf83;MFF;NYAP2;TM4SF20;SPHKAP;SLC19 AGFG1;IRS1;TRIP12; A3;RHBDD1;DNER;SP140L;FBXO36;SLC16A14;WDR69;LOC6 MFF;RHBDD1;SLC16A Deletion 2q37.1 chr2:225444715-231285905 5,42E-15 5,42E-15 69% 46736;MIR4439 14 TRIP12 0,63 1,16E-03 1,05E-02 hsa-mir-1305; AGA;SLC25A4;CASP3;DCTD;F11;ACSL1;FAT1;FRG1;GPM6A; HSP90AA4P;ING2;IRF2;KLKB1;MTNR1A;TLR3;VEGFC;SORB S2;DUX4;FAM149A;DUX2;PDLIM3;CLDN22;NEIL3;UFSP2;CD KN2AIP;ODZ3;LRP2BP;STOX2;KIAA1430;SPCS3;TRAPPC11; MLF1IP;WWC2;SNX25;MGC45800;WDR17;ZFP42;SPATA4;EN AGA;SLC25A4;CASP3 PP6;ASB5;C4orf38;RWDD4;CCDC111;TRIML2;CCDC110;CYP ;DCTD;FAT1;FRG1;IN 4V2;LOC285441;LOC285501;LOC339975;TRIML1;ANKRD37; G2;IRF2;TLR3;SORBS LOC389247;HELT;LOC401164;FAM92A3;C4orf47;DUX4L4;FR 2;NA;CLDN22;UFSP2; G2;SLED1;FLJ38576;DUX4L6;DUX4L5;DUX4L3;LINC00290;L CDKN2AIP;SPCS3;TR OC728175;DUX4L2;LOC731424;CLDN24;LOC100288255;MIR APPC11;CCDC111;CY Deletion 4q34.3 chr4:175863196-191154276 1,41E-07 1,41E-07 60% 1305;MIR3945;LOC100506229 P4V2;ANKRD37 DCTD 0,73 5,93E-03 2,01E-02 hsa-mir-582; TRIM23;ARSB;BTF3;C TRIM23;ARSB;BHMT;BTF3;CCNB1;CDK7;CKMT2;ERCC8;CRH DK7;ERCC8;CRHBP;H BP;DHFR;F2R;F2RL1;F2RL2;FOXD1;GTF2H2;HEXB;HMGCR;H EXB;TNPO1;MAP3K1; TR1A;IL6ST;KIF2A;TNPO1;CD180;MAP1B;MAP3K1;MSH3;NAI MSH3;PDE4D;PIK3R1; P;PDE4D;PIK3R1;PMCHL2;RAD17;RASGRF2;RPS23;SMN1;S RAD17;RASGRF2;RP MN2;TAF9;TBCA;THBS4;SERF1A;ENC1;AP3B1;PPAP2A;PDE S23;SMN1;TAF9;TBC 8B;HOMER1;SCAMP1;CARTPT;ZFYVE16;COL4A3BP;LHFPL2 A;ENC1;AP3B1;SCAM ;CWC27;NSA2;PLK2;IQGAP2;SMA4;SMA5;ADAMTS6;SV2C;M P1;ZFYVE16;COL4A3 RPS27;PPWD1;OTP;SSBP2;BHMT2;PART1;FAM169A;RNU5E- BP;LHFPL2;CWC27;N 1;RNU5D- SA2;PLK2;MRPS27;P 1;DIMT1;DMGDH;IPO11;GCNT4;POLK;DDX4;SGTB;AGGF1;W PWD1;DMGDH;IPO11; DR41;DEPDC1B;BDP1;ERBB2IP;NLN;ZSWIM6;ANKRA2;MCCC POLK;AGGF1;WDR41; 2;CENPK;RGNEF;SLC30A5;CENPH;GPBP1;ANKRD55;PTCD2; BDP1;ERBB2IP;ZSWI ELOVL7;C5orf44;ATG10;UTP15;ZCCHC9;ZBED3;GFM2;SPZ1; M6;ANKRA2;SLC30A5 NDUFAF2;MRPS36;ATP6AP1L;FCHO2;RAB3C;C5orf35;IL31R ;GPBP1;PTCD2;C5orf A;JMY;TMEM171;TMEM174;POC5;ACOT12;SREK1;SLC38A9; 44;ATG10;UTP15;ZCC MARVELD2;MIER3;PAPD4;ZNF366;FAM151B;S100Z;CCDC12 HC9;GFM2;NDUFAF2; 5;GAPT;CMYA5;ANKRD31;SERINC5;C5orf64;RNF180;SREK1I MRPS36;FCHO2;C5orf P1;ANKRD34B;ACTBL2;MTX3;MAST4;RNF138P1;RGS7BP;CR 35;POC5;SREK1;SLC SP8P;C5orf43;LOC644936;LOC647859;GUSBP3;GTF2H2B;S 38A9;MIER3;PAPD4;S NORA47;GTF2H2C;SERF1B;LOC728723;GTF2H2D;GUSBP9; ERINC5;SREK1IP1;MT LRRC70;LOC100131067;FAM159B;LOC100170939;LOC1002 X3;GTF2H2B;GTF2H2 Deletion 5q12.3 chr5:54672788-82136646 9,61E-04 9,61E-04 69% 72216;NCRUPAR;LOC100303749;MTRNR2L2;OCLN;MIR4804; C UTP15 0,70 7,59E-06 5,77E-01 FBXO25;C8orf42;ERICH1;ZNF596;LOC286083;OR4F21;RPL2 FBXO25;C8orf42;ERIC Deletion 8p23.3 chr8:1-1252643 2,31E-05 2,36E-05 75% 3AP53 H1 ERICH1 0,48 3,92E-03 2,63E-01 hsa-mir-759;hsa-mir-15a; RCBTB2;KPNA3;NEK3 ATP7B;RCBTB2;MLNR;GUCY1B2;HTR2A;KPNA3;NEK3;RB1;S ;RB1;SUCLA2;DLEU2; UCLA2;DLEU2;ITM2B;UTP14C;LPAR6;TRIM13;DLEU1;SUGT1; ITM2B;UTP14C;TRIM1 LECT1;FNDC3A;INTS6;CKAP2;MED4;VPS36;PHF11;RCBTB1; 3;DLEU1;SUGT1;LEC NUDT15;THSD1;CYSLTR2;SPRYD7;RNASEH2B;DHRS12;CDA T1;FNDC3A;INTS6;ME DC1;CAB39L;CCDC70;SETDB2;EBPL;ARL11;WDFY2;HNRNP D4;VPS36;PHF11;RC A1L2;ST13P4;DLEU7;FAM124A;TPTE2P3;CTAGE10P;KCNRG BTB1;NUDT15;RNASE ;LINC00282;NEK5;THSD1P1;MIR15A;MIR16- H2B;DHRS12;CAB39L Deletion 13q14.2 chr13:47383549-53391461 1,45E-10 1,45E-10 55% 1;ALG11;SERPINE3;MIR759;MIR3613;MIR4703 ;SETDB2;EBPL;KCNR FNDC3A 0,75 1,86E-02 3,13E-01 hsa-mir-1288;hsa-mir-548h-3; ADORA2B;COX10;MEIS3P1;PMP22;NCOR1;HS3ST3B1;HS3S T3A1;TRIM16;TTC19;ZNF286A;ELAC2;TEKT3;MGC12916;CD RT7;CDRT15P1;ZSWIM7;CDRT15;FAM18B2;CDRT4;TBC1D26; Deletion 17p12 chr17:12883014-16190274 3,22E-04 3,22E-04 61% CDRT1;CDRT15P2;MIR1288;FAM18B2-CDRT4;MIR4731 COX10;ELAC2 ELAC2 0,66 5,00E-02 2,45E-01 hsa-mir-3201; ACR;ARSA;CHKB;CPT1B;TYMP;MAPK11;MAPK12;SBF1;PPP 6R2;ZBED4;SCO2;RABL2B;MLC1;MAPK8IP2;PLXNB2;BRD1;F AM19A5;NCAPH2;MOV10L1;MIOX;PANX2;ALG12;CRELD2;A DM2;TRABD;SELO;HDAC10;SHANK3;TUBGCP6;LOC90834;L MF2;KLHDC7B;LOC284933;RPL23AP82;C22orf34;CHKB- ZBED4;PLXNB2;BRD1 CPT1B;IL17REL;FAM116B;PIM3;ODF3B;SYCE3;LOC1001289 ;ALG12;TRABD;TUBG Deletion 22q13.32 chr22:48632499-51304566 1,44E-06 1,44E-06 74% 46;LOC100144603;MIR3201;MIR4535 CP6 ALG12 0,54 3,63E-08 8,66E-03 Stroma-rich (n=73) Amplification 10p14 chr10:7080255-9016922 2,03E-06 2,03E-06 41% ATP5C1;GATA3;ITIH2;KIN;SFMBT2;ITIH5;TAF3;FLJ45983 ATP5C1;KIN;TAF3 KIN 0,67 1,52E-01 7,54E-01 hsa-mir-548k;CCND1;DHCR7;CTTN;FGF3;FGF4;KRTAP5- 9;PPFIA1;FADD;FGF19;SHANK2;ANO1;NADSYN1;FAM86C1;K CCND1;DHCR7;CTTN; RTAP5-8;ORAOV1;DEFB108B;KRTAP5-10;FLJ42102;KRTAP5- PPFIA1;FADD;ANO1; Amplification 11q13.3 chr11:69412193-71582733 2,95E-05 2,95E-05 19% 7;KRTAP5-11;LOC100133315;MIR548K;MIR3664 ORAOV1 CTTN 0,86 3,57E-01 9,97E-01 hsa-mir- 1279;CPM;LYZ;MDM2;YEATS4;CCT2;FRS2;CPSF6;SLC35E3; Amplification 12q15 chr12:69138791-70277882 2,03E-06 2,03E-06 23% RAB3IP;BEST3;LRRC10;MIR1279;MIR3913-2;MIR3913-1 LYZ;CCT2 LYZ 0,54 1,00E+00 9,74E-01 COL6A3;GBX2;LRRFIP1;ARL4C;RAMP1;COPS8;SH3BP4;PRL RAMP1;COPS8;MLPH; Deletion 2q37.3 chr2:235399942-238876307 8,08E-05 8,08E-05 37% H;CXCR7;RAB17;MLPH;IQCA1;AGAP1;RBM44;ASB18 AGAP1 COPS8 0,59 9,95E-01 8,61E-01 Deletion 9p21.3 chr9:21865498-21996995 7,87E-23 7,87E-23 48% CDKN2A;C9orf53 CDKN2A;C9orf53 CDKN2A 0,71 9,31E-01 7,83E-01 Basal/Squamous (n=219) NDUFS2;NIT1;PFDN2; APOA2;CD48;FCER1G;LY9;MPZ;NDUFS2;NIT1;PFDN2;PPOX; PPOX;SDHC;USF1;B4 SDHC;USF1;B4GALT3;DEDD;ADAMTS4;NR1I3;USP21;F11R;U GALT3;DEDD;USP21; FC1;CD244;ITLN1;SLAMF7;PVRL4;TOMM40L;KLHDC9;ITLN2; F11R;UFC1;PVRL4;TO Amplification 1q23.3 chr1:160657911-161296133 7,20E-22 7,20E-22 55% ARHGAP30;PCP4L1;TSTD1 MM40L NDUFS2 0,77 9,19E-01 8,82E-01 PPARG;RAF1;CAND2;MKRN2;TMEM40;TSEN2;LOC10012948 PPARG;RAF1;CAND2; Amplification 3p25.2 chr3:12256456-12853006 3,88E-07 3,88E-07 28% 0 MKRN2;TSEN2 RAF1 0,75 9,65E-01 1,00E+00 hsa-mir-548a- 1;E2F3;GMPR;ID4;ATXN1;SOX4;TPMT;DEK;NUP153;CAP2;FA E2F3;TPMT;DEK;NUP M8A1;CDKAL1;KIF13A;MBOAT1;KDM1B;RBM24;RNF144B;NH 153;CDKAL1;MBOAT1 Amplification 6p22.3 chr6:16292176-21929179 6,24E-27 1,05E-23 47% LRC1;FLJ23152;LINC00340;MIR548A1 ;KDM1B E2F3 0,74 7,58E-01 8,16E-03 hsa-mir-4283-2;hsa-mir-3147;hsa-mir-4283- 1;CCT6A;EGFR;GBAS;HPVC1;PHKG1;PSPH;SEC61G;SUMF2; CHCHD2;MRPS17;ZNF107;LANCL2;VOPP1;ZNF479;ZNF679;V STM2A;DKFZp434L192;POM121L12;LOC285878;ZNF680;SE PT14;ZNF713;FKBP9L;LOC389493;FLJ45974;ZNF716;ZNF72 7;LOC641746;GUSBP10;LOC643955;LOC649395;LOC65022 6;SNORA15;ZNF736;ZNF735;LOC100130849;LOC100287704 ;LOC100287834;MIR4283-2;MIR4283- CCT6A;SEC61G;CHC Amplification 7p11.2 chr7:52311481-64134207 3,30E-18 1,15E-16 53% 1;MIR3147;LOC100506050 HD2;MRPS17;LANCL2 MRPS17 0,53 5,68E-02 5,20E-02

EIF4EBP1;STAR;ASH 2L;BAG4;ERLIN2;PRO ADRB3;EIF4EBP1;STAR;ASH2L;BAG4;ERLIN2;PROSC;DDHD SC;DDHD2;LSM1;WHS 2;GPR124;LSM1;WHSC1L1;BRF2;ZNF703;RAB11FIP1;PPAPD C1L1;BRF2;ZNF703;R Amplification 8p11.23 chr8:36530653-38237581 2,80E-07 9,51E-05 27% C1B;GOT1L1;KCNU1;LOC728024 AB11FIP1;PPAPDC1B ASH2L 0,82 9,16E-01 6,94E-01 hsa-mir-1208;hsa-mir-1207;hsa-mir-1205;hsa-mir- 1204;MYC;POU5F1B;PVT1;ASAP1- IT1;ASAP1;FAM49B;GSDMC;FAM84B;LOC727677;LOC72872 4;MIR1205;MIR1206;MIR1207;MIR1204;MIR1208;LOC100507 Amplification 8q24.21 chr8:127568139-131748010 1,94E-10 1,48E-08 68% 117;PCAT1 ASAP1;FAM49B FAM49B 0,51 9,78E-02 1,45E-03 Amplification 10p14 chr10:7299867-8354143 4,84E-05 4,84E-05 44% ATP5C1;GATA3;ITIH2;KIN;SFMBT2;ITIH5;TAF3;FLJ45983 ATP5C1;KIN;TAF3 KIN 0,67 9,42E-01 4,47E-01 hsa-mir-139;hsa-mir-3165;hsa-mir-548k;hsa-mir- 3164;PHOX2A;CCND1;DHCR7;CTTN;FGF3;FGF4;FOLR1;FOL R2;FOLR3;INPPL1;KRTAP5- 9;NUMA1;P2RY2;P2RY6;PDE2A;PPFIA1;FADD;ARHGEF17;FC HSD2;FGF19;IL18BP;STARD10;SHANK2;FAM168A;C11orf51; MYEOV;LAMTOR1;ANO1;NADSYN1;FAM86C1;RNF121;KRTA P5- CCND1;DHCR7;CTTN; 8;CLPB;RELT;ATG16L2;MRGPRD;MRGPRF;ARAP1;TPCN2;O P2RY2;P2RY6;PDE2A RAOV1;LRTOMT;DEFB108B;KRTAP5- ;PPFIA1;FADD;FCHSD 10;FLJ42102;MIR139;KRTAP5-7;KRTAP5- 2;FAM168A;MYEOV;A 11;LOC100129216;LOC100133315;MIR548K;MIR3165;MIR36 NO1;ARAP1;TPCN2;O Amplification 11q13.3 chr11:68743663-73279571 9,50E-25 1,05E-23 38% 64;MIR4692 RAOV1 CTTN 0,86 5,11E-01 9,55E-03 BIRC2;BIRC3;MMP1;MMP7;MMP8;MMP10;PGR;TRPC6;MMP2 0;YAP1;CNTN5;KIAA1377;MMP27;TMEM133;C11orf70;TMEM1 BIRC2;YAP1;TMEM12 Amplification 11q22.2 chr11:99872870-102680246 2,32E-09 5,76E-04 22% 23;ARHGAP42;ANGPTL5;LOC100288077;MIR3920 3 BIRC2 0,53 1,21E-01 1,55E-01 Amplification 12q15 chr12:69136426-69250547 3,54E-07 3,54E-07 20% CPM;MDM2;SLC35E3;NUP107 NUP107 0,36 1,00E+00 1,00E+00 APLP1;ATP4A;CD22;CEBPA;CEBPG;COX6B1;ETV2;GPI;FFA R1;FFAR3;FFAR2;HPN;LRP3;MAG;NPHS1;PEPD;FXYD1;FXY D3;SCN1B;TYROBP;USF2;URI1;PDCD5;KIAA0355;ZNF536;ML L4;UBA2;TMEM147;HCST;UPK1A;SLC7A9;ZNF507;HAUS5;LS M14A;GAPDHS;ZBTB32;LSR;FXYD7;FXYD5;GPATCH1;PSEN EN;ZNF302;LIN37;SLC7A10;TSHZ3;GRAMD1A;HAMP;PRODH 2;CHST8;KCTD15;RBM42;LRFN3;IGFLR1;LOC80054;KIRREL2 APLP1;CD22;CEBPG; ;ANKRD27;PDCD2L;NFKBID;CEP89;RHPN2;ZNF30;C19orf40;T COX6B1;FFAR1;LRP3 DRD12;DMKN;DKFZp566F0947;ARHGAP33;WDR88;WTIP;ZNF ;FXYD1;SCN1B;USF2; 792;HSPB6;DPY19L3;ZNF599;FAM187B;C19orf55;LGI4;U2AF MLL4;UBA2;LSM14A; 1L4;SCGB2B2;ZNF181;SBSN;RGS9BP;KRTDAP;NUDT19;LOC LSR;PSENEN;LIN37;R 400684;LOC400685;SCGB1B2P;LOC100128675;LOC100128 BM42;PDCD2L;ZNF18 Amplification 19q12 chr19:30395327-36476812 4,11E-05 1,52E-04 36% 682;SCGB2B3P;LOC100506469;THEG5;LOC100652909 1 LSM14A 0,66 7,52E-01 9,95E-01 hsa-mir-1976; CD52;SFN;GPR3;HMGN2;RPS6KA1;SLC9A1;ARID1A;NR0B2; FCN3;MAP3K6;WASF2;CNKSR1;NUDC;WDTC1;ZNF593;GPN2; AIM1L;PIGV;GPATCH3;CEP85;LIN28A;FAM110D;DHDDS;SH3 BGRL3;TMEM222;ZDHHC18;SYTL1;UBXN11;FAM46B;C1orf17 ARID1A;WASF2;NUDC Deletion 1p36.11 chr1:26450207-27851706 2,61E-05 6,59E-05 26% 2;ZNF683;CATSPER4;TRNP1;CD164L2;LOC644961;MIR1976 ;GPN2;DHDDS NUDC 0,60 3,25E-04 3,02E-01 hsa-mir-186;PTGER3;ZRANB2;NEGR1;MIR186;ZRANB2- Deletion 1p31.1 chr1:71233954-74582502 4,08E-07 8,82E-07 17% AS1;NEGR1-IT1;ZRANB2-AS2 ZRANB2 0,36 4,55E-01 7,45E-01 Deletion 2q22.1 chr2:138155013-143637838 3,06E-19 2,15E-16 26% HNMT;NXPH2;LRP1B;SPOPL;LOC647012 SPOPL SPOPL 0,46 8,82E-01 1,82E-05 hsa-mir-3133;hsa-mir-149;hsa-mir-4269;hsa-mir-562;hsa-mir- 1471;hsa-mir-1244-1;hsa-mir- 4268;AGXT;ALPI;ALPP;ALPPL2;KIF1A;BOK;CHRND;CHRNG; COL4A3;COL4A4;COL6A3;DTYMK;EPHA4;ACSL3;GBX2;GPC 1;GPR35;HDLBP;AGFG1;HTR2B;SP110;INPP5D;IRS1;KCNJ1 3;NCL;NDUFA10;SEPT2;NEU2;NPPC;PAX3;PDCD1;PDE6D;S ERPINE2;PPP1R7;PSMD1;PTMA;SNORD20;SAG;CCL20;SP1 00;SPP2;SCG2;CUL3;DGKD;PER2;LRRFIP1;GPR55;TRIP12;E CEL1;EIF4E2;HDAC4;FARP2;FARSB;ARL4C;RAMP1;NMUR1; STK25;COPS8;CAPN10;SP140;PASK;ATG4B;SH3BP4;KCNE 4;NGEF;SNORD82;SNED1;GIGYF2;TRAF3IP1;ANO7;PRLH;TH AP4;ANKMY1;SCLY;ASB1;CAB39;UGT1A10;UGT1A8;UGT1A 7;UGT1A6;UGT1A5;UGT1A9;UGT1A4;UGT1A1;UGT1A3;PID1; ATG16L1;USP40;HJURP;HES6;DOCK10;C2orf83;MFF;CXCR7; ACSL3;GPC1;HDLBP; RNPEPL1;WDFY1;NYAP2;GAL3ST2;RAB17;COPS7B;MRPL44 AGFG1;IRS1;NCL;ND ;TRPM8;MLPH;IQCA1;FAM124B;TM4SF20;C2orf54;ARMC9;EF UFA10;SEPT2;PPP1R HD1;SPHKAP;SLC19A3;ILKAP;ITM2C;RHBDD1;ING5;MGC160 7;PSMD1;PTMA;SP10 25;DNER;B3GNT7;SP140L;MOGAT1;AGAP1;TWIST2;DIS3L2; 0;CUL3;DGKD;TRIP12 NEU4;AP1S3;SGPP2;SPATA3;FBXO36;MTERFD2;UBE2F;OT ;EIF4E2;FARSB;RAMP OS;MYEOV2;OR6B3;LOC150935;LOC151171;LOC151174;CC 1;STK25;COPS8;GIG DC140;SLC16A14;LOC151475;LINC00471;LOC151484;MSL3 YF2;TRAF3IP1;THAP4 P1;WDR69;C2orf57;TIGD1;LOC200772;C2orf72;CXXC11;DUS ;SCLY;ASB1;CAB39;A P28;ESPNL;ECEL1P2;LOC348761;RBM44;AQP12A;KLHL30; TG16L1;USP40;MFF;R C2orf82;OR6B2;ASB18;FLJ43879;MIR149;DNAJB3;LOC64338 NPEPL1;WDFY1;COP 7;PRR21;LOC646736;PRSS56;AQP12B;SNORA75;SCARNA6; S7B;MRPL44;MLPH;IL SCARNA5;D2HGDH;LOC728323;PP14571;LOC100286922;MI KAP;RHBDD1;AGAP1; R1471;MIR1244-1;BOK-AS1;MIR1244-3;MIR1244- DIS3L2;MTERFD2;UB 2;MIR4268;MIR4269;UBE2F- E2F;MYEOV2;SLC16A Deletion 2q37.2 chr2:220763187-243199373 4,23E-19 3,64E-15 48% SCLY;MIR4439;MIR4777;MIR2467;MIR4440;MIR4786;MIR444 14;PP14571 MRPL44 0,69 7,88E-01 9,57E-01 Deletion 3p14.2 chr3:59027871-61548111 1,28E-18 5,57E-10 49% FHIT FHIT 0,36 1,50E-13 1,01E-01

hsa-mir-4273;hsa-mir-1324;hsa-mir-1284;hsa-mir-3136;hsa-mir- 4272;COL8A1;CPOX;EPHA3;GBE1;GPR15;GPR27;HTR1F;MI TF;CNTN3;POU1F1;PROS1;ROBO1;ROBO2;TMF1;CGGBP1;S UCLG2;UBA3;MAGI1;TOMM70A;TFG;ST3GAL6;ARL6IP5;FILI P1L;PDZRN3;FRMD4B;RYBP;ABI3BP;CHMP2B;LRIG1;OR5K1; OR5H1;FOXP1;TMEM45A;EBLN2;SHQ1;ZNF654;TBC1D23;LM OD3;CLDND1;NIT2;PROK2;NSUN3;OR5H6;OR5H2;OR5AC2;A RL6;C3orf26;KBTBD8;MINA;GPR128;SLC25A26;DCBLD2;FAM 19A4;PPP4R2;ARL13B;DHFRL1;GABRR3;LOC201617;CADM2 ;LOC255025;C3orf64;EPHA6;C3orf38;EIF4E3;LNP1;VGLL3;L OC401074;OR5K2;OR5H14;OR5H15;OR5K3;OR5K4;FAM19A COL8A1;TMF1;CGGB 1;STX19;LOC440970;TMEM30C;FLJ20518;FAM86DP;GXYLT2 P1;UBA3;TOMM70A;R ;ZNF717;FRG2C;MIR1284;MIR1324;MIR548G;MIR3136;MIR42 YBP;SHQ1;NIT2;STX1 Deletion 3p14.1 chr3:64994325-100946454 1,76E-13 5,76E-06 48% 72;MIR4273;MIR3921;MIR4795;MIR4444-1 9 TOMM70A 0,54 1,09E-08 4,64E-01 hsa-mir-1305;DCTD;ING2; CLDN22;CDKN2AIP;ODZ3;STOX2;TRAPPC11;WWC2;MGC458 00;ENPP6;C4orf38;RWDD4;LOC389247;FAM92A3;LINC00290 DCTD;ING2;CLDN22;C Deletion 4q34.3 chr4:178909911-185281856 4,66E-06 5,13E-06 53% ;LOC728175;CLDN24;MIR1305 DKN2AIP;TRAPPC11 DCTD 0,73 4,34E-04 5,46E-01 hsa-mir-582;ERCC8;HTR1A;KIF2A;PDE4D;PART1;DIMT1; IPO11;DEPDC1B;ZSWIM6;ELOVL7;NDUFAF2;C5orf64;RNF18 ERCC8;PDE4D;IPO11; Deletion 5q11.2 chr5:58138609-63566532 7,91E-07 7,91E-07 47% 0;C5orf43;LRRC70 ZSWIM6;NDUFAF2 NDUFAF2 0,51 5,67E-01 5,62E-01 hsa-mir-548i-3;hsa-mir-596;ANGPT2;DEFA1;DEFA3;DEFA4; DEFA5;DEFA6;DEFB1;DEFB4A;CLN8;MYOM2;ARHGEF10;KB TBD11;SPAG11B;AGPAT5;DEFB103B;CSMD1;MCPH1;CLDN2 3;DEFB104A;SGK223;DEFT1P;DEFB105A;DEFB106A;DEFB1 07A;FLJ10661;LOC349196;XKR5;DEFB103A;FAM90A13;FAM 90A5;FAM90A7;FAM90A8;FAM90A18;FAM90A9;FAM90A10;D EFA10P;DEFB107B;DEFB104B;DEFB106B;DEFB105B;DEFB1 09P1B;FAM90A14;SPAG11A;MIR596;DEFA1B;FAM90A20;FA M90A19;FAM66B;ZNF705G;FAM66E;LOC100132396;LOC100 287015;DEFT1P2;DEFB4B;MIR548I3;MIR4659A;MIR4659B;L CLN8;ARHGEF10;AG Deletion 8p23.2 chr8:1708815-8608591 8,39E-19 5,94E-18 69% OC100652791 PAT5;MCPH1;CLDN23 ARHGEF10 0,71 4,02E-04 1,08E-01 Deletion 8p11.22 chr8:39140305-39601518 4,82E-07 2,15E-05 39% ADAM3A;ADAM18;ADAM5P;LOC100130964 ADAM5P 0,23 4,36E-03 3,16E-01 hsa-mir-31;hsa-mir-491;CDKN2A;CDKN2B; IFNA1;IFNA2;IFNA4;IFNA5;IFNA6;IFNA7;IFNA8;IFNA10;IFNA1 CDKN2A;CDKN2B;IFN 3;IFNA14;IFNA16;IFNA17;IFNA21;IFNA22P;IFNB1;IFNW1;MLL A2;MLLT3;MTAP;C9orf T3;MTAP;C9orf53;KIAA1797;KLHL9;IFNE;PTPLAD2;MIR31;MI 53;KIAA1797;KLHL9;I Deletion 9p21.3 chr9:20182512-22447986 1,61E-77 1,61E-77 48% R31HG;MIR491;CDKN2B-AS1;MIR4473;MIR4474 FNE CDKN2A 0,71 9,85E-01 1,65E-01 hsa-mir-346;BMPR1A;GLUD1;PTEN;SNCG;PAPSS2; MINPP1;C10orf116;LDB3;WAPAL;FAM35A;MMRN2;ATAD1;OP BMPR1A;GLUD1;PTE N4;AGAP11;CFL1P1;LOC439994;MIR346;FAM25A;FAM22A;F N;PAPSS2;WAPAL;FA Deletion 10q23.31 chr10:87488881-90040578 2,53E-07 2,42E-05 43% AM22D;LOC728190;LOC728218;KLLN;MIR4678 M35A;ATAD1 PTEN 0,69 8,09E-01 9,09E-01 Deletion 11p15.4 chr11:5725421-5776594 1,56E-05 1,56E-05 46% OR56B1 OR56B1 0,12 1,00E+00 1,00E+00 Deletion 13q14.2 chr13:48977813-49043551 2,10E-26 2,10E-26 44% LPAR6 LPAR6 0,24 5,04E-05 1,12E-01 ADCY9;CREBBP;DNASE1;HMOX2;MEFV;OR1F1;OR2C1;SRL; TFAP4;ZNF75A;ZNF174;ZNF200;ZNF205;ZNF213;CLDN6;CLD N9;PKMYT1;DNAJA3;IL32;ZNF263;TRAP1;PRSS21;CLUAP1; OR1F2P;PAM16;TNFRSF12A;ZNF434;HCFC1R1;NMRAL1;PRS CREBBP;HMOX2;TFA S22;MMP25;THOC6;KREMEN2;CORO7;NAA60;MGC3771;FLY P4;ZNF174;ZNF205;Z WCH1;SLX4;GLIS2;ZSCAN10;TIGD7;FLYWCH2;VASN;ZG16B; NF213;DNAJA3;ZNF26 PRSS30P;PAQR4;ZNF597;CCDC64B;NLRC3;PRSS33;LINC00 3;TRAP1;CLUAP1;ZNF 514;FLJ39639;PRSS41;C16orf90;MTRNR2L4;LOC100507501; 434;NMRAL1;THOC6; Deletion 16p13.3 chr16:2830687-4566438 4,86E-07 4,82E-07 45% CYB5A;GALR1;MBP;NFATC1;ZNF236;CTDP1;SOCS6;ZNF516;CORO7-PAM16 FLYWCH1 TFAP4 0,72 1,13E-01 2,81E-01 TSHZ1;CD226;TXNL4A;ADNP2;RTTN;KCNG2;SALL3;TIMM21; ZNF407;CNDP2;RBFA;PQLC1;NETO1;PARD6G;CNDP1;FAM6 CTDP1;SOCS6;ZNF51 9C;CBLN2;FBXO15;DOK6;ZADH2;C18orf62;LOC284276;LOC3 6;TSHZ1;TXNL4A;ADN 39298;ATP9B;LOC400655;LOC400657;HSBP1L1;C18orf63;L P2;RTTN;TIMM21;ZNF OC100130522;LOC100131655;LOC100505776;LOC1005058 407;PQLC1;ZADH2;AT Deletion 18q23 chr18:66739040-78077248 5,22E-05 5,44E-05 51% 17 P9B;LOC400657 ZADH2 0,68 1,11E-02 3,71E-01

Deletion 19p13.3 chr19:1018761-1212533 2,05E-05 2,15E-05 37% CNN2;GPX4;POLR2E;ABCA7;SBNO2;HMHA1 CNN2;POLR2E CNN2 0,45 1,10E-02 3,02E-01 hsa-mir-3201;hsa-let-7b;hsa-mir-1249;ACR;ARSA;CHKB; PT1B;TYMP;FBLN1;PPARA;MAPK11;MAPK12;SBF1;UPK3A; WNT7B;CELSR1;PPP6R2;ZBED4;SCO2;PKDREJ;NUP50;RAB L2B;GRAMD4;MLC1;KIAA0930;MAPK8IP2;PLXNB2;BRD1;AR HGAP8;TBC1D22A;ATXN10;FAM19A5;RIBC2;SMC1B;NCAPH 2;GTSE1;MOV10L1;FAM118A;TTC38;C22orf26;MIOX;PRR5;T RMU;PANX2;CERK;ALG12;CRELD2;ADM2;TRABD;SELO;HDA C10;SHANK3;TUBGCP6;LOC90834;LMF2;PHF21B;KLHDC7B; LOC150381;C22orf40;CN5H6.4;LOC284933;RPL23AP82;LOC 339685;C22orf34;CHKB- CPT1B;LINC00207;MIRLET7BHG;FLJ46257;IL17REL;MIRLET WNT7B;ZBED4;NUP50 7A3;MIRLET7B;LINC00229;FAM116B;PIM3;ODF3B;PRR5- ;KIAA0930;PLXNB2;B ARHGAP8;SYCE3;LOC730668;LOC100128946;LOC1001446 RD1;TBC1D22A;ATXN 03;LOC100271722;MIR1249;MIR3201;MIR3619;LOC1005067 10;ALG12;TRABD;TU Deletion 22q13.32 chr22:44916734-51304566 5,73E-07 5,73E-07 48% 14;MIR4763;MIR4762;MIR4535 BGCP6 ATXN10 0,64 1,33E-02 1,23E-01 Neuroendocrine-like (n=19) E2F3;CDKAL1;MBOAT Amplification 6p22.3 chr6:19802236-21607634 2,20E-11 2,20E-11 58% E2F3;ID4;SOX4;CDKAL1;MBOAT1 1 E2F3 0,74 4,84E-02 2,59E-01 RCBTB2;ESD;KPNA3; RB1;SUCLA2;DLEU2;I hsa-mir-15a;RCBTB2;ESD;MLNR;GUCY1B2; TM2B;TRIM13;DLEU1; HTR2A;KPNA3;RB1;SUCLA2;DLEU2;ITM2B;LPAR6;TRIM13;D FNDC3A;LRCH1;INTS LEU1;FNDC3A;LRCH1;INTS6;MED4;PHF11;RCBTB1;NUDT15; 6;MED4;PHF11;RCBT CYSLTR2;SPRYD7;RNASEH2B;DHRS12;CDADC1;CAB39L;SE B1;NUDT15;RNASEH2 TDB2;EBPL;ARL11;WDFY2;ST13P4;DLEU7;FAM124A;CTAGE B;DHRS12;CAB39L;S Deletion 13q14.2 chr13:46955257-52387891 2,11E-04 2,11E-04 74% 10P;KCNRG;MIR15A;MIR16-1;SERPINE3;MIR3613;MIR4703 ETDB2;EBPL;KCNRG FNDC3A 0,75 3,43E-03 5,34E-02 Supplementary Table 5 : Univariate and multivariate cox regression models. Patients who were said to have received neoadjuvant chemotherapy were excluded from the survival analyses (a) Univariate Cox regression models were performed based on 873 MIBC patients with available clinical data. Factors significantly associated with survival have likelihood p-values highlighted in bold letters. Only clinical factors that were significant in the univariate Cox regressions were kept to build the multivariate Cox model in (b), which included 509 patients with complete clinical information. A multivariate Cox model was also built for each consensus class separately to assess the added prognostic value of each class subtyping as compared to the other clinical factors. a. Univariate Cox regression stratified on datasets n HR Wald pval CI.low CI.high LumP vs other tumours 873 0,65 2,12E-04 0,51 0,81 Consensus classes (ref : LumP); logrank pval = 5,45E-04 LumNS 873 1,51 4,72E-02 1,01 2,28 LumU 873 1,32 1,20E-01 0,93 1,86 Stroma-rich 873 1,18 3,20E-01 0,85 1,63 Ba/Sq 873 1,81 5,74E-06 1,40 2,33 NE-like 873 2,38 3,25E-03 1,34 4,25 Clinical tumour stage (ref : T2); logrank pval < 1E-16 T3 815 2,30 1,79E-10 1,78 2,97 T4 815 3,78 0,00E+00 2,80 5,11 Clinical LN status; logrank pval = 4,01E-14 N > N0 756 2,37 1,64E-14 1,90 2,95 Clinical M status; logrank pval = 2,32E-12 M > M0 587 3,10 2,31E-13 2,29 4,19 Age category (ref : < 60 y.o.); logrank pval = 2,70E-05 60-80 847 1,36 1,81E-02 1,05 1,75 > 80 847 2,24 2,72E-06 1,60 3,13 Age; logrank pval = 6,56E-08 continuous variable 847 1,03 1,14E-07 1,02 1,04 Gender; logrank pval = 1,15E-01 Male 775 0,82 1,09E-01 0,65 1,04 Cystectomy; logrank pval = 9,21E-01 Yes 411 1,03 9,21E-01 0,58 1,83 b. Multivariate Cox models (ref subtype : LumP) n HR Wald pval CI.low CI.high Consensus class : LumNS 509 0,93 7,97E-01 0,54 1,62 Consensus class : LumU 509 1,35 2,11E-01 0,84 2,17 Consensus class : Stroma-rich 509 0,93 7,39E-01 0,60 1,44 Consensus class : Ba/Sq 509 1,73 2,26E-03 1,22 2,45 Consensus class : NE-like 509 2,18 4,60E-02 1,01 4,69 Stage > T2 509 2,17 3,08E-06 1,57 3,01 N > N0 509 1,89 2,56E-05 1,40 2,54 M > M0 509 2,87 7,24E-09 2,01 4,10 Patient age 509 1,02 8,50E-04 1,01 1,04 c. Multivariate Cox models for each consensus class n HR Wald pval CI.low CI.high Consensus class : LumP 509 0,74 5,97E-02 0,54 1,01 Stage > T2 509 2,19 2,88E-06 1,58 3,05 N > N0 509 1,77 1,56E-04 1,32 2,38 M > M0 509 2,73 2,55E-08 1,92 3,88 Patient age 509 1,02 2,03E-03 1,01 1,03 Consensus class : LumNS 509 0,72 2,01E-01 0,44 1,19 Stage > T2 509 2,23 1,77E-06 1,61 3,10 N > N0 509 1,88 2,69E-05 1,40 2,52 M > M0 509 2,53 1,60E-07 1,79 3,58 Patient age 509 1,02 4,62E-04 1,01 1,04 Consensus class : LumU 509 1,09 6,69E-01 0,73 1,64 Stage > T2 509 2,20 2,59E-06 1,58 3,05 N > N0 509 1,84 4,38E-05 1,37 2,47 M > M0 509 2,57 1,02E-07 1,81 3,64 Patient age 509 1,02 9,34E-04 1,01 1,04 Consensus class : Stroma-rich 509 0,68 3,78E-02 0,48 0,98 Stage > T2 509 2,14 4,51E-06 1,55 2,96 N > N0 509 1,91 1,52E-05 1,42 2,56 M > M0 509 2,60 7,00E-08 1,84 3,67 Patient age 509 1,02 1,08E-03 1,01 1,04 Consensus class : Ba/Sq 509 1,64 2,99E-04 1,26 2,15 Stage > T2 509 2,13 6,38E-06 1,53 2,95 N > N0 509 1,88 2,48E-05 1,40 2,51 M > M0 509 2,82 6,48E-09 1,99 4,01 Patient age 509 1,02 1,01E-03 1,01 1,04 Consensus class : NE-like 509 1,80 1,12E-01 0,87 3,73 Stage > T2 509 2,22 1,88E-06 1,60 3,08 N > N0 509 1,85 3,91E-05 1,38 2,48 M > M0 509 2,54 1,33E-07 1,80 3,59 Patient age 509 1,02 7,74E-04 1,01 1,04 Supplementary Table 6 : Gene signatures associated with response to therapies, summarized in Figure 5

Gene Signature Genes Source EGFR ligands EGFR, AREG, AREGB, EREG, HBEGF, TGFA PMID: 25009231 C3orf54, CAPNS2, SEMA4B, WNT7B, DUOXA1, C16orf74, ZNF385A, FGFR3-coexpressed genes SMAD3, SLC2A9, D4S234E, TP63, CLCA4, IRS1, SYTL1, PLCH2, SSH3, PMID:22553347 FGFR3, PTPN13, DUOX1, TMPRSS4 Antigen presenting machinery B2M, HLA-A, HLA-B, HLA-C, TAP1, TAP2 PMID: 27855702 Immune checkpoints CD274, CTLA4, HAVCR2, LAG3, PDCD1, PDCD1LG2, TIGIT TIGIT, CD27, CD8A, PDCD1LG2, LAG3, CD274, CXCR6, CMKLR1, NKG7, IFN-gamma CCL5, PSMB10, IDO1, CXCL9, HLA-DQA1, CD276, STAT1, HLA-DRB1, PMID: 28650338 HLA-E CD8 T effector CD8A, CXCL10, CXCL9, GZMA, GZMB, IFNG, PRF1, TBX21 PMID: 26952546 ACTA2, ACTG2, ADAM12, ADAM19, CNN1, COL4A1, CTGF, CTPS1, pan-fibroblast TGF-β FAM101B, FSTL3, HSPB1, IGFBP3, PXDC1, SEMA7A, SH3PXD2A, TAGLN, PMID: 29443960 TGFBI, TNS1, TPM1 CAV1, COL5A1, ITGA5, P4HA2, SLC16A1, TGFBI, DPYSL2, SRPX, TRAM2, Hypoxia SYDE1, LRP1, PDLIM2, SAV1, AHNAK2, CAD, CYP1B1, DAAM1, DSC2, PMID: 28400426 SLC2A3, FUT11, GLG1, GULP1, LDLR, THBS4

ABL1, ANAPC1, ANAPC10, ANAPC11, ANAPC13, ANAPC2, ANAPC4, ANAPC5, ANAPC7, ATM, ATR, BUB1, BUB1B, BUB3, CCNA1, CCNA2, CCNB1, CCNB2, CCNB3, CCND1, CCND2, CCND3, CCNE1, CCNE2, CCNH, CDC14A, CDC14B, CDC16, CDC20, CDC23, CDC25A, CDC25B, CDC25C, CDC26, CDC27, CDC45, CDC6, CDC7, CDK1, CDK2, CDK4, CDK6, CDK7, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CHEK1, CHEK2, CREBBP, CUL1, DBF4, E2F1, E2F2, E2F3, Cell cycle KEGG hsa4110 E2F4, E2F5, EP300, ESPL1, FZR1, GADD45A, GADD45B, GADD45G, GSK3B, HDAC1, HDAC2, MAD1L1, MAD2L1, MAD2L2, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, MDM2, MYC, ORC1, ORC2, ORC3, ORC4, ORC5, ORC6, PCNA, PKMYT1, PLK1, PRKDC, PTTG1, PTTG2, RAD21, RB1, RBL1, RBL2, RBX1, SFN, SKP1, SKP2, SMAD2, SMAD3, SMAD4, SMC1A, SMC1B, SMC3, STAG1, STAG2, TFDP1, TFDP2, TGFB1, TGFB2, TGFB3, TP53, TTK, WEE1, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ, ZBTB17

DNA2, FEN1, LIG1, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, PCNA, DNA replication POLA1, POLA2, POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3, KEGG hsa3030 POLE4, PRIM1, PRIM2, RFC1, RFC2, RFC3, RFC4, RFC5, RNASEH1, RNASEH2A, RNASEH2B, RNASEH2C, RPA1, RPA2, RPA3, RPA4, SSBP1 References 1. Marzouka, N. et al. A validation and extended description of the Lund taxonomy for

urothelial carcinoma using the TCGA cohort. Sci. Rep. 8, 3737 (2018).

2. Lerner, S. P. et al. Bladder Cancer Molecular Taxonomy: Summary from a

Consensus Meeting. Bladder Cancer Amst. Neth. 2, 37–47 (2016).