Figure 1 Gene expression profiles define 3 molecular sub-groups of CNS-PNET

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1 Supplemental Figure Legends Figure 1 Gene expression profiles define 3 molecular sub-groups of CNS-PNET Multiple unsupervised analyses were performed on human HT-1v4 expression array (Illumina) data from 51 primary CNS-PNET samples. Cluster patterns were determined re-iteratively using an initial set of 1 genes with the highest co-efficient of variation to establish the most stable tumour clusters achievable with a minimal sub-set of genes. Three molecular sub-groups of CNS-PNETs were independently indicated by A. Unsupervised Hierarchical Cluster (HCL)analyses, B.Non-negative Matrix Factorization (NMF) and,c. Principal Component Analysis (PCA). Individual tumours corresponding to sub-groups 1, and 3 are respectively indicated by green, blue and purple coloured boxes or spheres. Figure Validation of sub-group specific gene expression signatures Quantitative RT-PCR analysis was performed to confirm gene expression patterns observed from supervised analyses of microarray data; gene expression levels ( C t ) determined relative to actin are represented. A. Expression levels of select qrt-pcr validated genes significantly enriched within each tumour group (p.5) is shown in a global syline plot; a mean value of n=3 is plotted/sample. B.Meanexpression levels of individual specific lineage/signalling genes (n=3 replicas) with robust and significant over-expression in each tumour sub-group are represented with SEM for specific mrna (horizontal bars). Group 1, and 3 specific genes are indicated by green, blue and purple bars or spheres respectively. Figure 3 Immuno-histochemical analyses of IGF Placental trophoblastic cells are nown to express high levels of IGF and exhibit cytoplasmic and membranous IGF immuno-stain patterns ( thus polyclonal IGF antibodies (Santa Cruz, California) were tested for IHC analyses using placental tissues as 1

2 positive controls as described in methods. Staining patterns of placenta tissue treated with primary IGF antibody at 1:5 (A), 1:75 (B), 1:1 (C) dilutions, and no primary antibody as negative control (D) are shown. Figure 4 Immuno-histochemical analyses of LIN8 and OLIG expression in CNS-PNET A. LIN8 and OLIG which exhibited highest differential gene expression levels between tumour sub-groups, was tested by corresponding immuno-assays on a test cohort of CNS- PNET for which sub-group specific gene expression patterns had been established (Supplementary Table 1). Levels of LIN8 and OLIG protein expression in tumours of each sub-group was determined by IHC analyses of tumour cores on TMA or on individual tumour slides and scored as described in methods;protein expression levels are represented as SEM. B.Heat map shows gene expression values for LIN8 and OLIG as determined from Illumina HT-1 v4 expression arrays, in relation to LIN8 and OLIG IHC scores determined for each of the individual tumours as described in Figure A. C. Summaryof all CNS-PNET samplesthat could be classified into molecular sub-groups based on gene expression profiles and/or immuno-histochemical analyses of LIN8 and OLIG. Figure 5 Expression of lineage and signalling pathway genes in CNS-PNETs A. Gene expression patterns of glial and neurogenic marers conventionally used to distinguish malignant glial from neural tumours in CNS-PNET sub-groups 1, and 3. Normalized array expression values and significance of enrichment, derived from supervised t-test of sub-group specific gene sets, are represented in relation to tumour sub-groups. For enrichment of specific genes in individual sub-groups, sub-groups were collapsed to allow binary comparisons. B. Quantitative RT-PCR analyses of cell lineage genes in 51 CNS-PNET primary samples profiled with Illumina gene expression arrays. Meanexpression levels ( C t ) of individual specific lineage genes (n=3 replicas) in each tumour sub-group are represented in relation to

3 SEM for specific mrna (horizontal bars). Group 1, and 3 specific genes are indicated by green, blue and purple bars or spheres respectively. C. Quantitative RT-PCR analyses of cell signalling genes, PDGFRA and ERBB3, in primary 51 CNS-PNET. Meanexpression levels ( C t ) of individual specific signalling genes (n=3 replicas) in each tumour sub-group are represented in relation to SEM for specific mrna (horizontal bars). Group 1, and 3 specific genes are indicated by green, blue and purple bars or spheres respectively. Figure 6 Recurrent focal copy number abnormalities (CNAs) in CNS-PNETs DNA copy number profiles of 85 primary CNS-PNETs were generated using the Human Omni.5 Quad SNP array, and analysed using Parte genomics and dchip.heat map and copy number profiles of specific CNAs were generated using dchip and plotted relative to chromosome ideograms. A. Heat map and copy number plots of recurrent focal C19MC locus amplification on chr19q13.41 in group 1 tumours. B. Heat map and copy number plotsof recurrent chr gains in group 1 CNS-PNET. C. Copy number plot and FISH analyses of focal MYCNamplification on chrp4 in one subgroup 3 tumour. D. Heat map, copy number plot and FISH validation of focal CDKNA/B loss on chr9p1 seen in 1primary group and 3 CNS-PNET. Figure 7 Molecular sub-groups of CNS-PNET have distinct DNA copy number patterns DNA copy number profiles of primary CNS-PNET were generated using the Human Omni.5 Quad SNP array and recurrent copy number patterns established using CNV partition (Parte) analyses. Significant enrichment of specific copy number abnormalities (CN lesion) in tumour sub-groups was determined based on 59 primary samples with nown molecular sub-grouping. 3

4 Heat map shows select CN lesions which correlate significantly, as determined using Chi-square analyses, with specific CNS-PNET sub-groups. Recurrent focal lesions targeting CDKNA/B in group and 3, and C19MC in group 1 CNS-PNET are indicated by asteriss. 4

5 Picard et al Supplemental Fig 1 A Hierachical Clustering Tumour Sub-groups B samples samples genes = 3 samples Cophenetic coef.=.9711 GROUP 1 GROUP GROUP 3 genes 5 genes Cophenetic Coefficient Cophenetic Coefficient Cophenetic Coefficient Coefficient 1.Cophenetic genes 35 genes 4 genes Cophenetic Coefficient Cophenetic Coefficient Coefficient Coefficient Coefficient 1.Cophenetic 1.Cophenetic 1.Cophenetic Cophenetic Coefficient 45 genes 5 genes 55 genes Cophenetic Coefficient genes 75 genes 1 genes

6 Picard et al Supplemental Fig 1 C Principal Component Analysis (46.6%) PCA Mapping (46.6%) PC # 15.% PC # 15.% PC #3 9.43% PC #3 9.43% PC #1 1.9% PC #1 1.9 % -1

7 Picard et al Supplemental Fig mrna Relative to Actin (1-1) A Group 1 Group Group 3 B NKX6-5 p=.56 4 CRABP1 3 p< mrna Relative to Actin (1 -) 5 1 Grp 1 Grp OLIG1 15 Grp 1 Grp 3 p=.15 1 Grp Grp 3 GLI 1 p= Grp 1 15 Grp Grp 3 MSX1 Grp Grp 3 p=.45 Grp Grp 3 vp=.43v 4 Grp 1 TGFBR3 6 ZIC 4 5 Grp 1 6 p=. 1 Grp 1 Grp Grp 3 Grp 1 Grp Grp 3

8 Picard et al Supplemental Fig 3 A B 5µm 5µm C D 5µm 5µm

9 Picard et al Supplemental Fig 4 A Average % Immuno-positive Cells LIN8 * IHC OLIG * * p<.1 B Tumour Sub-group Group 1 Group Group 3 PNET LIN8 Expression IHC score Expression OLIG IHC score Expression C Gene Expression Tumour Sub-group 1 3 Total samples IHC Pos Neg IHC Total Samples / Group % / Group 7% 33% 4% 1%

10 Picard et al Supplemental Fig 5 A Group 1 Group Group 3 Genes GFAP p Value <.1 Comparison grp 1 vs &3 ASCL1 <.1 grp vs 1&3 ATOH1.4 MAP.6 NES.35 NEUROD1.36 grp 1 vs &3 NEUROD.64 NEUROG1.58 NEUROG.4 grp vs 1&3 SYP.49 grp 3 vs 1& SYPL1.1 grp 3 vs 1& B mrna Relative to Actin (1-1 ) 3 1 LIN8B p=.31 Grp 1 Grp Grp 3 mrna Relative to Actin (1-1 ) ASCL1 p=.31 Grp 1 Grp Grp 3 mrna Relative to Actin NESTIN p=.11 Grp 1 Grp Grp 3 C mrna Relative to Actin mrna Relative to Actin (1-1 ) NEUROG TUBB3 GFAP p=.18 5 p=.91 5 p=.1 Grp 1 Grp Grp 3 PDGFRA p=.1 Grp 1 Grp Grp 3 mrna Relative to Actin (1-1 ) mrna Relative to Actin (1 - ) Grp 1 Grp Grp 3 ERBB3 p=.65 Grp 1 Grp Grp 3 mrna Relative to Actin Grp 1 Grp Grp 3

11 Picard et al Supplemental Fig 6 A B Chr 19q13 CN Profile Chr CN Profile Tumours Tumours 19q13.41 Chromosome q p Chr p CN Profile Loss D DDX1 Gain Chr 9p CN Profile FISH Tumours 9p1.3 Tumour p4.3 Gain FISH CDKNA MYCN Loss 9p1.1 p4.1 CDKNB Gain MYCN, Chrp4.3 control, Chrq11. Loss Gain CDKNA/B, Chr9p1 control, Chr9p1 875 PNET111 PNET19 PNET135 PNET138 PNET14 PNET148 PNET15 PNET3 PNET4 PNET4 PNET43 PNET5 PNET54 PNET6 PNET91 Loss C PNET93 PNET94 C19MC

12 Picard et al Supplemental Fig 7 Group 1 Group Group 3 CN Lesion p Value 1 Chr Gain <.1 3 Chr 3 Gain Chromosome Chr 8 p Gain.7 Chr 9 p Loss.9 CDKNA/B Loss Chr 13 Gain.9 Chr 14 Loss.9 C19MC Amp <.1 Chr Gain.39 Loss Gain

13 Supplemental Table 1: Participating Centres 1. Hospital for Sic Children, Toronto, Canada.. Queen s Medical Centre, Nottingham, UK. 3. John Hopins University School of Medicine, Baltimore, USA. 4. Seoul National University Children s Hospital, Seoul, South Korea 5. Asan Medical Center, Seoul, Korea 6. German Cancer Research Center, Heidelberg, Germany 7. Children s Memorial Hospital, Chicago, USA 8. Schneider Hospital, PetachTiva, Israel 9. Kumamoto University, Japan 1. Virginia Commonwealth University, Virginia, USA 11. Newcastle University, Newcastle Upon Tyne, United Kingdom 1. Alberta Children's Hospital, Calgary, Canada 13. Children s Hospital Boston, Boston, USA 14. Texas Children s Hospital, Texas, USA 15. Chinese University of Hong Kong, Hong Kong, China 16. Institute of Cancer Research, Sutton, United Kingdom 17. St. Jude Research Hospital, Memphis, USA 18. Birmingham Children s Hospital, Birmingham, UK 19. Cooridge Hospital, Leeds, UK

14 Supplemental Table : Clinicopathologic characteristics of tumour samples Annotation Alternate Annotation Group Gender Diagnosis Age at Diagnosis (years) Treatment Metastasis Status Survival Status Survival Time (years) Illumina HT-1 v4 OmniQuad.5 SNP Immunohistochemistry PNET3 Group 1 female PNET/EP 4.8 Chemo M Dead.5 PNET4 Group female PNET 1.75 Chemo/XRT M Dead.67 PNET5 Group 1 female PNET/EP 1.67 Chemo M Dead.58 PNET6 Group 1 female PNET/EP.4 Chemo M Dead 1. PNET7 Group male PNET n/a n/a n/a n/a n/a no material PNET8 Group 3 male PNET 6. n/a M + Alive n/a no material PNET9 Group 3 male PNET 4.8 n/a M + Alive.4 PNET1 n/a n/a PNET n/a n/a n/a n/a n/a no material no material PNET11 n/a n/a PNET n/a n/a n/a n/a n/a no material no material PNET15 Group 1 male PNET/ME.4 None M Alive n/a no material PNET17 Group 3 male PNET 1.83 Chemo/XRT M Dead 6.33 no material PNET Group 3 female PNET 11. n/a n/a Dead 1. PNET Group female PNET 9.67 n/a n/a Dead. PNET5 Group 3 male PNET. n/a n/a n/a n/a PNET8 Group 3 male PNET 4. n/a n/a n/a n/a no material PNET3 Group male PNET 1. n/a n/a n/a n/a PNET31 Group female PNET n/a n/a n/a n/a n/a no material PNET36 Group male PNET 1. Chemo/XRT n/a Alive 4. no material PNET37 Group 3 female PNET 8. Chemo/XRT n/a Alive 3.9 no material PNET4 Group 1 male PNET.5 None M Dead.1 no material PNET4 Group 1 female PNET 3.17 Chemo/XRT M Dead.83 no material PNET43 Group 1 male PNET 1.5 Chemo M + Dead.83 no material PNET44 Group male PNET 11. Chemo M Dead 1.75 no material PNET47 Group female PNET.58 Chemo/XRT M + Alive no material PNET48 Group 3 female PNET 1. Chemo M Dead.33 no material PNET49 n/a male PNET 17 n/a n/a n/a n/a no material no material

15 PNET51 n/a female PNET 3 n/a n/a n/a n/a no material no material PNET5 n/a female PNET 8 n/a n/a n/a n/a no material no material PNET53 n/a female PNET 3 n/a n/a n/a n/a no material no material PNET54 Group 1 male PNET/EP 3 n/a M n/a n/a no material no material PNET55 n/a female PNET n/a n/a n/a n/a no material no material PNET56 Group 1 female PNET/ETNATR 1.67 n/a M Dead.5 no material no material PNET59 Group 3 n/a PNET n/a n/a n/a n/a n/a no material no material PNET61 Group 3 female PNET.67 n/a n/a Dead n/a no material no material PNET6 Group 3 female PNET 1. n/a n/a Dead n/a no material no material PNET64 Group 3 male PNET 16. n/a n/a Alive n/a no material no material PNET65 Group 3 male PNET 1. n/a n/a Alive n/a no material no material PNET66 Group female PNET 6. n/a n/a Dead n/a no material no material PNET67 Group 1 male PNET/ETNATR 3. n/a n/a Dead n/a no material no material PNET68 Group 3 male PNET. n/a n/a Alive n/a no material no material PNET71 Group male PNET 7. n/a n/a Alive n/a no material no material PNET7 Group 3 male PNET.6 n/a n/a Dead n/a no material no material PNET75 Group 3 male PNET.9 n/a n/a Dead n/a no material no material PNET78 Group 3 male PNET 4. n/a n/a Alive n/a no material no material PNET79 Group 3 male PNET/ME 4. n/a n/a Dead n/a no material no material PNET81 Group 1 female PNET/ETNATR 3. n/a n/a Alive n/a no material no material PNET8 Group 1 female PNET/ME 1. n/a n/a Alive n/a no material no material PNET91 Group 1 female PNET n/a n/a n/a n/a n/a no material PNET93 Group 1 female PNET n/a n/a n/a n/a n/a no material PNET94 Group 1 female PNET 15. n/a n/a n/a n/a no material PNET95 Group 3 female PNET 3.8 n/a n/a n/a n/a no material PNET96 Group 3 male PNET 8. n/a n/a n/a n/a no material PNET97 Group male PNET 1. n/a n/a n/a n/a no material PNET99 n/a male PNET 6 n/a M + Dead 1.5 no material no material PNET1 n/a female PNET 11 n/a M + Dead 8.7 no material no material PNET11 n/a male PNET 3 n/a M Alive 6.6 no material no material PNET15 n/a female PNET n/a n/a n/a n/a n/a no material no material

16 PNET16 n/a male PNET n/a n/a n/a n/a n/a no material no material PNET19 Group 1 female PNET 1.58 n/a n/a Dead n/a PNET111 Group 1 male PNET.33 n/a n/a Dead n/a PNET11 Group male PNET. n/a n/a Dead n/a no material no material PNET113 Group 3 male PNET 7. n/a n/a Dead n/a no material no material PNET114 Group male PNET n/a n/a n/a n/a n/a no material PNET116 Group male PNET 14. Chemo/XRT M Dead 1.79 no material no material PNET118 Group 1 male PNET.9 XRT M Dead.38 no material no material PNET119 Group male PNET 17.9 Chemo/XRT M Dead.58 no material no material PNET1 Group 3 male PNET 16.7 Chemo/XRT M Dead 4.33 no material no material PNET13 Group male PNET 17.9 Chemo M + Dead.88 no material no material PNET16 Group male PNET 3. n/a n/a n/a n/a no material no material PNET19 Group male PNET 8. n/a n/a n/a n/a no material no material PNET131 Group 3 female PNET.83 n/a n/a n/a n/a no material no material PNET13 Group 3 male PNET 4. n/a n/a n/a n/a no material PNET135 Group 1 male PNET n/a n/a n/a Dead. no material PNET138 Group 1 male PNET.83 n/a M Dead 1.58 PNET139 n/a n/a PNET n/a n/a n/a n/a n/a no material no material PNET14 n/a n/a PNET n/a n/a n/a n/a n/a no material no material PNET141 n/a n/a PNET n/a n/a n/a n/a n/a no material no material PNET14 n/a n/a PNET n/a n/a n/a n/a n/a no material no material PNET143 Group female PNET 1.9 n/a M Dead.75 no material PNET146 Group 3 male PNET 1.58 n/a M + Alive 3.58 no material PNET148 Group 1 female PNET. n/a M Alive 3.6 no material no material PNET149 Group male PNET 6.4 n/a M Dead 1.5 no material PNET157 Group 3 male PNET.5 n/a M Dead 8.17 no material PNET158 Group male PNET.3 n/a M Dead 6.8 PNET16 Group 3 male PNET 5.75 XRT M + Alive 1.75 no material no material PNET161 Group 1 female PNET 1.75 Chemo/XRT M Dead 3.17 no material no material PNET163 Group female PNET 1.4 Chemo M Dead.8 no material no material PNET164 Group 1 female PNET 8.9 n/a M + Dead 1.33 no material no material

17 PNET166 n/a female PNET.6 n/a M Dead.5 no material no material PNET167 Group 3 female PNET 1.8 n/a n/a Dead.71 no material no material PNET169 Group female PNET 4.8 n/a n/a Dead.17 no material no material PNET17 Group female PNET n/a None n/a n/a n/a no material PNET171 Group male PNET Chemo/XRT M + Dead 4.4 PNET17 Group 3 female PNET 3.5 Chemo/XRT M Alive.17 PNET173 Group male PNET Chemo/XRT M Dead 1.83 PNET174 Group male PNET 7.83 Chemo/XRT M Dead.33 PNET Group female PNET Chemo/XRT M Alive.9 PNET188 Group male PNET 1.67 Chemo M Dead 3.4 no material PNET19 38 Group 3 male PNET XRT M + Dead.5 PNET191 Group female PNET 4.4 Chemo M Alive 5.17 PNET Group female PNET 1.67 None M Dead. PNET Group 3 male PNET 1.17 Chemo/XRT M Alive 7.5 PNET199 Group female PNET 9.67 Chemo/XRT M Dead.8 no material PNET Group 3 female PNET 7. Chemo/XRT M + Dead 1.67 no material PNET6 Group 1 female PNET 3.4 n/a n/a Dead no material no material PNET55 Group 1 female PNET 1.9 Chemo/XRT M + Alive 4.67 no material no material PNET56 Group female PNET 13. Chemo/XRT M Dead 1.17 no material no material PNET58 Group 3 male PNET 7.5 Chemo/XRT M + Alive.8 no material no material PNET59 Group 1 male PNET 3.67 Chemo/XRT M + Dead.67 no material no material PNET6 Group female PNET 8.5 XRT M Alive 7.75 no material no material PNET65 n/a female PNET 1.33 Chemo M + Dead.5 no material no material PNET66 33 Group 3 male PNET 8.9 XRT M + Dead 5.9 no material PNET67 3 n/a female PNET 4.5 Chemo/XRT M Dead. no material no material PNET68 n/a male PNET.75 None M Dead. no material no material PNET69 n/a male PNET 1.75 None M Dead. no material no material PNET7 n/a female PNET.4 Chemo M + Dead 1.17 no material no material PNET71 8 n/a female PNET 5.9 XRT M Dead.58 no material

18 PNET7 9 Group 1 female PNET.83 Chemo M + Dead 3.4 no material PNET73 Group 1 female PNET 8.5 Chemo/XRT M Dead.67 no material no material PNET74 Group 3 male PNET 15.5 Chemo/XRT M Alive 1.33 no material no material PNET76 n/a male PNET 1.5 Chemo/XRT M Dead 1.33 no material no material PNET77 n/a female PNET 3.58 Chemo/XRT M Alive. no material no material PNET79 n/a female PNET 4.17 None M Dead.17 no material no material PNET81 Group 3 female PNET Chemo/XRT M + Dead 4.83 no material no material PNET8 Group 3 female PNET 7.8 Chemo/XRT M Alive 9.33 no material no material PNET83 4 Group 3 male PNET None M Dead. no material PNET84 5 Group 3 male PNET 4.9 Chemo/XRT M + Dead.75 no material PNET85 18 n/a female PNET. Chemo M Dead.5 no material PNET86 Group 1 male PNET 5.17 Chemo M Dead 3.17 no material no material PNET87 n/a male PNET.5 Chemo M n/a. no material no material PNET88 Group 1 male PNET.5 None M Dead 3.17 no material no material PNET89 3 n/a male PNET 7. Chemo/XRT M + Dead 1.67 no material no material PNET9 Group 3 male PNET.17 n/a n/a Dead. no material no material PNET91 Group 1 female PNET 3.75 Chemo/XRT n/a Dead 1. no material no material PNET93 Group female PNET 1.75 n/a n/a n/a n/a no material no material PNET94 Group 3 female PNET 1. n/a n/a n/a n/a no material no material PNET95 Group male PNET 5.33 n/a n/a n/a n/a no material no material PNET96 n/a female PNET 9.17 n/a n/a n/a n/a no material no material PNET97 Group 3 female PNET Chemo/XRT n/a Dead.8 no material no material PNET3 Group 3 female PNET 5.67 n/a n/a n/a n/a no material no material PNET31 Group 1 female PNET 3.5 Chemo M Alive no material no material PNET3 n/a female PNET 8.75 Chemo/XRT M Dead 1.75 no material no material

19 samples can be found with same annotation in Li, M., K. F. Lee, et al. (9). "Frequent amplification of a chr19q13.41 microrna polycistron in aggressive primitive neuroectodermal brain tumors." Cancer Cell 16(6): tumors." Cancer Cell 16(6): samples can be found with alternate annotation in Miller, S., H. A. Rogers, et al. (11). "Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma." NeuroOncol 13(8): n/a = not available Chemo = Chemotherapy XRT = Radation therapy PNET/ME: PNET with features of medulloepithelioma PNET/EP: PNET with features of ependymal or ependymoblasticdifferentiation PNET/ETNATR: PNET variant with excess neuropil and true rosettes

20 Supplemental Table 3: Quantitative qrt-pcr primers and probes Gene Probe # ASCL1 Hs6993_m1 COL1A1 Hs1644_m1 COL1A Hs16499_m1 COL5A1 Hs6988_m1 CRABP1 Hs171635_m1 ERBB3 Hs176538_m1 FOXJ1 Hs3964_m1 GFAP Hs9933_m1 GLI Hs _m1 GLI3 Hs6933_m1 IGF Hs17154_m1 LIN8A Hs788_s1 LIN8B Hs11379_m1 MSX1 Hs47183_m1 NCAM Hs18985_m1 Nestin Hs771_s1 NEUROG Hs7774_s1 NKX6- Hs75986_s1 OLIG1 Hs74493_s1 OLIG Hs3778_m1 PDGFRA Hs99818_m1 SMO Hs194_m1 TGFB3 Hs186_m1 TGFBR3 Hs111453_m1 TUBB3 Hs8139_s1 ZIC Hs6845_m1

21 Supplemental Table 4: Samples with inconclusive IHC analyses Annotation LIN8 OLIG PNET166 missing core missing core PNET65 missing core missing core PNET67 missing core missing core PNET68 missing core missing core PNET69 missing core missing core PNET7 missing core missing core PNET71 missing core missing core PNET76 failed negative PNET77 failed negative PNET79 missing core missing core PNET85 missing core missing core PNET87 missing core negative PNET89 missing core negative PNET96 missing core positive PNET3 missing core missing core

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