Cao, Song

Ding, Li

Fiala, Mark A.

Foltz, Steven M.

Gao, Qingsong

Jayasinghe, Reyka G.

King, Justin

Kohnen, Daniel R.

Li, Yize

Sun, Hua

Vij, Ravi

Yao, Lijun

Yoon, Christopher J.

English

Digital Commons@Becker

Evolution and structure of clinically relevant gene fusions in multiple myelomaFoltz et al.103571429027015513412873 37 36 35 34 32 29 16 16 12 10 7 7 6 6 4 3 3 20300600900Intersection SizeEricScriptSTAR-FusionFusionCatcherINTEGRATEPRADA   05001000150020002500Set SizeNot Available (100)Non−Hyperdiploid (269)Hyperdiploid (373)0 20 40 60020406002040600204060Number of Fusions DetectedNumber of SamplesabSupplementary Figure 1. Related to Figure 1. a. Number of fusions detected per sample, stratified by hyperdiploid sta-tus. b. Fusion caller overlap after filtering. Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494.PFS ~ ISS + Age + WHSC1 fusion# Events: 364; Global p−value (Log−Rank): 5.7613e−09 AIC: 4212.35; Concordance Index: 0.6FusionAgeISS StageWHSC1NoneIIIIII(N=76)(N=545)(N=621)(N=188)(N=222)(N=211)1.43reference1.021.53reference(1.07 − 1.90)(1.00 − 1.03)(1.46 − 2.50)(1.18 − 1.99)HR 11.911.2 1.4 1.6 2 2.4 2.80.01570.00282.15x10-60.0015p-value# Events: 364; Global p−value (Log−Rank): 6.1594e−09 AIC: 4212.49; Concordance Index: 0.6PFS ~ ISS + Age + PVT1 fusionFusionAgeISS StagePVT1NoneIIIIII(N=18)(N=603)(N=621)(N=188)(N=222)(N=211)2.01reference1.021.881.55reference(1.17 − 3.46)(1.01 − 1.03)(1.43 − 2.46)(1.19 − 2.01)HR 1 1.5 2 2.5 3 3.5 40.01140.00214.66x10-69.98x10-4p-value# Events: 364; Global p−value (Log−Rank): 9.4689e−10 AIC: 4208.58; Concordance Index: 0.62 3 4 5 6 7 8PFS ~ ISS + Age + PVT1--IGLFusionAgeISS Stage3.24x10-40.00262.85x10-60.0013PVT1−−IGLNoneIIIIII(N=10)(N=611)(N=621)(N=188)(N=222)(N=211)3.42reference1.021.901.53reference(1.75 − 6.69)(1.01 − 1.03)(1.45 − 2.49)(1.18 − 1.99)p-valueHR 1# Events: 364; Global p−value (Log−Rank): 7.6926e−09 AIC: 4212.96; Concordance Index: 0.61N fusionsAgeISS Stage1.2 1.4 1.61.8 2 2.2 2.6PFS ~ ISS + Age + Total fusions0.01780.00293.4x10-67.54x10-4IIIIII(N=621)(N=621)(N=188)(N=222)(N=211)1.021.021.891.56reference(1.00 − 1.04)(1.01 − 1.03)(1.44 − 2.47)(1.21 − 2.03)p-valueHR 1# Events: 43; Global p−value (Log−Rank): 0.034825 AIC: 300.27; Concordance Index: 0.660.2 0.5 1 2 5 10PFS ~ ISS + Age + FGFR3 Mutation + FGFR3 Expression(among samples with IGH--WHSC1 or related fusions only)Exp HighMutationAgeISS Stage0.1170.40770.73060.00680.222IIIIII(N=61)(N=61)(N=61)(N=20)(N=30)(N=11)0.5930.6361.0064.2481.856reference(0.308 −  1.14)(0.218 −  1.86)(0.974 −  1.04)(1.490 − 12.11)(0.688 −  5.01)p-valueHR# Events: 289; Global p−value (Log−Rank): 2.875e−09 AIC: 3240.48; Concordance Index: 0.61FusionAgeISS Stage0.1 0.2 0.5 1 2 5 10PFS ~ ISS + Age + MYC--IGL + PVT1--IGL1.81x10-40.0590.0011.52x10-40.0107PVT1−−IGLMYC−−IGLNoneIIIIII(N=9)(N=10)(N=496)(N=515)(N=156)(N=181)(N=178)3.9000.261reference1.0201.7851.461reference(1.9127 − 7.95)(0.0649 − 1.05)(1.0078 − 1.03)(1.3226 − 2.41)(1.0920 − 1.95)p-valueHRa bc de fSupplementary Figure 2. Related to Figures 1, 5, 6. a-f. Progression-free survival (PFS) models using multivariate Cox proportional hazards. Error bars indicate a 95% confidence interval on each hazard ratio estimate. Covariate p-values derived from z-scores are two-sided. Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494.0 0.25 0.5 0.75 1ExpressionPercentile1024113711791193122912351242130914331462149615871627165617781783189719311992201520172039208720892122212623732401241924902531262112313 34123 351231215121 1 1 1 1 1 12 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 21 1 1341 1 1 11 1 13 3 3 33 3 31213 31411 112 211 1121121 121212 212123 313 3 312 21 12 21 1212121 11 111ADCK3−−NEK7*AGK−−BRAF*APC*−−MED20ARHGEF2−−NTRK1*ARID5B−−NFE2L2*ATR−−NMRK1*BRD7*−−CMTM1CAMK1D*−−KLBCCDC88C−−CALM1*CCNL1−−TRIB1*CDC42BPB*−−RRP9CDK11A*−−YWHABCPSF6−−DYRK2*CRIM1−−MAP4K3*DAAM1−−MNAT1*DIP2A−−CDC42BPA*DLG1−−ATR*DUSP26−−GAK*EEF2*−−MVPEFTUD2−−MAP3K14*EIF3A−−ADK*EIF3A−−RNF111*FCHSD2−−MAP3K14*FGFR3*−−IGHGAK−−PDXK*HIST1H1E*−−ATP5EIGH−−WHSC1*ITPK1*−−SLC38A1KCNT2−−ADCK3*KRAS*−−CCDC91LEMD2*−−KDM2ALLGL2−−PRKCA*LRMP−−ATM*MAP3K1*−−CDC42SE2MARK3*−−SELRC1MCL1−−TXNIP*MGAT4C−−PIP5K1B*MKNK2*−−ZNF598MSH2*−−CAMKMTMYC*−−IGLNPM1*−−MATR3PCGF5−−PRKCQ*PDCD6−−PMVK*PFKFB3*−−ATF3PHF6*−−HMGB1PIM3*−−FOXK2PIM3*−−SKIPMVK*−−WARS2−IT1PRKD3*−−UBBPUM1−−CDC42BPB*PVT1*−−IGHRHOA*−−UBBRND3−−CIC*RTTN−−BCL2*RUNX1*−−KCNT2SFXN3−−RPL5*SP4−−STK31*SPECC1−−MAP3K14*TBL1XR1*−−PCCBTESK1*−−ACAT1TEX261−−HK2*TMC8−−ZFP36L1*TPM3−−NTRK1*WHSC1*−−IGHWHSC1*−−IGLYTHDC2−−APC*Zero detectedMMRF Patient ID3 BM2 BM1 BM4 BM3 BM1 BM2 BM1 BM5 BM3 BM3 BM2 BM1 BM2 BM1 BM5 BM1 BM2 BM1 BM2 BM1 BM4 BM3 BM1 BM3 PB3 BM1 PB1 BM2 BM1 BM3 BM1 BM4 BM1 BM1 PB1 BM2 BM1 BM1 PB1 BM2 BM1 BM2 BM1 PB1 BM2 BM1 BM2 BM1 BM2 BM1 BM2 BM1 BM3 BM2 BM1 BM3 BM1 BM2 BM1 BM2 BM1 BM2 BM1 BM2 BM1 BM2 BM1 BM1 PB1 BM1 PB1 BM0.84 SRR41894870.84 SRR15872570.77 SRR21288030.89 SRR21297140.63 SRR41894980.84 SRR15872750.85 SRR41892660.87 SRR15872810.85 SRR31635020.75 SRR21297170.85 SRR31636560.85 SRR41894860.90 SRR15872860.54 SRR21288060.88 SRR15670190.86 SRR21288070.83 SRR15872870.85 SRR41892860.83 SRR15670240.66 SRR41897180.88 SRR15670410.89 SRR41897210.88 SRR31635050.79 SRR1567054SRR31636700.88 SRR3163668SRR15670620.86 SRR15670630.84 SRR41889890.85 SRR15670920.84 SRR41892670.89 SRR21288230.81 SRR41890000.84 SRR2128837SRR21288810.82 SRR21288800.84 SRR41889690.84 SRR2128883SRR21297470.90 SRR21297460.88 SRR41897420.79 SRR21297620.72 SRR4189270SRR21297880.80 SRR21297870.88 SRR41897530.89 SRR21297980.57 SRR31635090.78 SRR31636940.65 SRR41889990.80 SRR21298040.71 SRR31635100.79 SRR31636880.92 SRR41897590.89 SRR41892750.84 SRR21298250.88 SRR41897660.87 SRR21298390.86 SRR41897690.82 SRR21298410.85 SRR41897800.81 SRR31635780.82 SRR41892790.83 SRR41891690.87 SRR41892850.88 SRR31635920.83 SRR41894810.93 SRR4188998SRR41891490.88 SRR4189140SRR41892870.89 SRR4189258Visit TumorPuritySampleNumberTissueSourceSupplementary Figure 3. Related to Figure 3. Expression percentile of cancer-related genes (marked with *) in patients with samples from multiple clinic visits or tissue sites (bone marrow, BM, or peripheral blood, PB). Tumor purity of PB samples was not quantified. Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494.B CellsCD4+ T CellsCD8+ T CellsDendritic CellsMonocytesPlasma CellsUMAP 1UMAP 227522_1t(4;14)UMAP 1UMAP 2B CellsCD4+ T CellsCD8+ T CellsDendritic CellsMacrophagesMonocytesNatural Killer CellsPlasma CellsUMAP 1UMAP 227522_4t(4;14)UMAP 1UMAP 2B CellsCD4+ T CellsDendritic CellsMacrophagesMonocytesNatural Killer CellsPlasmaCellsUMAP 1UMAP 2CD8+ T Cells56203_1t(8;14)UMAP 1UMAP 2B Cells CD4+ T CellsCD8+ T CellsDendritic CellsMacrophagesMonocytesNaturalKiller CellsPlasma CellsUMAP 1UMAP 256203_2t(8;14)UMAP 1UMAP 2Plasma CellsUMAP 1UMAP 247499_pt(11;14)UMAP 1UMAP 2B CellsCD4+ T CellsCD8+ T CellsDendritic Cells MacrophagesMonocytesNatural Killer CellsPlasma CellsUMAP 1UMAP 277570t(11;14)UMAP 1UMAP 2B CellsCD4+ T CellsCD8+ T CellsMonocytesNatural Killer CellsPlasma CellsUMAP 1UMAP 281012_1t(11;14)UMAP 1UMAP 2CD4+ T CellsCD8+ T CellsMacrophagesMonocytesNatural KillerCellsPlasma CellsUMAP 1UMAP 281012_2t(11;14)UMAP 1UMAP 2a bc de fg hSupplementary Figure 4. Related to Figure 4. a-b. Cell types and Fuscia scRNA-seq fusion discovery for Patient 27522 (primary, relapse) with t(4;14). Results from overlapping and non-overlapping regions. c-d. Patient 56203 (pri-mary, relapse) with t(8;14). e. Patient 47499 (CD138+ sorted primary) with t(11;14). f. Patient 77570 (primary) with t(11;14). g-h. Patient 81012 (primary, relapse) with t(11;14). Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494 and doi.org/10.6084/m9.figshare.11941506.FGFR3UMAP 1UMAP 2WHSC1UMAP 1UMAP 2IGH with WHSC1 (27522_1 only)IGH with Other Genes (multiple samples)105.75 106.00 106.25 106.50050100150050100150200250IGH chr14 Genomic Coordinates (Mb) (GRCh38)Number of 'Chimeric Transcripts''Partner' GeneCD27SDC1SLAMF7TNFRSF17WHSC1Overlapswith othersNo overlap withother genes andsamplesacSupplementary Figure 5. Related to Figure 4. a. Single cell expression of WHSC1. b. Single cell expression of FGFR3. c. Mapping location and number of ‘Chimeric Transcripts’ linking IGH with various ‘Partner’ genes which do not form real fusions with IGH except for WHSC1. Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494.bFGFR3 Expression High FGFR3 Expression Low105.9106.2106.5106.8107.1105.9106.2106.5106.8107.11.841.861.881.901.92IGH Genome Breakpoint (chr14 Mb)WHSC1 Genome Breakpoint (chr4 Mb)WHSC1WHSC1FGFR3 Expression High FGFR3 Expression Low105.9106.2106.5106.8107.1105.9106.2106.5106.8107.11.841.861.881.901.92IGH Fusion Breakpoint (chr14 Mb)WHSC1 Fusion Breakpoint (chr4 Mb)WHSC1WHSC1WHSC1 CNV (log2 ratio)FGFR3 CNV (log2 ratio)−1.0−0.50.00.5−1.0 −0.5 0.0 0.5FGFR3 ExpressionFGFR3 HighFGFR3 LowWHSC1 Genome BP (chr4 Mb)WHSC1 Fusion BP (chr4 Mb)1.8501.8751.9001.850 1.875 1.900MB4-1MB4-3MB4-2WHSC1WHSC1DNA Mutation VAFRNA Mutation VAFMMRF_1391MMRF_1560MMRF_2250MMRF_2297MMRF_2401MMRF_2604MMRF_269402550751000 25 50 75 100MMRF_1260MMRF_1216 m = 1m = 2ab cSupplementary Figure 6. Related to Figure 5. a. Breakpoint mapping locations at IGH and WHSC1, split by FGFR3 expression. b. WHSC1 and FGFR3 copy number in samples with IGH fusion. c. Breakpoint (BP) mapping location at WHSC1. d. FGFR3 DNA and RNA variant allele frequency (VAF) comparison. Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494.dIGH (chr14)Position (Mb)106.2106.5106.8107.1IGK (crh2)Position (Mb)89.489.689.8IGL (chr22)Position (Mb)22.823.023.2MYC PVT1128.75 128.80 128.85 128.90 128.95 129.00chr8 Position (Mb)5’ 5’Supplementary Figure 7. Related to Figure 6. Fusion breakpoint mapping locations at Ig loci, MYC, and PVT1. Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494.Gamma secretease inhibitorc−Met inhibitor, Trk inhibitorAngiogenesis inhibitor, MEK inhibitorJAK kinase inhibitorALK inhibitor, c−Met inhibitorBET inhibitorEGFR inhibitor, HER−2 inhibitorKIT inhibitorAngiogenesis inhibitor, MEK inhibitorDNA−PK inhibitorFGFR inhibitorFGFR3NOTCH2NTRK1BRAFJAK2ALKBRD4NRG1PDGFRARAF1TMPRSS20 1 2 3 5 12Patient CountTarget Gene SND1−−BRAFTPM3−−NTRK1NOTCH2−−SEC22B0123 TCGA Sample CountUCECTHCATHCABLCA LUSCSARC PRADTPM3 NTRK1Tropomyosin Tyrosine Kinase5' 3'TPR NTRK1Tyrosine Kinase5' 3'ARHGEF2 NTRK1RhoGEF PH Tyrosine Kinase5' 3'0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300Amino Acid PositionSupplementary Figure 8. a. Overlap of fusion calls with DEPO drug target database. b. Cancer types with exact fusion overlaps. c. Protein structures of NTRK1 gene fusions. Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494.abc111111121111ARHGEF25CELEPHB2IRF2BP2LMNASQSTM1SSBP2TFGTPM3ZBTB7BBLCALGGPAADSARCSKCMTHCATCGA Cancer Type5' Partner of NTRK12 4 1 3 1 2 11 1 121 1 1 11 1 1 1 2 11111 11 1 11 111 1 1 1 1211 1 1 1 112 1 13 1 111121 12 11 3 2 112 1 1 2 11 21 11 2 4 1 31112 1 1 112 11 1 1 36 96ADK (2)AKT2 (1)ALPK2 (1)ATM (1)BRAF (2)BRD3 (1)CDC42BPA (1)CSF1R (1)CSNK1E (7)DAPK1 (1)DGKI (2)DYRK1A (1)DYRK2 (1)EIF2AK1 (1)ETNK1 (1)FGFR3 (1)HK2 (1)JAK2 (1)KSR1 (1)MAP3K14 (13)MAP3K7 (1)MAP4K5 (1)MAPK14 (1)MAPK4 (1)MELK (1)MNAT1 (1)NEK7 (2)NTRK1 (3)PIP5K1B (1)PRKCD (1)RAF1 (1)RIOK2 (1)STK25 (1)STK31 (1)STK38L (1)TRIB1 (1)TYK2 (1)ULK2 (1)ACCBLCABRCACESCESCAGBMHNSCKIRCKIRPLGGLUADLUSC OVPAADPRADREADSARCSKCMSTADTHCAUCECUCSTCGA Cancer TypeMMRF 3' Intact Kinase FusionsabSupplementary Figure 9. a. MMRF 3’ intact kinase fusion partner genes overlapping with TCGA cancer types (number of samples). b. MMRF NTRK1 partner genes overlapping with TCGA cancer types. Source data and scripts are available at doi.org/10.6084/m9.figshare.11941494.

Evolution and structure of clinically relevant gene fusions in multiple myeloma

https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?filename=0&article=10431&context=open_access_pubs&type=additional

Evolution and structure of clinically relevant gene fusions in multiple myeloma

Abstract

Similar works

Full text

Available Versions

Digital Commons@Becker