A brain tumor and NGS/multiplexing
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1 A brain tumor and NGS/multiplexing Santiago Ramón y Cajal Jefe de Servicio. Hospital Vall d Hebron Catedrático de Anatomía Patológica U.A.B. Académico de Número de la Real Academia Nacional de Medicina
2 A 3 year-old girl with seizures in early childhood underwent temporal lobectomy and partial tumour resection, in She received radio- and chemotherapy Recurrence and second biopsy at age 10 (2001). The residual tumour had been stable by imaging for another 12 years until 2014 In 2015, significantly grew showing nodular ependymal extension requiring further resection
3
4 nodules with neuropil and occasional rosettes. Immunohistochemistry with GFAP showed astrocytes Synaptophysin highlighted the neuropil rosettes. No mitotic activity, vascular proliferation or necrosis were noted. The proliferation index by Ki67 was 1-2% A Dysembryoplastic neuroepithelial tumors-like glioneuronal tumor
5 2001 Axial and coronal FLAIR and T1 post-gadolinium shows nodular enhancement in temporal lobe corresponding to residual neoplastic component
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7 More tumour cells had pleomorphic hyperchromatic nuclei and eosinophilic processes, with ganglion cell morphology. Ganglioglioma grade II
8 2015 Axial and coronal FLAIR and T1 post-gadolinium shows significant growth of the tumor with leptomeningeal dissemination (red arrows).
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10 IDH1 R132H ATRX A predominantly fascicular arrangement of pleomorphic astrocytic tumour cells. Xanthomatous tumour cells. IHQ and molecular studies: Negative for IDH1/2, ATRX, 1 19q del, p53, H3F3A K27M MALIGNANT XANTOASTROCYTOMA PLEOMORPHIC
11 DUPLICACIÓN DE BRAF Y FUSIÓN CON KIAA1549 (GEN DE FUSIÓN KIAA1549-BRAF)>70% Xantoastrocitomas pleomórficos: 66% XAP con rasgos anaplásicos: 65% Gangliogliomas: 18% Gangliogliomas anaplásicos (3/6) Astrocitomas pilocíticos: 9% (DIENCEFÁLICOS Y EXTRACEREBELOSOS)
12 MiSeq (Illumina) ncounter (Nanostring)
13 Prescreening Program Activity mutations & indels Chemistry: Multiplex-PCR and NGS We amplify 637 regions (1456 amplicons) in 65 genes frequently mutated in cancer and/or with matched approved/ in clinical trials targeted therapy (oncogenes and tumor supressors) AMPLICON-SEQ VHIO-CARD PANEL V3 ABL1 EGFR GNAS MSH6 RB1 AKT1 ERBB2 HRAS MTOR RET AKT2 ERBB3 IDH1 MYC RNF43 AKT3 ESR1 IDH2 NF2 RUNX1 ALK FBXW7 JAK1 NOTCH1 SMAD4 APC FGFR1 JAK3 NOTCH2 SMARCB1 BRAF FGFR2 KIT NOTCH3 SRC BRCA1 FGFR3 KRAS NRAS STK11 BRCA2 FGFR4 MAG PDGFRA TP53 CDH1 FLT3 MAP2K1 PIK3CA TSC1 CDKN2A GATA1 MET PIK3R1 TSC2 CSF1R GNA11 MLH1 PIK3R5 VHL CTNNB1 GNAQ MPL PTEN ZNRF3 The panel is especially suited for FFPE derived DNA. 2.6% failure rate in FFPE (n=882 samples 16) There is flexibility, new genes or regions may be included in the panel in less than 8 weeks. Min. Tumor area 20%, sensitivity 5% MAF TAT: <2 weeks Cost: 215 /sample
14 Prescreening Program Activity Copy Number Alterations Beta-testing Copy Number Panel v2 AKT2 FGFR1 NOTCH3 AKT3 FGFR2 NOTCH4 APC FGFR3 NTRK1 ATM FGFR4 NTRK2 BRCA1 IGF1R NTRK3 CCND1 INPP4B PDGFRA CCND2 KDR PIK3CA CCNE1 KIT PIK3CB CDK4 KRAS PIK3R1 CDK6 MAP2K4 PRKCI CDKN1A MAP3K5 PTEN CDKN2A MAPK7 RSPO2 CDKN2C MDM2 SHH EGFR MDM4 STK11 ERBB2 MEN1 TERT ESR1 MET TP53 FBXW7 MYC TSC1 FGF19 NF1 VEGFA FGF3 NOTCH1 VHL FGF4 NOTCH2 1-SCREEN 2-VALIDATE Nanostring VHIO CNA Panel Sure FISH 3% failure rate in FFPE (n=165 samples 16) There is a certain flexibility, new genes may be included in the panel in less than 16 weeks. Min. Tumor area 50% TAT: <3 weeks Cost: 479 /sample Validating sensitivity, specificity of the test
15 Prescreening Program Gene Fusions New Exon junction 1-Direct exon junction detection (unable to detect novel fusions) RNA E1 E2 E3 E2 E3 E4 E5 2-5 to 3 bias (able to detect novel fusions, but not all genes have this property) RNA 5 AND 3 EXONS E1 E2 E3 E4 E5 1-SCREEN Nanostring VHIO Fusion Panel VHIO Fusion panel v5 ncounter (Nanostring) Oct'16 Exon junctions: Gene expression: EML4 E13-ALK E20 SLC45A3 E1-FGFR2 E2 PTPRK E13-RSPO3 E2 BRCA1 EML4 E20-ALK E20 FGFR3 E17-AES E2 PTPRK E1-RSPO3 E2 BRCA2 EML4 E6-ALK E20 FGFR3 E17-ELAVL3 E2 PTPRK E2-RSPO3 E2 EGFR AKAP9 E8-BRAF E9 FGFR3 E17-LETM1 intron10 PTPRK E6-RSPO3 E2 ERBB2 KIAA1549 E15-BRAF E9 FGFR3 E17 intron-tacc3 E4 PTPRK E7-RSPO3 E2 ERBB3 KIAA1549 E14-BRAF E9 FGFR3 E17-BAIAP2L1 E2 CCDC6 E1-RET E12 ERBB4 KIAA1549 E15-BRAF E11 FGFR3 E17-TACC3 E4 KIF5B E15-RET E12 ESR1 BAG4 E2-FGFR1 E6 FGFR3 E17-TACC3 E8 KIF5B E16-RET E12 FGF19 ERLIN2 E10-FGFR1 E4 FGFR3 E17-TACC3 E10 KIF5B E22-RET E12 FGF3 FGFR1 E17-TACC1 E7 FGFR3 E17-TACC3 E11 NCOA4 E8-RET E12 FGF4 FGFR2 E17-AFF3 E8 RANBP17 E28-FGFR3 E14 PRKAR1A E7-RET E12 FGFR1 FGFR2 E17-AHCYL1 E2 EGFR viii (E1-E8) CD74 E6-ROS1 E34 FGFR2 FGFR2 E17-ATE1 E12 MET E13-E15 EZR E10-ROS1 E34 FGFR3 FGFR2 E17-BICC1 E3 LMNA E2- NTRK1 E10 SLC34A2 E4-ROS1 E32 FGFR4 FGFR2 E17-CASP7 E4 LMNA E2- NTRK1 E11 IRS2 FGFR2 E17-CCDC147 E2 LMNA E10- NTRK1 E12 5' to 3' bias MET FGFR2 E17-CIT E23 LMNA E10- NTRK1 E13 ALK NOTCH1 FGFR2 E17-FAM76A E2 TPM3 E7-NTRK1 E10 ROS NOTCH2 FGFR2 E17-GAB2 E2 TPR E21-NTRK1 E10 NTRK1 NOTCH3 FGFR2 E17-KIAA1967 E5 ETV6 E5-NTRK3 E15 NTRK3 NOTCH4 FGFR2 E17-MCU E2 ETV6 E4-NTRK3 E14 NTRK1 FGFR2 E17-OFD1 E3 PAX8 E8-PPARG E2 NTRK2 FGFR2 E17-VCL E15 PAX8 E9-PPARG E2 NTRK3 FGFR2 E2-WDR11 E20 PAX8 E10-PPARG E2 PDGFRA FGFR2 E16-KIAA1598 E7 EIF3E E1-RSPO2_E1 RSPO1 FGFR2 E16-TACC3 E11 EIF3E E1-RSPO2_E2 RSPO2 FGFR2 E17-NOL4 E7 EIF3E E5-RSPO2_E1 RSPO3 CD44 E1-FGFR2 E3 EIF3E E5-RSPO2 E2 RSPO4 2-VALIDATE qpcr / FISH <1% failure rate in FFPE (n=281 samples 16) There is a certain flexibility, new fusions may be included in the panel in less than 16 weeks. Min. Tumor area 10% TAT: <3 weeks Cost: 214 /sample
16 Nanostring fusion panel: FGFR1 E17-TACC1 E7 translocación
17 Baseline (20/11/17) First control (04/01/2018) Second control (12/02/2018)
18 In summary a DNT-like GNT that transformed into PXA In a panel of druggable targets, FGFR1-TACC1 fusion was detected. This FGFR1-TACC1 fusion and FGFR3-TACC3 fusion have been described in a small subset of IDHwt glioblastomas, but not in PXA. FGFR alterations emerge as the main MAPK activator after BRAF alterations and open new avenues in the treatment of these lowgrade tumors. In the present case this genetic alteration was detected only in the third biopsy and has been reported that inhibition of FGFR1 sensitizes human glioblastoma to radiotherapy.
19 Take home messages NGS and multiplexing technologies for diagnosis and selected treatment These methods can be used in LCR, blood and any sample
20 Histologic class IDH1 IDH2 TP53 T CSF T CSF T CSF GBM IDH WT Gliosarcoma GBM IDH mut Anaplastic astrocytoma Diffuse astrocytoma Oligodendroglioma Diffuse midline glioma ATRX TERT promoter T CSF T CSF No mutation 0.2-5% 5-20% 20-50% >50% Undetermined H3F3A K27M CSF Martínez-Ricarte et al. Clinical Cancer Res. 2018
21 Muchas gracias!!!!!! Santiago Ramón y Cajal Vall d Hebron University Hospital Barcelona, Spain
22 Survival probability The status of TERT, IDH, ATRX, p53 sub-classify diffuse glioma Group 1 TERT mut, IDH wt Suggestive IDH WT GBM; Group 2 ATRX/p53 mut, IDH mut Suggestive IDH mut GBM/ astrocytoma; Group 3 TERT mut, IDH mut Suggestive IDH mut Oligodendroglioma; Days Martínez-Ricarte et al. Clinical Cancer Res. 2018
23 Response evaluation Xanthoastrocytoma FGFR1 E17-TACC1 E7 fusion
24 Baseline (20/11/17) RANO table Brain MRI TARGET LESIONS First control (04/01/2018) Second control (04/01/2018) T1) Anterior lesion 16 mm x 10 mm= mm x 6 mm=60 10 mm x 4 mm = 40 Sum DM 160 mm 60 mm 40 mm % changes in basal Sum DM - 63% -75% Target lesions response Partial response Partial response N1) Peri-residual cavity implants NON TARGET LESIONS Present Present reduced Present reduced N2) Ependimary infiltration Present Present reduced Present reduced N3) Leptomeningeal infiltration Present Present reduced Present reduced Non Target lesions response Non CR/Non PD Non CR/Non PD OVERALL RESPONSE PARTIAL RESPONSE PARTIAL RESPONSE
25 BM (3) CSF ctdna Plasma ctdna LAMA1 G403R KMT2C V1163I BLM C685Y LAMA5 S2832C DOCK11 L958P PLEC R1350H NEB E6109D MAP3K1 R54W CSF ctdna versus plasma ctdna Norma BMBC3 KMT2D (R2966fs) AHNAK2 (P2390R) RB1 (I324fs) Liver ma NA Gene Amino acid RB1 I324fs KMT2D R2966fs AHNAK2 P2390R PAK7 S407* MSH5 Q292E PIK3CB M819L PIK3CB Q818H AHNAK2 L5292V ROS1 P1152Q MDN1 C2694S LAMA5 Q1100H CUBN S1887C XBP1. KMT2D G1916S FH S11W FOXA1 S384F RAD54L R320Q Amino Gene acid EGFR L858R FBXW7 S678* GREM1 P36L NFE2L2 E79K BM BMLC1 (E256) BM Men. CSF ctdna Amino Gene acid MAP3K1 T457fs Liver Liver POLE (1) E318K (2) TP53 R248Q ARID5B E815K ARID5B E587K HECW1 R797Q GNAS P97L MDN1 G1699E Plasma ctdna Normal tissue TP53 germline Normal tissue TP53 germline MDN1 (C2694S) PIK3CB (M819L) Meninges PIK3CB (Q818H) AHNAK2 Amino (L5292V) Gene acid Brain CSF MAP3K1 met ctdna T457fs Liver POLE CSF Plasma LN E318K (3) ctdna ctdna TP53 R248Q ARID5B E815K ARID5B E587K HECW1 R797Q GNAS P97L MDN1 G1699E Plasma ctdna Brain met ROS1 (P1152Q) PAK7 (S407*) MSH5 (Q292E) LAMA5 (Q1100H) CUBN (S1887C) KMT2D (G1916S) XBP1 (.) FH (S11W) FOXA1 (S384F) RAD54L (R320Q) CSF ctdna Brain Gene TBX3 TP53 MAP2K4 NCOR1 ASXL2 FLT3 MET MAP3K1 MLL ESR1 U2AF1 HIST1H3B TNFAIP3 JAK2 PIK3C2G BRCA1 DIS3 ERBB4 Plasma ctdna Amino acid K137fs P177fs E372X R507X A1269I T820S N1081H G607fs R2344T Y537S P176R D78N W113C T557fs S231F splicing L237R V851L BM (1) MAF > 50% MAF 20-50% MAF 5-20% MAF 1-5% No mutation BM (2) BM (3 De Mattos-Arruda et al Nature Comm. 2015
26 Targeted sequencing de tumores cerebrales
27 Baseline (20/11/17) First control (04/01/2018) Second control (12/02/2018)
28 Baseline (20/11/17) First control (04/01/2018) Second control (12/02/2018)
29
30
31 IDH1 R132H - ASTROCITOMA DIFUSO SIN MUTACIÓN DE IDH, GRADO II Astrocitoma difuso Grado II Ausencia de mutación de IDH (IDH1/2) y de ATRX ATRX SEC IDH1/2 SIN MUTACIO NES
32 Sequencing Circulating biomarkers PDX Gene expression IHC Tumoroids Patient Characterization and Functional Analysis Preclinical studies Patient Cancer Biology
33 ASTROCITOMA PILOCÍTICO Células bipolares en estroma fibrilar compacto con fibras de Rosenthal Áreas laxas con celulas estrelladas, microquistes y cuerpos granulares eosinófilos IHQ: GFAP+ IDH1 - Ki67 bajo EGB PAS+
34 - ASTROCITOMA DIFUSO CON MUTACIÓN DE IDH, GRADO II - Morfología glial mixta - Grado II - Mutación de IDH, mutación de ATRX, ausencia de codeleción de 1p/19q MUTACIÓN DE IDH1 R132H NO CODEL 1p/19q MUTACIÓN DE ATRX
35 VHIO Fusion panel v3 EML4 E13-ALK E20 EML4 E20-ALK E20 EML4 E6-ALK E20 AKAP9 E8-BRAF E9 KIAA1549 E15-BRAF E9 KIAA1549 E14-BRAF E9 KIAA1549 E15-BRAF E11 BAG4 E2-FGFR1 E6 ERLIN2 E10-FGFR1 E4 FGFR1 E17-TACC1 E7 FGFR2 E17-AFF3 E8 FGFR2 E17-AHCYL1 E2 FGFR2 E17-ATE1 E12 FGFR2 E17-BICC1 E3 FGFR2 E17-CASP7 E4 FGFR2 E17-CCDC147 E2 FGFR2 E17-CIT E23 FGFR2 E17-FAM76A E2 FGFR2 E17-GAB2 E2 FGFR2 E17-KIAA1967 E5 FGFR2 E17-MCU E2 FGFR2 E17-OFD1 E3 FGFR2 E17-VCL E15 CD44 E1-FGFR2 E3 SLC45A3 E1-FGFR2 E2 FGFR3 E17-AES E2 FGFR3 E17-ELAVL3 E2 FGFR3 E17-LETM1 intron10 FGFR3 E17 intron-tacc3 E4 FGFR3 E17-BAIAP2L1 E2 FGFR3 E17-TACC3 E10 FGFR3 E17-TACC3 E11 FGFR3 E17-TACC3 E4 FGFR3 E17-TACC3 E8 RANBP17 E28-FGFR3 E14 EGFR viii (E1-E8) RSPO1 RSPO2 RSPO3 RSPO4 EIF3E E1-RSPO2_E1 EIF3E E1-RSPO2_E2 EIF3E E5-RSPO2_E1 EIF3E E5-RSPO2 E2 PTPRK E13-RSPO3 E2 PTPRK E1-RSPO3 E2 PTPRK E2-RSPO3 E2 NAV2 E1-TCF7L1 E4 NAV2 E3-TCF7L1 E4 VTI1A E2-TCF7L2 E4 VTI1A E2-TCF7L2 E5 VTI1A E2-TCF7L2 E6 VTI1A E3-TCF7L2 E4 VTI1A E3-TCF7L2 E5 VTI1A E3-TCF7L2 E6 VTI1A E4-TCF7L2 E4 VTI1A E4-TCF7L2 E5 VTI1A E4-TCF7L2 E6 CCDC6 E1-RET E12 KIF5B E15-RET E12 KIF5B E16-RET E12 KIF5B E22-RET E12 NCOA4 E8-RET E12 PRKAR1A E7-RET E12 TPM3 E7-NTRK1 E10 TPR E21-NTRK1 E10 ETV6 E5-NTRK3 E15 ETV6 E4-NTRK3 E14
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