IDH1 mutations frequently occur in primary glioblastoma ...



Epidermal growth factor receptor variant III (EGFRvIII) positivity in EGFR-amplified glioblastomas: Prognostic role and comparison between primary and recurrent tumorsJ?rg Felsberg, Bettina Hentschel, Kerstin Kaulich, Dorothee Gramatzki, Angela Zacher, Bastian Malzkorn, Marcel Kamp, Michael Sabel, Matthias Simon, Manfred Westphal, Gabriele Schackert, J?rg C. Tonn, Torsten Pietsch, Andreas von Deimling, Markus L?ffler, Guido Reifenberger, Michael Weller, for the German Glioma NetworkSupplementary MaterialsSupplementary Table 1. Overview of the individual survival times, MGMT promoter methylation status and results of EGFRvIII testing by immunohistochemistry (IHC) or reverse transcription-PCR (RT-PCR) in primary tumors (PT) and recurrent tumors (RT) of 106 patients with newly diagnosed EGFR-amplified glioblastomas, IDH-wildtype. PFS, progression-free survival; OS, overall survival; n.d., not determined; * deceased patients; ** no progression documented; § excluded for Kaplan-Meier analyses because EGFRvIII was determined at second recurrence.Patient numberAge(years)PFS (months)OS (months)MGMT promoter statusPTEGFRvIIIIHCPTEGFRvIIIRT-PCRRTEGFRvIIIIHCRTEGFRvIIIRT-PCR14616.023.1*unmethylatednegativenegative--26344.972.8*methylatednegativen.d.--3661.5**6.2*unmethylatednegativenegative--4509.727.2*unmethylatednegativen.d.--5638.68.6*unmethylatednegativen.d.--6605.014.2*methylatednegativen.d.--7552.62.6*unmethylatednegativenegative--83716.121.4*methylatednegativenegative--9528.28.2*methylatednegativenegative--10522.94.5*unmethylatedn.d.negative--11618.09.0*unmethylatednegativenegative--12567.140.2*methylatednegativenegative--136623.049.7*methylatedn.d.negativen.d.n.d.144715.515.5*unmethylatednegativenegative--156211.415.0*methylatednegativenegative--165030.358.3*methylatednegativen.d.--17677.520.9*methylatednegativen.d.--184520.033.4*methylatednegativenegative--19615.98.7*unmethylatednegativenegative--20620.50.5*unmethylatednegativenegative--21563.56.0*methylatednegativenegativen.d.n.d.226112.912.9*unmethylatednegativenegative--23532.210.4*methylatednegativenegativen.d.n.d.24556.66.6*unmethylatednegativenegative--25574.812.6*unmethylatednegativenegative--26644.59.6*unmethylatednegativenegative--27724.813.3*unmethylatednegativenegative--28650.716.6*unmethylatedn.d.negativen.d.n.d.297113.613.6*unmethylatednegativenegative--303919.623.1*unmethylatedn.d.negativen.d.n.d.315412.819.7*unmethylatedn.d.negativen.d.n.d.32588.718.7*methylatednegativepositive--33766.06.0*methylatedpositiven.d.--345911.511.5*unmethylatedpositivepositive--354711.230.0*methylatedpositiven.d.n.d.n.d.36576.912.9*unmethylatedpositiven.d.n.d.n.d.376911.611.6*unmethylatedpositivepositive--38686.36.3*unmethylatedpositivepositive--39372.12.1*methylatedpositivepositive--40693.2**9.1*methylatedpositiven.d.--41626.616.1*methylatedpositiven.d.--42509.99.9*methylatedpositiven.d.--43700.30.3*methylatedpositivepositive--442913.721.9*methylatedpositivepositive--45599.011.2*unmethylatedpositivepositive--46569.521.5*methylatedpositivepositive--475632.339.6*unmethylatedpositivepositive--48667.57.5*methylatedpositivepositive--49572.32.3*methylatedpositivepositive--507454.060.0*unmethylatedpositivepositive--51755.15.1*unmethylatednegativepositive--52542.42.4*methylatedpositivepositive--53682.22.6*unmethylatedpositivepositive--546322.427.2*methylatedpositivepositiven.d.n.d.55706.79.6*unmethylatedpositivepositiven.d.n.d.56572.72.7*unmethylatednegativepositive--57765.510.8*methylatednegativepositive--58487.816.3*unmethylatedpositivepositiven.d.n.d.59548.311.6*methylatedpositivepositive--606894.6**94.6methylatedn.d.positive--61822.34.2*methylatedpositivepositive--62637.17.1*unmethylatedpositivepositive--63656.26.2*unmethylatedpositivepositive--645716.634.9*methylatedpositiven.d.--65637.427.5*methylatedpositivepositive--66863.024.9*methylatedn.d.positiven.d.n.d.676710.217.0*methylatednegativenegativenegativenegative68588.720.4*unmethylatednegativenegativen.d.negative697214.321.3*unmethylatednegativenegativenegativen.d.70505.213.2*unmethylatedn.d.negativen.d.negative71595.2 §23.7*methylatedn.d.negativen.d.negative725230.454.5*methylatednegativenegativen.d.negative734840.261.9*methylatednegativenegativen.d.negative74713.741.2*unmethylatednegativenegativenegativenegative757113.123.1*unmethylatednegativen.d.negativen.d.765812.050.4*unmethylatednegativen.d.negativen.d.77475.87.5unmethylatednegativenegativenegativenegative78607.719.4methylatednegativenegativenegativenegative79504.621.2*unmethylatednegativenegativenegativepositive80626.626.9methylatednegativenegativenegativenegative81613.113.9*unmethylatednegativenegativenegativenegative82493.314.9*unmethylatednegativepositivepositivepositive83546.511.0*methylatedpositivepositivepositivepositive845815.124.0*methylatedpositivepositivenegativenegative85703.812.3*methylatednegativepositivenegativepositive866419.624.9*unmethylatedpositivepositivepositiven.d.876313.017.9*unmethylatednegativepositivenegativepositive88697.620.1*methylatedpositivepositivepositivepositive895718.126.1*methylatedpositivepositiven.d.positive90588.816.8*unmethylatednegativepositiven.d.positive915621.333.2*methylatednegativepositiven.d.positive924018.125.8*unmethylatedpositivepositiven.d.positive93607.0 §61.0*methylatedpositivepositivepositivepositive94589.616.8*unmethylatedpositivepositivepositivepositive95673.918.8*unmethylatedpositivepositivenegativen.d.963918.938.2*unmethylatedpositivepositivenegativenegative97739.212.2unmethylatedpositivepositivepositivepositive984910.017.0*unmethylatedpositivepositivepositivepositive99649.610.7unmethylatedpositivepositivenegativenegative1007527.732.3*methylatedpositivepositivepositivepositive1017123.937.0unmethylatedpositiven.d.positivepositive1026632.749.2*unmethylatedpositiven.d.positiven.d.103553.0 §20.8*unmethylatedpositiven.d.positiven.d.104436.434.1unmethylatedpositivepositivepositivepositive1057226.148.4methylatedpositivepositivepositivepositive106656.115.5*unmethylatedpositivepositivepositivepositiveSupplementary Table 2. Overview of individual survival times, MGMT promoter methylation status and results of EGFRvIII testing by immunohistochemistry (IHC) or reverse transcription-PCR (RT-PCR) in primary tumors (PT) and recurrent tumors (RT) of 33 patients with newly diagnosed IDH-wildtype, EGFR-non-amplified glioblastomas. N.d., not determined. * Deceased patients.Patient numberAgePFS (months)OS (months)MGMT promoter statusPTPTRTRT(years)EGFRvIIIEGFRvIIIEGFRvIIIEGFRvIII?IHCRT-PCRIHCRT-PCR1076410.325.3*methylatednegativen.d.negativen.d.108552.417.9*methylatednegativen.d.negativen.d.109683.616.7*unmethylatedn.d.negativen.d.negative1107510.913.8*unmethylatednegativen.d.negativen.d.111673.7 21.9*methylatednegativen.d.negativen.d.112663.3 22.9*unmethylatednegativen.d.negativen.d.1135342.747.5*methylatednegativen.d.negativen.d.114365.512.2*unmethylatednegativen.d.negativen.d.115338.413.7methylatednegativen.d.negativenegative116423.232.5methylatednegativen.d.negativen.d.117595.215.8unmethylatednegativen.d.negativen.d.118387.415.5unmethylatednegativen.d.negativen.d.119465.512.7methylatednegativen.d.negativen.d.120483.1 11.9unmethylatednegativen.d.negativen.d.121543.4 23.7*methylatednegativen.d.negativen.d.122573.824.3unmethylatednegativen.d.negativen.d.123612.916.1*unmethylatednegativen.d.negativen.d.124725.95.9unmethylatednegativen.d.negativen.d.1257212.241.4unmethylatednegativen.d.negativen.d.126803.25.2methylatednegativen.d.negativen.d.127476.716.8unmethylatednegativen.d.negativen.d.128554.216.4*unmethylatednegativen.d.negativen.d.129534.214.0*methylatednegativen.d.negativen.d.130695.412.5unmethylatednegativen.d.negativen.d.1316111.617.4*unmethylatednegativen.d.negativen.d.132577.8 79.5*methylatednegativen.d.negativen.d.1336030.683.1*methylatednegativen.d.negativen.d.13458 3.7 16.0*methylatednegativen.d.negativen.d.135673.015.0*unmethylatednegativen.d.negativen.d.136533.115.9*methylatednegativen.d.negativen.d.137578.126.6*unmethylatednegativen.d.negativen.d.1384312.421.7*unmethylatednegativen.d.negativen.d.139633.114.1*methylatednegativen.d.negativen.d.Supplementary Table 3. Overview of the EGFR single nucleotide variants (SNVs) detected by next generation sequencing (NGS) in primary (PT) and recurrent (RT) glioblastomas of 27 patients. Mutant allele frequencies in percent are provided for each single nucleotide variant (SNV). * SNVs that are documented as pathogenic mutations in the catalogue of somatic mutations in cancer (COSMIC) database (). ** c.G1562A:p.R521K was reported as polymorphism in ref. 4. References are provided for those SNVs that were already reported in glioblastoma. The table also indicates the presence of EGFR amplification as detected by real-time PCR or NGS, and EGFRvIII as detected by NGS or by immunohistochemistry (IHC) and/or RT-PCR. Note that NGS detected all instances of EGFR amplification, but was less sensitive than IHC and RT-PCR in detecting EGFRvIII.Patient numberPT / RTEGFR amplification (real-timePCR)EGFR amplification (NGS)EGFRvIII(IHC and/or RT-PCR)EGFRvIII (NGS)EGFR SNVs (mutant allele frequencies in %)References69PT++--*c.G1793T:p.G598V (47); *c.A2941C:p.I981L (96)2, 3RT++--*c.G1793T:p.G598V (06); *c.A2941C:p.I981L (79)2, 379PT++---RT++++*c.C1088T:p.T363I (47)83PT++++-RT++++-84PT+++--RT++--*c.C866T:p.A289V (93)2, 3, 487PT+++-*c.T185G:p.L62R (94); **c.G1562A:p.R521K (04); c.G1280A:p.R427H (07)4RT+++-*c.T185G:p.L62R (07); **c.G1562A:p.R521K (07); c.G1280A:p.R427H (22)490PT++++-RT++++-93PT++++*c.C866A:p.A289D (11)1, 2, 4RT+++-*c.C866A:p.A289D (06)294PT+++-c.C574G:p.P192A (18)RT+++-c.C574G:p.P192A (06)96PT+++-c.G1784A:p.C595Y (12)RT++--*c.G2303T:p.S768I (04)97PT++++*c.A787C:p.T263P (70)2RT++++*c.A787C:p.T263P (70)298PT++++*c.G865A:p.A289T (15)2, 4RT++++-99PT++++-RT++--*c.C866T:p.A289V (29)1-4100PT+++-*c.G1793T:p.G598V (80)RT++++-108PT-----RT----c.G2045A:p.G682D (07) c.G3485A:p.S1162N (06)115PT-----RT-----116PT-----RT----*c.G1793T:p.G598V (16)2, 3117PT-----RT-----118PT-----RT-----119PT-----RT-----120PT-----RT-----123PT----*c.C1787T:p.P596L (13)2RT----*c.C1787T:p.P596L (10)2124PT-----RT-----125PT-----RT-----126PT-----RT-----127PT-----RT-----135PT-----RT-----137PT-----RT-----Supplementary Table 4. Overview of the validation cohort of 150 TCGA patients with IDH-wildtype glioblastoma (GBM). AF, allele frequency; WT, wildtype; M, methylated; UM, unmethylated; NA, not analyzed; SNV, single nucleotide variant; TMZ, temozolomide. * SNVs documented as pathogenic in the catalogue of somatic mutations in cancer (COSMIC) database ().Case-IDHistologyIDH statusMGMT promoter statusEGFR copy number [GISTIC-score]EGFR SNVEGFRvIII positive [AF > 0.01]Age [years]GenderTherapySurvival [months]Vital status [1: deceased; 0: censored]TCGA-02-0055GBMWTUM1-NA62femaleTMZ/radiation, TMZ2.51TCGA-06-0124GBMWTM2-NA67maleUnspecified radiation, TMZ 20.41TCGA-06-0125GBMWTM2*G598VNA63femaleTMZ/radiation, TMZ47.61TCGA-06-0130GBMWTUM1-NA54maleTMZ/radiation, TMZ12.91TCGA-06-0132GBMWTNA2-NA49maleStandard radiation, TMZ25.31TCGA-06-0139GBMWTUM1-NA40maleStandard radiation, TMZ11.91TCGA-06-0141GBMWTUM1-NA62maleTMZ/radiation, TMZ10.31TCGA-06-0168GBMWTNA1-NA59femaleTMZ/radiation, TMZ19.61TCGA-06-0169GBMWTUM2-NA68maleTMZ/radiation, TMZ3.31TCGA-06-0171GBMWTNA1-NA65maleNon-standard radiation, TMZ13.11TCGA-06-0184GBMWTNA2-NA63maleStandard radiation, TMZ40.30TCGA-06-0185GBMWTNA2*V651MNA54maleTMZ/radiation, TMZ37.00TCGA-06-0188GBMWTNA1-NA71maleStandard radiation, TMZ28.50TCGA-06-0189GBMWTNA2-NA55maleStandard radiation, TMZ15.41TCGA-06-0190GBMWTNA1-NA62maleStandard radiation, TMZ10.41TCGA-06-0237GBMWTNA2*L62RNA75femaleTMZ/radiation, TMZ13.61TCGA-06-0238GBMWTNA1-NA46maleTMZ/radiation, TMZ13.31TCGA-08-0386GBMWTNA2-NA74maleTMZ/radiation, TMZ18.01TCGA-12-0615GBMWTNA2-NA78femaleNon-standard radiation, TMZ15.31TCGA-12-0616GBMWTNA2*G598VNA36femaleTMZ/radiation, TMZ14.71TCGA-12-0618GBMWTNA1-NA49maleTMZ/radiation, TMZ13.01TCGA-12-0619GBMWTNA2*G598VNA60maleTMZ/radiation, TMZ34.91TCGA-06-0644GBMWTNA1-NA71maleStandard radiation, TMZ12.30TCGA-06-0646GBMWTNA2-NA60maleTMZ/radiation, TMZ5.71TCGA-06-0648GBMWTNA1-NA77maleStandard radiation, TMZ9.81TCGA-06-0650GBMWTUM2-NA39femaleTMZ/radiation, TMZ23.61TCGA-06-0686GBMWTNA2-NA53maleStandard radiation, TMZ9.40TCGA-12-0688GBMWTNA2-NA74maleStandard radiation, TMZ26.61TCGA-12-0692GBMWTNA1-NA75femaleTMZ Chemo3.61TCGA-15-0742GBMWTNA2C636YNA65maleNon-standard radiation, TMZ13.81TCGA-06-0744GBMWTNA2-NA66maleStandard radiation, TMZ19.50TCGA-14-0786GBMWTM2*A289VNA50femaleStandard radiation, TMZ23.01TCGA-14-0789GBMWTM2-NA54maleTMZ/radiation, TMZ11.21TCGA-14-0790GBMWTM2*A289VNA64femaleTMZ/radiation, TMZ13.81TCGA-06-0875GBMWTUM1-NA61femaleStandard radiation, TMZ9.20TCGA-06-0876GBMWTM2*G598V*R108KNA72femaleStandard radiation, TMZ8.90TCGA-06-0878GBMWTUM2-NA74maleTMZ/radiation, TMZ7.20TCGA-06-0879GBMWTM1-NA52maleStandard radiation, TMZ23.00TCGA-06-0881GBMWTUM2*A289VNA50maleStandard radiation, TMZ5.80TCGA-06-0882GBMWTUM1-NA30maleTMZ/radiation, TMZ5.40TCGA-06-0939GBMWTUM1-NA79femaleTMZ/radiation, TMZ20.90TCGA-26-1439GBMWTUM2*G598VNA63maleTMZ/radiation, TMZ13.91TCGA-14-1450GBMWTM1-NA57femaleTMZ/radiation, TMZ58.70TCGA-28-1747GBMWTM2*G598V*H304Y+44maleNon-standard radiation, TMZ2.51TCGA-14-1823GBMWTM2*A289T?58femaleTMZ/radiation, TMZ17.81TCGA-14-1829GBMWTUM2*T363I?57maleTMZ/radiation, TMZ7.20TCGA-27-1830GBMWTUM1-?57maleStandard radiation, TMZ5.11TCGA-27-1831GBMWTUM2*R108K?66maleTMZ/radiation, TMZ16.61TCGA-27-1832GBMWTUM2-?59femaleNon-standard radiation, TMZ9.91TCGA-27-1833GBMWTUM2-NA67femaleStandard radiation, TMZ24.21TCGA-27-1834GBMWTM1-?56maleTMZ/radiation, TMZ40.51TCGA-27-1835GBMWTM1-?53femaleTMZ/radiation, TMZ21.31TCGA-27-1836GBMWTM2-NA33femaleTMZ/radiation, TMZ30.01TCGA-27-1837GBMWTM2-?36maleStandard radiation, TMZ14.01TCGA-27-1838GBMWTUM2*A289DNA59femaleStandard radiation, TMZ11.51TCGA-32-1970GBMWTUM1*A289V?59maleTMZ/radiation, TMZ15.41TCGA-32-1986GBMWTUM1-NA68maleStandard radiation, TMZ12.71TCGA-32-1991GBMWTUM2-NA60maleTMZ/radiation, TMZ16.91TCGA-02-2470GBMWTUM1-NA57maleTMZ/radiation, TMZ12.91TCGA-02-2485GBMWTUM1*A289D?53maleTMZ/radiation, TMZ15.40TCGA-02-2486GBMWTUM1-?64maleTMZ/radiation, TMZ16.20TCGA-32-2491GBMWTUM1-NA63maleTMZ/radiation, TMZ12.21TCGA-32-2494GBMWTM2-NA58femaleTMZ/radiation, TMZ20.81TCGA-32-2495GBMWTUM2-NA59femaleTMZ/radiation, TMZ15.01TCGA-28-2509GBMWTM1-?77femaleStandard radiation, TMZ4.80TCGA-28-2513GBMWTUM2-?69femaleTMZ/radiation, TMZ7.30TCGA-28-2514GBMWTUM2-?45maleStandard radiation, TMZ5.30TCGA-27-2518GBMWTUM2-NA52maleTMZ/radiation, TMZ24.71TCGA-27-2519GBMWTUM1-?48maleTMZ/radiation, TMZ10.40TCGA-27-2523GBMWTM2-?63maleStandard radiation, TMZ16.11TCGA-27-2524GBMWTUM1-?56maleStandard radiation, TMZ7.61TCGA-27-2528GBMWTM2*R222C?62maleTMZ/radiation, TMZ15.81TCGA-06-2559GBMWTM1-?83maleTMZ/radiation, TMZ4.91TCGA-06-2561GBMWTUM1*R149W?53femaleTMZ/radiation, TMZ9.30TCGA-06-2562GBMWTUM1-?81maleNonStandard radiation, TMZ2.80TCGA-06-2563GBMWTM2*R252C?72femaleTMZ/radiation, TMZ8.50TCGA-06-2564GBMWTUM2-+50maleNon-standard radiation, TMZ5.90TCGA-06-2565GBMWTM2*R108K?59maleTMZ/radiation, TMZ6.80TCGA-06-2567GBMWTM1-?65maleNon-standard radiation, TMZ4.41TCGA-41-2571GBMWTUM1-?89maleTMZ Chemo0.91TCGA-41-2572GBMWTUM2-?67maleTMZ/radiation, TMZ13.31TCGA-41-2573GBMWTM1-NA59maleTMZ/radiation, TMZ8.90TCGA-41-2575GBMWTUM2-NA75maleTMZ/radiation, TMZ9.51TCGA-32-2615GBMWTUM2-?62maleNon-standard radiation, TMZ15.91TCGA-19-2619GBMWTM2-?55femaleTMZ/radiation, TMZ9.70TCGA-19-2620GBMWTM2*G598V+70maleTMZ/radiation, TMZ4.91TCGA-19-2623GBMWTM1-NA65maleTMZ/radiation, TMZ7.50TCGA-32-2634GBMWTM0-?82maleTMZ/radiation, TMZ8.90TCGA-32-2638GBMWTM2-?67maleTMZ/radiation, TMZ7.40TCGA-41-3393GBMWTUM2-NA81femaleTMZ/radiation, TMZ4.41TCGA-12-3649GBMWTUM2-NA76maleTMZ Chemo15.21TCGA-12-3650GBMWTUM2*A289V?46maleTMZ/radiation, TMZ10.91TCGA-12-3652GBMWTUM2*R252P+60maleTMZ/radiation, TMZ34.91TCGA-12-3653GBMWTUM2-?34femaleTMZ/radiation, TMZ14.51TCGA-41-3915GBMWTM1-?48maleTMZ/radiation, TMZ6.00TCGA-32-4211GBMWTUM1-NA56maleTMZ/radiation, TMZ12.61TCGA-32-4213GBMWTM2-?47femaleTMZ/radiation, TMZ11.70TCGA-32-4719GBMWTUM2-NA73maleTMZ/radiation, TMZ10.81TCGA-76-4925GBMWTM1-?76maleNonStandard radiation, TMZ4.81TCGA-76-4926GBMWTUM2-+68maleNonStandard radiation, TMZ4.51TCGA-76-4928GBMWTM1-?85femaleNonStandard radiation→TMZ3.11TCGA-76-4931GBMWTUM2*G598V?70femaleNonStandard radiation→TMZ9.21TCGA-76-4935GBMWTM1-NA52femaleStandard radiation, TMZ10.80TCGA-26-5132GBMWTM2-+74maleTMZ/radiation, TMZ9.40TCGA-26-5133GBMWTUM0-?59maleTMZ/radiation, TMZ14.90TCGA-28-5204GBMWTUM2-+72maleTMZ/radiation, TMZ14.91TCGA-28-5207GBMWTUM1*A289T?71maleNonStandard radiation, TMZ11.31TCGA-28-5208GBMWTM1-?52maleTMZ/radiation, TMZ15.60TCGA-28-5209GBMWTM2*G598A?66femaleNonStandard radiation, TMZ2.50TCGA-28-5211GBMWTUM2-NA42maleTMZ/radiation, TMZ11.80TCGA-28-5213GBMWTUM1*G598V?72maleStandard radiation, TMZ9.80TCGA-28-5214GBMWTUM2-NA53maleNonStandard radiation, TMZ14.20TCGA-28-5215GBMWTM1-?62femaleNonStandard radiation, TMZ11.01TCGA-28-5216GBMWTUM0-?52maleTMZ/radiation, TMZ13.60TCGA-28-5218GBMWTUM1-?63maleStandard radiation, TMZ5.21TCGA-28-5219GBMWTM1-NA47femaleNonStandard radiation, TMZ8.50TCGA-28-5220GBMWTUM1-+67maleStandard radiation, TMZ10.50TCGA-32-5222GBMWTM1-?66maleTMZ/radiation, TMZ5.40TCGA-12-5295GBMWTM2-+60femaleTMZ/radiation, TMZ14.91TCGA-12-5299GBMWTUM1-?56femaleTMZ/radiation, TMZ3.21TCGA-12-5301GBMWTM1-NA59maleTMZ/radiation, TMZ2.01TCGA-06-5408GBMWTUM2-+54femaleStandard radiation, TMZ11.71TCGA-06-5411GBMWTUM1-?51maleStandard radiation, TMZ8.31TCGA-06-5412GBMWTM1-?78femaleStandard radiation, TMZ4.51TCGA-06-5413GBMWTUM2-?67maleStandard radiation, TMZ8.80TCGA-06-5414GBMWTUM2-+61maleTMZ/radiation, TMZ9.00TCGA-06-5415GBMWTUM2-+60maleTMZ/radiation, TMZ8.50TCGA-41-5651GBMWTM1-?59femaleTMZ/radiation, TMZ11.50TCGA-06-5858GBMWTUM1-?45femaleTMZ/radiation, TMZ6.10TCGA-06-5859GBMWTUM1-?63maleTMZ/radiation, TMZ4.60TCGA-19-5950GBMWTM2-NA52femaleTMZ/radiation, TMZ11.30TCGA-19-5951GBMWTUM2-NA76femaleTMZ/radiation, TMZ8.01TCGA-19-5954GBMWTM2-NA72femaleTMZ/radiation, TMZ8.00TCGA-19-5958GBMWTUM1-NA56maleTMZ/radiation, TMZ5.40TCGA-19-5959GBMWTM2-NA77femaleTMZ/radiation, TMZ5.30TCGA-19-5960GBMWTUM1-?56maleTMZ/radiation, TMZ5.40TCGA-26-6173GBMWTUM2-NA57maleTMZ/radiation, TMZ7.90TCGA-26-6174GBMWTM1-NA65femaleTMZ/radiation, TMZ2.30TCGA-76-6191GBMWTUM1*C620WNA57maleTMZ/radiation, TMZ16.71TCGA-76-6192GBMWTUM1-NA74maleStandard radiation, TMZ3.31TCGA-76-6193GBMWTUM0-NA78maleStandard radiation, TMZ2.71TCGA-76-6282GBMWTUM2C571SNA63maleTMZ/radiation, TMZ17.11TCGA-76-6285GBMWTUM1-NA64femaleTMZ Chemo8.31TCGA-06-6388GBMWTUM1-NA64femaleTMZ/radiation, TMZ5.21TCGA-06-6390GBMWTUM1-NA58maleTMZ/radiation, TMZ5.41TCGA-28-6450GBMWTUM2-NA60maleTMZ/radiation, TMZ5.41TCGA-74-6573GBMWTUM2-NA67maleTMZ/radiation, TMZ3.41TCGA-06-6695GBMWTM1-NA64maleTMZ/radiation, TMZ8.30TCGA-06-6698GBMWTUM1-NA53femaleNon-standard radiation, TMZ4.80TCGA-06-6700GBMWTM2-NA76maleTMZ/radiation, TMZ4.80References: Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell 2013;155:462-77.Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, et al. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 2006;3:e485.Idbaih A, Aimard J, Boisselier B, Marie Y, Paris S, Crinière E, et al. Epidermal growth factor receptor extracellular domain mutations in primary glioblastoma. Neuropathol Appl Neurobiol 2009;35:208-13. Cimino PJ, Bredemeyer A, Abel HJ, Duncavage EJ. A wide spectrum of EGFR mutations in glioblastoma is detected by a single clinical oncology targeted next-generation sequencing panel. Exp Mol Pathol 2015;98:568-73.?Supplementary FiguresSupplementary Figure 1. Demonstration of regional heterogeneity of EGFRvIII expression in an EGFR-amplified primary glioblastoma, IDH-wildtype (patient 96). Shown are consecutive sections immunstained with antibodies against EGFR wildtype (EGFRwt, left side) and EGFRvIII (EGFRwt, right side). Note that EGFRwt expression is homogeneously distributed across the entire tumor specimen. In contrast, EGFRvIII-positivity is restricted to a subpopulation of tumor cells in the left upper area of the tumor while the tumor parts on the right-hand side are mostly negative for EGFRvIII. Sections are counterstained with hemalum. Scale bars correspond to 100 ?m in the high magnification images at the top and 1000 ?m in the low magnification images at the bottom. Supplementary Figure 2. EGFRvIII expression and MGMT promoter methylation status and survival outcome in 77 patients with EGFR-amplified glioblastomas treated with radiotherapy and temozolomide chemotherapy. (A) Overall survival (OS) in the 77 patients stratified according to EGFRvIII status. (B) OS in the 77 patients stratified according to MGMT promoter methylation status. (C) OS in the subgroup of patients with EGFRvIII-negative tumors stratified according to MGMT promoter methylation status. (D) OS in the subgroup of patients with EGFRvIII-positive tumors stratified according to MGMT promoter methylation status. Supplementary Figure 3. Survival of patients with EGFR-amplified glioblastomas, IDH-wildtype, according to the EGFRvIII status in the subgroups of patients who received second surgery (52 patients) or did not receive second surgery (54 patients). (A) PFS and (B) OS in patients who did not receive second surgery. (C) PFS and (D) OS in patients who received second surgery. Post-first progression PFS and OS from first progression in patients who were not re-operated (E,F) or were re-operated (G,H).Supplementary Figure 4. Survival of 27 German Glioma Network (GGN) patients with glioblastoma, IDH-wildtype, according to presence (9 patients) or absence (18 patients) of at least one EGFR single nucleotide variant (SNV) as detected by NGS of the EGFR coding sequence. Supplementary Figure 5. Survival of TCGA patients with glioblastoma, IDH-wildtype, according to EGFR amplification, presence of at least one EGFR single nucleotide variant (SNV), and EGFRvIII positivity. (A) OS in 150 TCGA patients with glioblastoma, IDH-wildtype, stratified according to presence (79 patients) or absence (71 patients) of EGFR amplification EGFR SNVs. (B) OS in 150 TCGA patients with glioblastoma, IDH-wildtype, stratified according to presence (31 patients) or absence (119 patients) of at least one EGFR SNV. (C) OS in 79 TCGA patients with EGFR-amplified glioblastoma, IDH-wildtype, stratified according to presence (25 patients) or absence (54 patients) of at least one EGFR SNV. (D) OS in 33 TCGA patients with EGFR-amplified glioblastoma, IDH-wildtype, stratified according to presence (11 patients) or absence (21 patients) of EGFRvIII positivity. Note that neither EGFR amplification nor presence of EGFR SNVs were associated with OS in the entire patient cohort (A-B). Within the subgroup of EGFR-amplified glioblastoma patients, neither presence of EGFR SNVs nor EGFRvIII were associated with OS (C-D). ................
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