EGAGenomicsIllumina MiSeqOtherhttps://ega-archive.org/studies/EGAS00001001324EGAEGA study EGAS00001001324JMML targeted sequencing of candidate genesEGArestrictedJMML, leukemia, juvenile myelomonocytic, chronic myelomonocytic.RAS, Ras, PRKBA, l(1)G0098, Akt/PKB, dP60, Vps34, acute non lymphoblastic leukemia, Myeloid, acetylglucosaminyltransferase-like protein, DAKT1/PKB, CG1201, BcDNA:LD15217, 1210, Ras-1, congenital defects, AKT1, VPS34, 11621, aplasia, Mutations, PI-3 kinase, DmelCG8318, p110-alpha, ras, c-ras2, Abnormal retropulsion test, type I, PDK1/Pk61C, CG1210, Scanning Transmission Electron Microscopy, Pk61C/PDK1, Whole Transcriptome, Transcriptome Sequencing, Fs(3)Hor, primary stem, myd, PDK-1, peripheral type, Dp60, like-acetylglucosaminyltransferase, E030030H24Rik, Spontaneous Regression, PI3K_59F, Mbp-1, U, PI3-kinase activity, NTef2, amlcr1, PI3Kgamma, RacPK, MCAP, high frequency, chronic myeloproliferative disorders, PI3K 68D, Spontaneous Regressions, Pk61C, [pyruvate dehydrogenase (lipoamide)] kinase activity, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, CG1799, acute myelogenous, dVps34, Ras2, RAS2, Ras1, RAS1, rea, Exome, familial, p50alpha, Myelomonocytic Leukemias, CG2699, DmelCG5373, Fs(3)Sz11, Juvenile Myelomonocytic Leukemia, Spontaneous Remission, AKT/PKB, C530050K14, pyruvate dehydrogenase kinase activity, T32M21_110, mKIAA0609, Recklinghausen's disease, type-1 PI3K, dRas85D, p-Akt, ras1, TOR complex 2, evi-1, ras2, activation, BcDNA:RE36103, fg, TORC 2 complex, CG11621, Juvenile Myelomonocytic Leukemias, Complete Transcriptome, polycomb repressive complex 2, Myeloblastic, Hras-1, Acute Myeloid Leukemia, Dm Ras1, PDK, dAKT/dPKB, PKB/dAKT, DmelCG4141, F8A5_4, APDS, RasI, MDC1D, enr, primary axis, PI3KBETA, Whole Exome Sequencing, CG2684, WSS, Harvey-ras, Hras1, RAC-ALPHA, DmelCG4006, dRas, CG1167, H-ras, DRAS1, stalk, DRas2, IMPDH, LARGE1, LD06825, myeloproliferative neoplasms, Dras2, Dras1, PIK3, D-Ras, dVps34/PI3K59F, Pi3Kp60, Spontaneous Healings, PI3K-dp110, Kras-2, dPI3K, anon-92Ed, TOR, defects, IMPdH, dPDK1, Ha-ras, Dras, acute myeloid leukaemia (AML), class I, ras 1, Leukemia, Complete, Exome Sequencings, juvenile myelomonocytic, raspberry/impd, MDDGB6, Nf-1, Ras[V12], NFNS, Pi3Kp110, EK3-4, VRNF, pebp2ab, culm, Sequencing, DRas, P110BETA, DRas85D/Ras, Dmras64B, Whole Exome, PI3K21B, AKT, Akt, Whole, dSTPK61, MCM, NF1, NF-1, nf1, constitutitional genetic, von Reklinghausen disease, PDH kinase activity, Cpk, leukemia, Spontaneous, PK61C, Complete Exome Sequencings, AA414921, BG02759, akt, class II, type III phosphoinositide 3-kinase activity, pyruvate dehydrogenase kinase activator protein activity, DAkt1, DAKT1, D-ras-1, Cell, PI(3)K, cpk, E(faf), AML, PI3K-92E/Dp110, DmelCG1167, Exome Sequencing, PIK3C1, PKB, CWS6, CWS5, agenesis, PKB-ALPHA, S35097, CG4006, 4632407F12Rik, aml1-evi-1, mTORC2, Dakt1, aml, RAS85D, Dmras85D, l(1)9Eb, PDHK, Von Recklinghausen disease, DmelCG11621, Lds, Juvenile Chronic Myelogenous Leukemia, chronic myelomonocytic, caPI3K, dAkt/PKB, CLOVE, Acute, like-glycosyltransferase, DmVps34, PDPK2P, IMD14, TOR Complex 2, PI3K_68D, PI3K-92D, Dmp110, hereditary, dPDK-1, pyruvate dehydrogenase kinase (phosphorylating) activity, JMML, Ras1/RAs85D, CG5373, D530020C15Rik, MTORC-2, ATVPS34, Mbp1, c-rasHa, PI3K, E(sev)3C, Dp110, PDK4, PDK3, CG11485, PDK2, PDK1, Pdk1, PHOSPHATIDYLINOSITOL 3-KINASE, DmelCG2699, F8A5.4, p110alpha, phosphatidylinositol 3-kinase activity, D-Ras1, DmelCG2684, RTK, Pi3K92D, CG4141, T32M21.110, Complete Exome Sequencing, Acute Myeloblastic Leukemia, l(1)G0436, Whole Transcriptome Sequencing, catalyst activity, hypoplasia, type 1 neurofibromatosis, Pi3k, ras85B, ras85D, aml1., PI[[3]]K, PKB|Akt, genetic, XAML, D-ras-2, p55alpha, ANLL, Pi3K, PI3k, associated, Healing, MCMTC, l(3)s1747, PI3K68D, DmelCG1210, dakt, gyltl1b-b, Ki-ras, P110DELTA, PtdIns-3-kinase activity, CG8318, DSTPK61, l(3)89Bq, deformities, vacuolar protein sorting 34, dPIK, 1-phosphatidylinositol 3-kinase activity, Electron Microscopy, PKB/Akt, PKB/AKT, dAkt, dAKT, MDDGA6, p21[Ras1], dRas1, dRAS1, KIAA0609, DAkt, Dras85D, dNF1, acetylglucosaminyltransferase-like 1A, ras-2, l(3)04226, atresia, Acute myelogenous leukemia, DPKB, l(1)G0351, LD02673, gyltl1b, pAkt, Transplantation, p85alpha, DmelCG1799, c-Ha-ras, D-ras1, l(1)G0238, D-ras2, susceptibility to, Heterogeneity, mdc1d, malformations, C-ras1, Dras64B, PI3K 68_D, LARGE_HUMAN, C-ras2, early, l(3)06677, l(1)G0002, l(1)G0482, p110D, Dakt, Dstpk61, acute myeloid leukemia (AML), Patient, c-H-ras, Horka, l(1)G0127, anomalies, dPKB, aml-1, STEM, Fs(3)Horka, inherited genetic, p120-PI3K, 3'-phosphoinositide-dependent protein kinase 1, Transcriptome Sequencings, droPIK57, DRAC-PK85, TORC2, B830012B01, RasV12, Extra Sex Combs/Enhancer of Zeste complex, Complete Exome, PI3K92E, Kras2, Pi3K_59F, DmelCG9375, neurofibromatosis, type I phosphatidylinositol kinase activity, froggy, Gyltl1a, phosphatidylinositol 3-kinase, l(1)G0388, Dpkb, acute non lymphoblastic leukaemia, p60, Genetic heterogeneity, PHOSPATIDYLINOSITOL 3-KINASE, Imbalance, DmF2, acute myeloid, l(1)G0380, Dp110/PI3K, PI3K-68D/E, lod, p21B, Runx-1, STK1, WES, dras1, Dm-ras-64B, PRC2 complex, LARGE, PI3'K, l(1)G0391, ATPDK1, pyruvate dehydrogenase (lipoamide) kinase activity, Juvenile Myelomonocytic, Ras 85D, BPFD#36, PI3K-68D, Myelomonocytic Leukemia, rapamycin and nutrient-insensitive TOR complex, Clients, DRAC-PK, Complex 2, Torc2, pk61c, ras-l, Spontaneous Healing, hPDK1, l(1)G0056, dP110, PRO0461, 6330412C24Rik, CG9375, axis, p120, p110, K-ras, Vps34p, Scanning Transmission, Client, Juvenile, neurofibromatosis type 1 microdeletion syndrome, PDPK2, fs(3)05703, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, vps34, EP(X)1093, dp110, D-Akt, 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1, rare (European definition), Target of Rapamycin Complex 2, AI929937, PI3CG, cbfa2, PI-3-K, CMPD, PI3K-59F, Complete Transcriptome Sequencing, frequent, PI3K-Dp110, akt1, dAkt1, Xaml1, DRAC-PK66, class III, p110gamma, Su(tor)3-2, ATP:pyruvate dehydrogenase (acetyl-transferring) phosphotransferase activity, dakt1, Regression, birth defects, PKBalpha, AW494271, dAKT1, RAC, Rac, glycosyltransferase-like protein LARGE1falseJMML targeted sequencing (2013)Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations (Chang, Dvorak et al. 2014). Clinical evolution is heterogeneous, with acute myeloid leukemia (AML) transformation in 1/3 of cases and frequent relapses after hematopoietic-stem-cell transplantation (HSCT), although some patients experience spontaneous remission (Locatelli, Nollke et al. 2005; Matsuda, Shimada et al. 2007; Takagi, Piao et al. 2013; Locatelli and Niemeyer 2015). The initiating lesion incompletely predicts outcome, suggesting the involvement of additional mutations. Genetic profiling of a large JMML cohort (n=118), including whole-exome sequencing (WES) in 30 cases, uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38/case/Mb) and restricted to sporadic (47/78; 60%) or NF1-associated (8/8; 100%) JMML. Multiple concomitant genetic hits were identified targeting the RAS pathway in 13/78 (17%), RAC2D63V, which activates the PI3K/PDK1/AKT and the mTORC2 pathways, and a novel pathway for JMML, the polycomb repressive complex 2 (PRC2), in 26/78 (33%) of the sporadic JMML cases. Interestingly, PRC2 imbalance was recently shown to synergize with RAS activation (De Raedt, Beert et al. 2014). JMML outcome was associated to the mutational profile, suggesting a dose-dependent effect for RAS-pathway activation, distinguishing very aggressive JMML rapidly progressing to AML.2019-02-01 16:51:14EGAS000010013249606EGAD00001001451EGAC00001000362