Abstract
Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p < 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively—laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT.
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References
Agamanolis DP, Katsetos CD, Klonk CJ, Bartkowski HM, Ganapathy S, Staugaitis SM, Kuerbitz SJ, Patton DF, Talaizadeh A, Cohen BH (2012) An unusual form of superficially disseminated glioma in children: report of 3 cases. J Child Neurol 27:727–733. https://doi.org/10.1177/0883073811426500
Amatu A, Sartore-Bianchi A, Siena S (2016) NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 1:e000023. https://doi.org/10.1136/esmoopen-2015-000023
Armao DM, Stone J, Castillo M, Mitchell KM, Bouldin TW, Suzuki K (2000) Diffuse leptomeningeal oligodendrogliomatosis: radiologic/pathologic correlation. AJNR Am J Neuroradiol 21:1122–1126
Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30:1363–1369. https://doi.org/10.1093/bioinformatics/btu049
Bonner T, O’Brien SJ, Nash WG, Rapp UR, Morton CC, Leder P (1984) The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4. Science 223:71–74
Bourne TD, Mandell JW, Matsumoto JA, Jane JA Jr, Lopes MB (2006) Primary disseminated leptomeningeal oligodendroglioma with 1p deletion. Case report. J Neurosurg 105:465–469. https://doi.org/10.3171/ped.2006.105.6.465
Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, Koelsche C, Sahm F, Chavez L, Reuss DE et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474. https://doi.org/10.1038/nature26000
Chen R, Macdonald DR, Ramsay DA (1995) Primary diffuse leptomeningeal oligodendroglioma. Case report. J Neurosurg 83:724–728. https://doi.org/10.3171/jns.1995.83.4.0724
Chiang JCH, Harreld JH, Orr BA, Sharma S, Ismail A, Segura AD, Ellison DW (2017) Low-grade spinal glioneuronal tumors with BRAF gene fusion and 1p deletion but without leptomeningeal dissemination. Acta Neuropathol 134:159–162. https://doi.org/10.1007/s00401-017-1728-4
Cho HJ, Myung JK, Kim H, Park CK, Kim SK, Chung CK, Choi SH, Park SH (2015) Primary diffuse leptomeningeal glioneuronal tumors. Brain Tumor Pathol 32:49–55. https://doi.org/10.1007/s10014-014-0187-z
Cin H, Meyer C, Herr R, Janzarik WG, Lambert S, Jones DT, Jacob K, Benner A, Witt H, Remke M et al (2011) Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol 121:763–774. https://doi.org/10.1007/s00401-011-0817-z
Dodgshun AJ, SantaCruz N, Hwang J, Ramkissoon SH, Malkin H, Bergthold G, Manley P, Chi S, MacGregor D, Goumnerova L et al (2016) Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation. J Neurooncol 128:293–302. https://doi.org/10.1007/s11060-016-2109-x
Dyson K, Rivera-Zengotita M, Kresak J, Weaver K, Stover B, Fort J, Rahman M, Pincus DW, Sayour EJ (2016) FGFR1 N546K and H3F3A K27M mutations in a diffuse leptomeningeal tumour with glial and neuronal markers. Histopathology 69:704–707. https://doi.org/10.1111/his.12983
Forshew T, Tatevossian RG, Lawson AR, Ma J, Neale G, Ogunkolade BW, Jones TA, Aarum J, Dalton J, Bailey S et al (2009) Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 218:172–181. https://doi.org/10.1002/path.2558
Gardiman MP, Fassan M, Orvieto E, D’Avella D, Denaro L, Calderone M, Severino M, Scarsello G, Viscardi E, Perilongo G (2010) Diffuse leptomeningeal glioneuronal tumors: a new entity? Brain Pathol 20:361–366. https://doi.org/10.1111/j.1750-3639.2009.00285.x
Gilmer-Hill HS, Ellis WG, Imbesi SG, Boggan JE (2000) Spinal oligodendroglioma with gliomatosis in a child. Case report. J Neurosurg 92:109–113
Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, Leiserson MDM, Niu B, McLellan MD, Uzunangelov V et al (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158:929–944. https://doi.org/10.1016/j.cell.2014.06.049
Hovestadt V, Jones DT, Picelli S, Wang W, Kool M, Northcott PA, Sultan M, Stachurski K, Ryzhova M, Warnatz HJ et al (2014) Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510:537–541. https://doi.org/10.1038/nature13268
Huang T, Zimmerman RA, Perilongo G, Kaufman BA, Holden KR, Carollo C, Chong WK (2001) An unusual cystic appearance of disseminated low-grade gliomas. Neuroradiology 43:868–874
Jeuken JW, Wesseling P (2010) MAPK pathway activation through BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic fusion gene with diagnostic, prognostic, and therapeutic potential. J Pathol 222:324–328. https://doi.org/10.1002/path.2780
Jones DT, Gronych J, Lichter P, Witt O, Pfister SM (2012) MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci 69:1799–1811. https://doi.org/10.1007/s00018-011-0898-9
Jones DT, Hutter B, Jager N, Korshunov A, Kool M, Warnatz HJ, Zichner T, Lambert SR, Ryzhova M, Quang DA et al (2013) Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45:927–932. https://doi.org/10.1038/ng.2682
Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677. https://doi.org/10.1158/0008-5472.CAN-08-2097
Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP (2009) Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28:2119–2123. https://doi.org/10.1038/onc.2009.73
Kessler BA, Bookhout C, Jaikumar S, Hipps J, Lee YZ (2015) Disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural disease: case report. Clin Imaging 39:300–304. https://doi.org/10.1016/j.clinimag.2014.11.018
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellison DW, Figarella-Branger D, Perry A, Reifenberger G, Von Deimling A (2016) WHO classification of tumours of the central nervous system. International Agency for Research on Cancer, Lyon, France
Perilongo G, Gardiman M, Bisaglia L, Rigobello L, Calderone M, Battistella A, Burnelli R, Giangaspero F (2002) Spinal low-grade neoplasms with extensive leptomeningeal dissemination in children. Childs Nerv Syst 18:505–512. https://doi.org/10.1007/s00381-002-0626-8
Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H et al (2008) BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118:1739–1749. https://doi.org/10.1172/JCI33656
Preuss M, Christiansen H, Merkenschlager A, Hirsch FW, Kiess W, Muller W, Kastner S, Henssler A, Pekrun A, Hauch H et al (2015) Disseminated oligodendroglial-like leptomeningeal tumors: preliminary diagnostic and therapeutic results for a novel tumor entity [corrected]. J Neurooncol 124:65–74. https://doi.org/10.1007/s11060-015-1735-z
Rhiew RB, Manjila S, Lozen A, Guthikonda M, Sood S, Kupsky WJ (2010) Leptomeningeal dissemination of a pediatric neoplasm with 1p19q deletion showing mixed immunohistochemical features of an oligodendroglioma and neurocytoma. Acta Neurochir (Wien) 152:1425–1429. https://doi.org/10.1007/s00701-010-0674-x
Rodriguez FJ, Perry A, Rosenblum MK, Krawitz S, Cohen KJ, Lin D, Mosier S, Lin MT, Eberhart CG, Burger PC (2012) Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. Acta Neuropathol 124:627–641. https://doi.org/10.1007/s00401-012-1037-x
Rodriguez FJ, Schniederjan MJ, Nicolaides T, Tihan T, Burger PC, Perry A (2015) High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN). Acta Neuropathol 129:609–610. https://doi.org/10.1007/s00401-015-1400-9
Rossi S, Rodriguez FJ, Mota RA, Dei Tos AP, Di Paola F, Bendini M, Agostini S, Longatti P, Jenkins RB, Giannini C (2009) Primary leptomeningeal oligodendroglioma with documented progression to anaplasia and t(1;19)(q10;p10) in a child. Acta Neuropathol 118:575–577. https://doi.org/10.1007/s00401-009-0565-5
Sahm F, Schrimpf D, Jones DT, Meyer J, Kratz A, Reuss D, Capper D, Koelsche C, Korshunov A, Wiestler B et al (2016) Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 131:903–910. https://doi.org/10.1007/s00401-015-1519-8
Schniederjan MJ, Alghamdi S, Castellano-Sanchez A, Mazewski C, Brahma B, Brat DJ, Brathwaite CD, Janss AJ (2013) Diffuse leptomeningeal neuroepithelial tumor: 9 pediatric cases with chromosome 1p/19q deletion status and IDH1 (R132H) immunohistochemistry. Am J Surg Pathol 37:763–771. https://doi.org/10.1097/PAS.0b013e31827bf4cc
Schwetye KE, Kansagra AP, McEachern J, Schmidt RE, Gauvain K, Dahiya S (2017) Unusual high-grade features in pediatric diffuse leptomeningeal glioneuronal tumor: comparison with a typical low-grade example. Hum Pathol. https://doi.org/10.1016/j.humpath.2017.06.004
Stodberg T, Deniz Y, Esteitie N, Jacobsson B, Mousavi-Jazi M, Dahl H, Zweygberg Wirgart B, Grillner L, Linde A (2002) A case of diffuse leptomeningeal oligodendrogliomatosis associated with HHV-6 variant A. Neuropediatrics 33:266–270. https://doi.org/10.1055/s-2002-36739
Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060–1072. https://doi.org/10.1016/j.cell.2016.01.015
Tatevossian RG, Lawson AR, Forshew T, Hindley GF, Ellison DW, Sheer D (2010) MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol 222:509–514. https://doi.org/10.1002/jcp.21978
Thorvaldsdottir H, Robinson JT, Mesirov JP (2013) Integrative genomics viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14:178–192. https://doi.org/10.1093/bib/bbs017
van der Maaten L, Hinton G (2008) Visualizing Data using t-SNE. J Mach Learn Res 9:2579–2605
Zebisch A, Troppmair J (2006) Back to the roots: the remarkable RAF oncogene story. Cell Mol Life Sci 63:1314–1330. https://doi.org/10.1007/s00018-006-6005-y
Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, Orisme W, Punchihewa C, Parker M, Qaddoumi I et al (2013) Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45:602–612. https://doi.org/10.1038/ng.2611
Acknowledgements
This work was supported by the Everest Centre for Low-grade Paediatric Brain Tumours (The Brain Tumour Charity, UK), A Kids’ Brain Tumor Cure (PLGA) Foundation, the German Cancer Consortium (DKTK), and fellowships from the Mildred-Scheel doctoral program of the German Cancer Aid and the German National Academic Foundation (to M.Y.D.). Sebastian Brandner was partially supported by the National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre. For excellent technical support and expertise we sincerely thank the Microarray Unit of the German Cancer Research Center (DKFZ) Genomics and Proteomics Core Facility, and Hai-Yen Nguyen and Laura Doerner (Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg).
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Deng, M.Y., Sill, M., Chiang, J. et al. Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. Acta Neuropathol 136, 239–253 (2018). https://doi.org/10.1007/s00401-018-1865-4
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DOI: https://doi.org/10.1007/s00401-018-1865-4