Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

被引：384

作者：

Capper, David ^{[1
,2
,3
,4
,5
]}

Stichel, Damian ^{[1
,2
]}

Sahm, Felix ^{[1
,2
]}

Jones, David T. W. ^{[6
,7
]}

Schrimpf, Daniel ^{[1
,2
]}

Sill, Martin ^{[6
,8
]}

Schmid, Simone ^{[3
,4
]}

Hovestadt, Volker ^{[9
,10
,11
,12
]}

Reuss, David E. ^{[1
,2
]}

Koelsche, Christian ^{[1
,2
,20
]}

Reinhardt, Annekathrin ^{[1
,2
]}

Wefers, Annika K. ^{[1
,2
]}

Huang, Kristin ^{[1
,2
]}

Sievers, Philipp ^{[1
,2
]}

Ebrahimi, Azadeh ^{[1
,2
]}

Schoeler, Anne ^{[3
,4
,5
]}

Teichmann, Daniel ^{[3
,4
]}

Koch, Arend ^{[3
,4
]}

Haenggi, Daniel ^{[13
]}

Unterberg, Andreas ^{[14
]}

Platten, Michael ^{[15
,16
]}

Wick, Wolfgang ^{[17
,21
]}

Witt, Olaf ^{[6
,18
,19
]}

Milde, Till ^{[6
,18
,19
]}

Korshunov, Andrey ^{[1
,2
]}

Pfister, Stefan M. ^{[6
,8
,18
]}

von Deimling, Andreas ^{[1
,2
]}

机构：

[1] Univ Hosp Heidelberg, Dept Neuropathol, Heidelberg, Germany

[2] German Canc Res Ctr, German Canc Consortium DKTK, Clin Cooperat Unit Neuropathol, Heidelberg, Germany

[3] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Dept Neuropathol, Berlin, Germany

[4] Berlin Inst Hlth, Berlin, Germany

[5] German Canc Res Ctr, German Canc Consortium DKTK, Partner Site Berlin, Heidelberg, Germany

[6] NCT Heidelberg KiTZ, Hopp Childrens Canc Ctr, Heidelberg, Germany

[7] German Canc Res Ctr, Pediat Glioma Res Grp, Heidelberg, Germany

[8] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[9] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[10] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[11] Harvard Med Sch, Boston, MA 02114 USA

[12] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[13] Heidelberg Univ, Univ Med Ctr Mannheim, Dept Neurosurg, Mannheim, Germany

[14] Heidelberg Univ Hosp, Dept Neurosurg, Heidelberg, Germany

[15] German Canc Res Ctr, German Canc Consortium DKTK, Clin Cooperat Unit Neuroimmunol & Brain Tumor Imm, Heidelberg, Germany

[16] Heidelberg Univ, Univ Med Mannheim, Med Fac Mannheim, Dept Neurol, Mannheim, Germany

[17] Heidelberg Univ Hosp, Dept Neurol, Heidelberg, Germany

[18] Heidelberg Univ Hosp, Dept Pediat Oncol Hematol Immunol & Pulmonol, Heidelberg, Germany

[19] German Canc Res Ctr, German Canc Consortium DKTK, CCU Pediat Oncol G340, Heidelberg, Germany

[20] Heidelberg Univ Hosp, Inst Pathol, Dept Gen Pathol, Heidelberg, Germany

[21] German Canc Res Ctr, Clin Cooperat Unit Neurooncol, Heidelberg, Germany

来源：

ACTA NEUROPATHOLOGICA | 2018年 / 136卷 / 02期

关键词：

DNA methylation; EPIC array; Tumor classification; Copy-number variation; NERVOUS-SYSTEM; INTRAOCULAR MEDULLOEPITHELIOMAS; MOLECULAR CLASSIFICATION; MUTATIONS; GLIOBLASTOMA; SUBGROUPS; ENTITIES; GLIOMA; MEDULLOBLASTOMA; CRANIOPHARYNGIOMAS;

D O I：

10.1007/s00401-018-1879-y

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Recently, we described a machine learning approach for classification of central nervous system tumors based on the analysis of genome-wide DNA methylation patterns [6]. Here, we report on DNA methylation-based central nervous system (CNS) tumor diagnostics conducted in our institution between the years 2015 and 2018. In this period, more than 1000 tumors from the neurosurgical departments in Heidelberg and Mannheim and more than 1000 tumors referred from external institutions were subjected to DNA methylation analysis for diagnostic purposes. We describe our current approach to the integrated diagnosis of CNS tumors with a focus on constellations with conflicts between morphological and molecular genetic findings. We further describe the benefit of integrating DNA copy-number alterations into diagnostic considerations and provide a catalog of copy-number changes for individual DNA methylation classes. We also point to several pitfalls accompanying the diagnostic implementation of DNA methylation profiling and give practical suggestions for recurring diagnostic scenarios.

引用

页码：181 / 210

页数：30

共 56 条

[1] Sensitivity Analysis of the MGMT-STP27 Model and Impact of Genetic and Epigenetic Context to Predict the MGMT Methylation Status in Gliomas and Other Tumors [J].

Bady, Pierre ;

Delorenzi, Mauro ;

Hegi, Monika E. .

JOURNAL OF MOLECULAR DIAGNOSTICS, 2016, 18 (03) :350-361

[2] MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status [J].

Bady, Pierre ;

Sciuscio, Davide ;

Diserens, Annie-Claire ;

Bloch, Jocelyne ;

van den Bent, Martin J. ;

Marosi, Christine ;

Dietrich, Pierre-Yves ;

Weller, Michael ;

Mariani, Luigi ;

Heppner, Frank L. ;

Mcdonald, David R. ;

Lacombe, Denis ;

Stupp, Roger ;

Delorenzi, Mauro ;

Hegi, Monika E. .

ACTA NEUROPATHOLOGICA, 2012, 124 (04) :547-560

[3] Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas [J].

Brastianos, Priscilla K. ;

Taylor-Weiner, Amaro ;

Manley, Peter E. ;

Jones, Robert T. ;

Dias-Santagata, Dora ;

Thorner, Aaron R. ;

Lawrence, Michael S. ;

Rodriguez, Fausto J. ;

Bernardo, Lindsay A. ;

Schubert, Laura ;

Sunkavalli, Ashwini ;

Shillingford, Nick ;

Calicchio, Monica L. ;

Lidov, Hart G. W. ;

Taha, Hala ;

Martinez-Lage, Maria ;

Santi, Mariarita ;

Storm, Phillip B. ;

Lee, John Y. K. ;

Palmer, James N. ;

Adappa, Nithin D. ;

Scott, R. Michael ;

Dunn, Ian F. ;

Laws, Edward R., Jr. ;

Stewart, Chip ;

Ligon, Keith L. ;

Hoang, Mai P. ;

Van Hummelen, Paul ;

Hahn, William C. ;

Louis, David N. ;

Resnick, Adam C. ;

Kieran, Mark W. ;

Getz, Gad ;

Santagata, Sandro .

NATURE GENETICS, 2014, 46 (02) :161-U100

[4] Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas [J].

Brat, Daniel J. ;

Verhaak, Roel G. W. ;

Al-dape, Kenneth D. ;

Yung, W. K. Alfred ;

Salama, Sofie R. ;

Cooper, Lee A. D. ;

Rheinbay, Esther ;

Miller, C. Ryan ;

Vitucci, Mark ;

Morozova, Olena ;

Robertson, A. Gordon ;

Noushmehr, Houtan ;

Laird, Peter W. ;

Cherniack, Andrew D. ;

Akbani, Rehan ;

Huse, Jason T. ;

Ciriello, Giovanni ;

Poisson, Laila M. ;

Barnholtz-Sloan, Jill S. ;

Berger, Mitchel S. ;

Brennan, Cameron ;

Colen, Rivka R. ;

Colman, Howard ;

Flanders, Adam E. ;

Giannini, Caterina ;

Grifford, Mia ;

Iavarone, Antonio ;

Jain, Rajan ;

Joseph, Isaac ;

Kim, Jaegil ;

Kasaian, Katayoon ;

Mikkelsen, Tom ;

Murray, Bradley A. ;

O'Neill, Brian Patrick ;

Pachter, Lior ;

Parsons, Donald W. ;

Sougnez, Carrie ;

Sulman, Erik P. ;

Vandenberg, Scott R. ;

Van Meir, Erwin G. ;

von Deimling, Andreas ;

Zhang, Hailei ;

Crain, Daniel ;

Lau, Kevin ;

Mallery, David ;

Morris, Scott ;

Paulauskis, Joseph ;

Penny, Robert ;

Shelton, Troy ;

Sherman, Mark .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (26) :2481-2498

[5] DNA methylation-based reclassification of olfactory neuroblastoma [J].

Capper, David ;

Engel, Nils W. ;

Stichel, Damian ;

Lechner, Matt ;

Gloess, Stefanie ;

Schmid, Simone ;

Koelsche, Christian ;

Schrimpf, Daniel ;

Niesen, Judith ;

Wefers, Annika K. ;

Jones, David T. W. ;

Sill, Martin ;

Weigert, Oliver ;

Ligon, Keith L. ;

Olar, Adriana ;

Koch, Arend ;

Forster, Martin ;

Moran, Sebastian ;

Tirado, Oscar M. ;

Sainz-Jaspeado, Miguel ;

Mora, Jaume ;

Esteller, Manel ;

Alonso, Javier ;

Garcia del Muro, Xavier ;

Paulus, Werner ;

Felsberg, Joerg ;

Reifenberger, Guido ;

Glatzel, Markus ;

Frank, Stephan ;

Monoranu, Camelia M. ;

Lund, Valerie J. ;

von Deimling, Andreas ;

Pfister, Stefan ;

Buslei, Rolf ;

Ribbat-Idel, Julika ;

Perner, Sven ;

Gudziol, Volker ;

Meinhardt, Matthias ;

Schueller, Ulrich .

ACTA NEUROPATHOLOGICA, 2018, 136 (02) :255-271

[6] DNA methylation-based classification of central nervous system tumours [J].

Capper, David ;

Jones, David T. W. ;

Sill, Martin ;

Hovestadt, Volker ;

Schrimpf, Daniel ;

Sturm, Dominik ;

Koelsche, Christian ;

Sahm, Felix ;

Chavez, Lukas ;

Reuss, David E. ;

Kratz, Annekathrin ;

Wefers, Annika K. ;

Huang, Kristin ;

Pajtler, Kristian W. ;

Schweizer, Leonille ;

Stichel, Damian ;

Olar, Adriana ;

Engel, Nils W. ;

Lindenberg, Kerstin ;

Harter, Patrick N. ;

Braczynski, Anne K. ;

Plate, Karl H. ;

Dohmen, Hildegard ;

Garvalov, Boyan K. ;

Coras, Roland ;

Hoelsken, Annett ;

Hewer, Ekkehard ;

Bewerunge-Hudler, Melanie ;

Schick, Matthias ;

Fischer, Roger ;

Beschorner, Rudi ;

Schittenhelm, Jens ;

Staszewski, Ori ;

Wani, Khalida ;

Varlet, Pascale ;

Pages, Melanie ;

Temming, Petra ;

Lohmann, Dietmar ;

Selt, Florian ;

Witt, Hendrik ;

Milde, Till ;

Witt, Olaf ;

Aronica, Eleonora ;

Giangaspero, Felice ;

Rushing, Elisabeth ;

Scheurlen, Wolfram ;

Geisenberger, Christoph ;

Rodriguez, Fausto J. ;

Becker, Albert ;

Preusser, Matthias .

NATURE, 2018, 555 (7697) :469-+

[7] Trilateral retinoblastoma: a systematic review and meta-analysis [J].

de Jong, Marcus C. ;

Kors, Wijnanda A. ;

de Graaf, Pim ;

Castelijns, Jonas A. ;

Kivela, Tero ;

Moll, Annette C. .

LANCET ONCOLOGY, 2014, 15 (10) :1157-1167

[8] Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features [J].

Deng, Maximilian Y. ;

Sill, Martin ;

Chiang, Jason ;

Schittenhelm, Jens ;

Ebinger, Martin ;

Schuhmann, Martin U. ;

Monoranu, Camelia-Maria ;

Milde, Till ;

Wittmann, Andrea ;

Hartmann, Christian ;

Sommer, Clemens ;

Paulus, Werner ;

Gaertner, Jutta ;

Brueck, Wolfgang ;

Ruediger, Thomas ;

Leipold, Alfred ;

Jaunmuktane, Zane ;

Brandner, Sebastian ;

Giangaspero, Felice ;

Nozza, Paolo ;

Mora, Jaume ;

Morales la Madrid, Andres ;

Cruz Martinez, Ofelia ;

Hansford, Jordan R. ;

Pietsch, Torsten ;

Tietze, Anna ;

Hernaiz-Driever, Pablo ;

Stoler, Iris ;

Capper, David ;

Korshunov, Andrey ;

Ellison, David W. ;

von Deimling, Andreas ;

Pfister, Stefan M. ;

Sahm, Felix ;

Jones, David T. W. .

ACTA NEUROPATHOLOGICA, 2018, 136 (02) :239-253

[9] Concurrent IDH1 and SMARCB1 Mutations in Pediatric Medulloblastoma: A Case Report [J].

El-Ayadi, Moatasem ;

Egervari, Kristof ;

Merkler, Doron ;

Mckee, Thomas A. ;

Gumy-Pause, Fabienne ;

Stichel, Damian ;

Capper, David ;

Pietsch, Torsten ;

Ansari, Marc ;

von Bueren, Andre O. .

FRONTIERS IN NEUROLOGY, 2018, 9

[10] A DNA methylation fingerprint of 1628 human samples [J].

Fernandez, Agustin F. ;

Assenov, Yassen ;

Ignacio Martin-Subero, Jose ;

Balint, Balazs ;

Siebert, Reiner ;

Taniguchi, Hiroaki ;

Yamamoto, Hiroyuki ;

Hidalgo, Manuel ;

Tan, Aik-Choon ;

Galm, Oliver ;

Ferrer, Isidre ;

Sanchez-Cespedes, Montse ;

Villanueva, Alberto ;

Carmona, Javier ;

Sanchez-Mut, Jose V. ;

Berdasco, Maria ;

Moreno, Victor ;

Capella, Gabriel ;

Monk, David ;

Ballestar, Esteban ;

Ropero, Santiago ;

Martinez, Ramon ;

Sanchez-Carbayo, Marta ;

Prosper, Felipe ;

Agirre, Xabier ;

Fraga, Mario F. ;

Grana, Osvaldo ;

Perez-Jurado, Luis ;

Mora, Jaume ;

Puig, Susana ;

Prat, Jaime ;

Badimon, Lina ;

Puca, Annibale A. ;

Meltzer, Stephen J. ;

Lengauer, Thomas ;

Bridgewater, John ;

Bock, Christoph ;

Esteller, Manel .

GENOME RESEARCH, 2012, 22 (02) :407-419

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