Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Dominik Sturm; David Capper; Felipe Andreiuolo; Marco Gessi; Christian Kölsche; Annekathrin Reinhardt; Philipp Sievers; Annika K. Wefers; Azadeh Ebrahimi; Abigail K. Suwala; Gerrit H. Gielen; Martin Sill; Daniel Schrimpf; Damian Stichel; Volker Hovestadt; Bjarne Daenekas; Agata Rode; Stefan Hamelmann; Christopher Previti; Natalie Jäger; Ivo Buchhalter; Mirjam Blattner-Johnson; Barbara C. Jones; Monika Warmuth-Metz; Brigitte Bison; Kerstin Grund; Christian Sutter; Steffen Hirsch; Nicola Dikow; Martin Hasselblatt; Ulrich Schüller; Nicolas U. Gerber; Christine L. White; Molly K. Buntine; Kathryn Kinross; Elizabeth M. Algar; Jordan R. Hansford; Nicholas G. Gottardo; Pablo Hernáiz Driever; Astrid Gnekow; Olaf Witt; Hermann L. Müller; Gabriele Calaminus; Gudrun Fleischhack; Uwe Kordes; Martin Mynarek; Stefan Rutkowski; Michael C. Frühwald; Christof M. Kramm; Andreas von Deimling; Torsten Pietsch; Felix Sahm; Stefan M. Pfister; David T.W. Jones

doi:10.1038/s41591-023-02255-1

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Dominik Sturm, David Capper, Felipe Andreiuolo, Marco Gessi, Christian Kölsche, Annekathrin Reinhardt, Philipp Sievers, Annika K. Wefers, Azadeh Ebrahimi, Abigail K. Suwala, Gerrit H. Gielen, Martin Sill, Daniel Schrimpf, Damian Stichel, Volker Hovestadt, Bjarne Daenekas, Agata Rode, Stefan Hamelmann, Christopher Previti, Natalie JägerIvo Buchhalter, Mirjam Blattner-Johnson, Barbara C. Jones, Monika Warmuth-Metz, Brigitte Bison, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Martin Hasselblatt, Ulrich Schüller, Nicolas U. Gerber, Christine L. White, Molly K. Buntine, Kathryn Kinross, Elizabeth M. Algar, Jordan R. Hansford, Nicholas G. Gottardo, Pablo Hernáiz Driever, Astrid Gnekow, Olaf Witt, Hermann L. Müller, Gabriele Calaminus, Gudrun Fleischhack, Uwe Kordes, Martin Mynarek, Stefan Rutkowski, Michael C. Frühwald, Christof M. Kramm, Andreas von Deimling, Torsten Pietsch, Felix Sahm, Stefan M. Pfister, David T.W. Jones

Paediatrics

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79 Citations (Web of Science)

Abstract

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

Original language	English
Pages (from-to)	917-926
Number of pages	10
Journal	Nature Medicine
Volume	29
Issue number	4
DOIs	https://doi.org/10.1038/s41591-023-02255-1
Publication status	Published - Apr 2023

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Sturm, D., Capper, D., Andreiuolo, F., Gessi, M., Kölsche, C., Reinhardt, A., Sievers, P., Wefers, A. K., Ebrahimi, A., Suwala, A. K., Gielen, G. H., Sill, M., Schrimpf, D., Stichel, D., Hovestadt, V., Daenekas, B., Rode, A., Hamelmann, S., Previti, C., ... Jones, D. T. W. (2023). Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology. Nature Medicine, 29(4), 917-926. https://doi.org/10.1038/s41591-023-02255-1

@article{351a2980c3154bdd977344d225f0b5d8,

title = "Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology",

abstract = "The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.",

author = "Dominik Sturm and David Capper and Felipe Andreiuolo and Marco Gessi and Christian K{\"o}lsche and Annekathrin Reinhardt and Philipp Sievers and Wefers, {Annika K.} and Azadeh Ebrahimi and Suwala, {Abigail K.} and Gielen, {Gerrit H.} and Martin Sill and Daniel Schrimpf and Damian Stichel and Volker Hovestadt and Bjarne Daenekas and Agata Rode and Stefan Hamelmann and Christopher Previti and Natalie J{\"a}ger and Ivo Buchhalter and Mirjam Blattner-Johnson and Jones, {Barbara C.} and Monika Warmuth-Metz and Brigitte Bison and Kerstin Grund and Christian Sutter and Steffen Hirsch and Nicola Dikow and Martin Hasselblatt and Ulrich Sch{\"u}ller and Gerber, {Nicolas U.} and White, {Christine L.} and Buntine, {Molly K.} and Kathryn Kinross and Algar, {Elizabeth M.} and Hansford, {Jordan R.} and Gottardo, {Nicholas G.} and {Hern{\'a}iz Driever}, Pablo and Astrid Gnekow and Olaf Witt and M{\"u}ller, {Hermann L.} and Gabriele Calaminus and Gudrun Fleischhack and Uwe Kordes and Martin Mynarek and Stefan Rutkowski and Fr{\"u}hwald, {Michael C.} and Kramm, {Christof M.} and {von Deimling}, Andreas and Torsten Pietsch and Felix Sahm and Pfister, {Stefan M.} and Jones, {David T.W.}",

year = "2023",

month = apr,

doi = "10.1038/s41591-023-02255-1",

language = "English",

volume = "29",

pages = "917--926",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "4",

}

Sturm, D, Capper, D, Andreiuolo, F, Gessi, M, Kölsche, C, Reinhardt, A, Sievers, P, Wefers, AK, Ebrahimi, A, Suwala, AK, Gielen, GH, Sill, M, Schrimpf, D, Stichel, D, Hovestadt, V, Daenekas, B, Rode, A, Hamelmann, S, Previti, C, Jäger, N, Buchhalter, I, Blattner-Johnson, M, Jones, BC, Warmuth-Metz, M, Bison, B, Grund, K, Sutter, C, Hirsch, S, Dikow, N, Hasselblatt, M, Schüller, U, Gerber, NU, White, CL, Buntine, MK, Kinross, K, Algar, EM, Hansford, JR, Gottardo, NG, Hernáiz Driever, P, Gnekow, A, Witt, O, Müller, HL, Calaminus, G, Fleischhack, G, Kordes, U, Mynarek, M, Rutkowski, S, Frühwald, MC, Kramm, CM, von Deimling, A, Pietsch, T, Sahm, F, Pfister, SM & Jones, DTW 2023, 'Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology', Nature Medicine, vol. 29, no. 4, pp. 917-926. https://doi.org/10.1038/s41591-023-02255-1

TY - JOUR

T1 - Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

AU - Sturm, Dominik

AU - Capper, David

AU - Andreiuolo, Felipe

AU - Gessi, Marco

AU - Kölsche, Christian

AU - Reinhardt, Annekathrin

AU - Sievers, Philipp

AU - Wefers, Annika K.

AU - Ebrahimi, Azadeh

AU - Suwala, Abigail K.

AU - Gielen, Gerrit H.

AU - Sill, Martin

AU - Schrimpf, Daniel

AU - Stichel, Damian

AU - Hovestadt, Volker

AU - Daenekas, Bjarne

AU - Rode, Agata

AU - Hamelmann, Stefan

AU - Previti, Christopher

AU - Jäger, Natalie

AU - Buchhalter, Ivo

AU - Blattner-Johnson, Mirjam

AU - Jones, Barbara C.

AU - Warmuth-Metz, Monika

AU - Bison, Brigitte

AU - Grund, Kerstin

AU - Sutter, Christian

AU - Hirsch, Steffen

AU - Dikow, Nicola

AU - Hasselblatt, Martin

AU - Schüller, Ulrich

AU - Gerber, Nicolas U.

AU - White, Christine L.

AU - Buntine, Molly K.

AU - Kinross, Kathryn

AU - Algar, Elizabeth M.

AU - Hansford, Jordan R.

AU - Gottardo, Nicholas G.

AU - Hernáiz Driever, Pablo

AU - Gnekow, Astrid

AU - Witt, Olaf

AU - Müller, Hermann L.

AU - Calaminus, Gabriele

AU - Fleischhack, Gudrun

AU - Kordes, Uwe

AU - Mynarek, Martin

AU - Rutkowski, Stefan

AU - Frühwald, Michael C.

AU - Kramm, Christof M.

AU - von Deimling, Andreas

AU - Pietsch, Torsten

AU - Sahm, Felix

AU - Pfister, Stefan M.

AU - Jones, David T.W.

PY - 2023/4

Y1 - 2023/4

N2 - The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

AB - The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

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U2 - 10.1038/s41591-023-02255-1

DO - 10.1038/s41591-023-02255-1

M3 - Article

C2 - 36928815

AN - SCOPUS:85150029805

SN - 1078-8956

VL - 29

SP - 917

EP - 926

JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Abstract

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