Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1

Philipp Sievers, Romain Appay, Daniel Schrimpf, Damian Stichel, David E Reuss, Annika K Wefers, Annekathrin Reinhardt, Roland Coras, Viktoria C Ruf, Simone Schmid, Karin de Stricker, Henning B Boldt, Bjarne Winther Kristensen, Jeanette Krogh Petersen, Benedicte P Ulhøi, Maria Gardberg, Eleonora Aronica, Martin Hasselblatt, Wolfgang Brück, Franck Bielle & 15 others Karima Mokhtari, Benoît Lhermitte, Wolfgang Wick, Christel Herold-Mende, Daniel Hänggi, Sebastian Brandner, Felice Giangaspero, David Capper, Elisabeth Rushing, Pieter Wesseling, Stefan M Pfister, Dominique Figarella-Branger, Andreas von Deimling, Felix Sahm, David T W Jones

Research output: Contribution to journalArticle

Abstract

Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease.

Original languageEnglish
JournalActa Neuropathologica
DOIs
Publication statusE-pub ahead of print - Jun 27 2019

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DNA Methylation
Mutation
Neoplasms
MAP Kinase Kinase 3
1-Phosphatidylinositol 4-Kinase
Genome
Rosette Formation
Tumor Suppressor Genes
Epigenomics
Brain Neoplasms
Glioma
Young Adult

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Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. / Sievers, Philipp; Appay, Romain; Schrimpf, Daniel; Stichel, Damian; Reuss, David E; Wefers, Annika K; Reinhardt, Annekathrin; Coras, Roland; Ruf, Viktoria C; Schmid, Simone; de Stricker, Karin; Boldt, Henning B; Kristensen, Bjarne Winther; Petersen, Jeanette Krogh; Ulhøi, Benedicte P; Gardberg, Maria; Aronica, Eleonora; Hasselblatt, Martin; Brück, Wolfgang; Bielle, Franck; Mokhtari, Karima; Lhermitte, Benoît; Wick, Wolfgang; Herold-Mende, Christel; Hänggi, Daniel; Brandner, Sebastian; Giangaspero, Felice; Capper, David; Rushing, Elisabeth; Wesseling, Pieter; Pfister, Stefan M; Figarella-Branger, Dominique; von Deimling, Andreas; Sahm, Felix; Jones, David T W.

In: Acta Neuropathologica, 27.06.2019.

Research output: Contribution to journalArticle

Sievers, P, Appay, R, Schrimpf, D, Stichel, D, Reuss, DE, Wefers, AK, Reinhardt, A, Coras, R, Ruf, VC, Schmid, S, de Stricker, K, Boldt, HB, Kristensen, BW, Petersen, JK, Ulhøi, BP, Gardberg, M, Aronica, E, Hasselblatt, M, Brück, W, Bielle, F, Mokhtari, K, Lhermitte, B, Wick, W, Herold-Mende, C, Hänggi, D, Brandner, S, Giangaspero, F, Capper, D, Rushing, E, Wesseling, P, Pfister, SM, Figarella-Branger, D, von Deimling, A, Sahm, F & Jones, DTW 2019, 'Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1', Acta Neuropathologica. https://doi.org/10.1007/s00401-019-02038-4
Sievers, Philipp ; Appay, Romain ; Schrimpf, Daniel ; Stichel, Damian ; Reuss, David E ; Wefers, Annika K ; Reinhardt, Annekathrin ; Coras, Roland ; Ruf, Viktoria C ; Schmid, Simone ; de Stricker, Karin ; Boldt, Henning B ; Kristensen, Bjarne Winther ; Petersen, Jeanette Krogh ; Ulhøi, Benedicte P ; Gardberg, Maria ; Aronica, Eleonora ; Hasselblatt, Martin ; Brück, Wolfgang ; Bielle, Franck ; Mokhtari, Karima ; Lhermitte, Benoît ; Wick, Wolfgang ; Herold-Mende, Christel ; Hänggi, Daniel ; Brandner, Sebastian ; Giangaspero, Felice ; Capper, David ; Rushing, Elisabeth ; Wesseling, Pieter ; Pfister, Stefan M ; Figarella-Branger, Dominique ; von Deimling, Andreas ; Sahm, Felix ; Jones, David T W. / Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. In: Acta Neuropathologica. 2019.
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abstract = "Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63{\%}). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33{\%}). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease.",
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T1 - Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1

AU - Sievers, Philipp

AU - Appay, Romain

AU - Schrimpf, Daniel

AU - Stichel, Damian

AU - Reuss, David E

AU - Wefers, Annika K

AU - Reinhardt, Annekathrin

AU - Coras, Roland

AU - Ruf, Viktoria C

AU - Schmid, Simone

AU - de Stricker, Karin

AU - Boldt, Henning B

AU - Kristensen, Bjarne Winther

AU - Petersen, Jeanette Krogh

AU - Ulhøi, Benedicte P

AU - Gardberg, Maria

AU - Aronica, Eleonora

AU - Hasselblatt, Martin

AU - Brück, Wolfgang

AU - Bielle, Franck

AU - Mokhtari, Karima

AU - Lhermitte, Benoît

AU - Wick, Wolfgang

AU - Herold-Mende, Christel

AU - Hänggi, Daniel

AU - Brandner, Sebastian

AU - Giangaspero, Felice

AU - Capper, David

AU - Rushing, Elisabeth

AU - Wesseling, Pieter

AU - Pfister, Stefan M

AU - Figarella-Branger, Dominique

AU - von Deimling, Andreas

AU - Sahm, Felix

AU - Jones, David T W

PY - 2019/6/27

Y1 - 2019/6/27

N2 - Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease.

AB - Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease.

U2 - 10.1007/s00401-019-02038-4

DO - 10.1007/s00401-019-02038-4

M3 - Article

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

ER -