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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

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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 NEUROPATHOL, Vol. 138, No. 3, 09.2019, p. 497-504.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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 NEUROPATHOL, vol. 138, no. 3, pp. 497-504. https://doi.org/10.1007/s00401-019-02038-4

APA

Sievers, P., Appay, R., Schrimpf, D., Stichel, D., Reuss, D. E., Wefers, A. K., Reinhardt, A., Coras, R., Ruf, V. C., Schmid, S., de Stricker, K., Boldt, H. B., Kristensen, B. W., Petersen, J. K., Ulhøi, B. P., Gardberg, M., Aronica, E., Hasselblatt, M., Brück, W., ... Jones, D. T. W. (2019). Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. ACTA NEUROPATHOL, 138(3), 497-504. https://doi.org/10.1007/s00401-019-02038-4

Vancouver

Sievers P, Appay R, Schrimpf D, Stichel D, Reuss DE, Wefers AK et al. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. ACTA NEUROPATHOL. 2019 Sep;138(3):497-504. https://doi.org/10.1007/s00401-019-02038-4

Bibtex

@article{948f3b8958cf4233816bc4d5d2e252c8,
title = "Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1",
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.",
keywords = "Adolescent, Adult, Aged, Brain Neoplasms/genetics, Child, Class I Phosphatidylinositol 3-Kinases/genetics, DNA Methylation, Female, Glioma/genetics, Humans, Male, Middle Aged, Mutation, Neurofibromin 1/genetics, Neurons/pathology, Receptor, Fibroblast Growth Factor, Type 1/genetics, Retrospective Studies, Young Adult",
author = "Philipp Sievers and Romain Appay and Daniel Schrimpf and Damian Stichel and Reuss, {David E} and Wefers, {Annika K} and Annekathrin Reinhardt and Roland Coras and Ruf, {Viktoria C} and Simone Schmid and {de Stricker}, Karin and Boldt, {Henning B} and Kristensen, {Bjarne Winther} and Petersen, {Jeanette Krogh} and Ulh{\o}i, {Benedicte P} and Maria Gardberg and Eleonora Aronica and Martin Hasselblatt and Wolfgang Br{\"u}ck and Franck Bielle and Karima Mokhtari and Beno{\^i}t Lhermitte and Wolfgang Wick and Christel Herold-Mende and Daniel H{\"a}nggi and Sebastian Brandner and Felice Giangaspero and David Capper and Elisabeth Rushing and Pieter Wesseling and Pfister, {Stefan M} and Dominique Figarella-Branger and {von Deimling}, Andreas and Felix Sahm and Jones, {David T W}",
year = "2019",
month = sep,
doi = "10.1007/s00401-019-02038-4",
language = "English",
volume = "138",
pages = "497--504",
journal = "ACTA NEUROPATHOL",
issn = "0001-6322",
publisher = "Springer",
number = "3",

}

RIS

TY - JOUR

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 - 2019/9

Y1 - 2019/9

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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Brain Neoplasms/genetics

KW - Child

KW - Class I Phosphatidylinositol 3-Kinases/genetics

KW - DNA Methylation

KW - Female

KW - Glioma/genetics

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Neurofibromin 1/genetics

KW - Neurons/pathology

KW - Receptor, Fibroblast Growth Factor, Type 1/genetics

KW - Retrospective Studies

KW - Young Adult

U2 - 10.1007/s00401-019-02038-4

DO - 10.1007/s00401-019-02038-4

M3 - SCORING: Journal article

C2 - 31250151

VL - 138

SP - 497

EP - 504

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 3

ER -