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Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

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Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. / Rivera, Barbara; Gayden, Tenzin; Carrot-Zhang, Jian; Nadaf, Javad; Boshari, Talia; Faury, Damien; Zeinieh, Michele; Blanc, Romeo; Burk, David L; Fahiminiya, Somayyeh; Bareke, Eric; Schüller, Ulrich; Monoranu, Camelia M; Sträter, Ronald; Kerl, Kornelius; Niederstadt, Thomas; Kurlemann, Gerhard; Ellezam, Benjamin; Michalak, Zuzanna; Thom, Maria; Lockhart, Paul J; Leventer, Richard J; Ohm, Milou; MacGregor, Duncan; Jones, David E; Karamchandani, Jason; Greenwood, Celia M T; Berghuis, Albert M; Bens, Susanne; Siebert, Reiner; Zakrzewska, Magdalena; Liberski, Pawel P; Zakrzewski, Krzysztof; Sisodiya, Sanjay M; Paulus, Werner; Albrecht, Steffen; Hasselblatt, Martin; Jabado, Nada; Foulkes, William D; Majewski, Jacek.

in: ACTA NEUROPATHOL, Jahrgang 131, Nr. 6, 06.2016, S. 847-63.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Rivera, B, Gayden, T, Carrot-Zhang, J, Nadaf, J, Boshari, T, Faury, D, Zeinieh, M, Blanc, R, Burk, DL, Fahiminiya, S, Bareke, E, Schüller, U, Monoranu, CM, Sträter, R, Kerl, K, Niederstadt, T, Kurlemann, G, Ellezam, B, Michalak, Z, Thom, M, Lockhart, PJ, Leventer, RJ, Ohm, M, MacGregor, D, Jones, DE, Karamchandani, J, Greenwood, CMT, Berghuis, AM, Bens, S, Siebert, R, Zakrzewska, M, Liberski, PP, Zakrzewski, K, Sisodiya, SM, Paulus, W, Albrecht, S, Hasselblatt, M, Jabado, N, Foulkes, WD & Majewski, J 2016, 'Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors', ACTA NEUROPATHOL, Jg. 131, Nr. 6, S. 847-63. https://doi.org/10.1007/s00401-016-1549-x

APA

Rivera, B., Gayden, T., Carrot-Zhang, J., Nadaf, J., Boshari, T., Faury, D., Zeinieh, M., Blanc, R., Burk, D. L., Fahiminiya, S., Bareke, E., Schüller, U., Monoranu, C. M., Sträter, R., Kerl, K., Niederstadt, T., Kurlemann, G., Ellezam, B., Michalak, Z., ... Majewski, J. (2016). Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. ACTA NEUROPATHOL, 131(6), 847-63. https://doi.org/10.1007/s00401-016-1549-x

Vancouver

Rivera B, Gayden T, Carrot-Zhang J, Nadaf J, Boshari T, Faury D et al. Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. ACTA NEUROPATHOL. 2016 Jun;131(6):847-63. https://doi.org/10.1007/s00401-016-1549-x

Bibtex

@article{2a3872be010f4c37a8fd6d2b0335d152,
title = "Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors",
abstract = "Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.",
keywords = "Journal Article",
author = "Barbara Rivera and Tenzin Gayden and Jian Carrot-Zhang and Javad Nadaf and Talia Boshari and Damien Faury and Michele Zeinieh and Romeo Blanc and Burk, {David L} and Somayyeh Fahiminiya and Eric Bareke and Ulrich Sch{\"u}ller and Monoranu, {Camelia M} and Ronald Str{\"a}ter and Kornelius Kerl and Thomas Niederstadt and Gerhard Kurlemann and Benjamin Ellezam and Zuzanna Michalak and Maria Thom and Lockhart, {Paul J} and Leventer, {Richard J} and Milou Ohm and Duncan MacGregor and Jones, {David E} and Jason Karamchandani and Greenwood, {Celia M T} and Berghuis, {Albert M} and Susanne Bens and Reiner Siebert and Magdalena Zakrzewska and Liberski, {Pawel P} and Krzysztof Zakrzewski and Sisodiya, {Sanjay M} and Werner Paulus and Steffen Albrecht and Martin Hasselblatt and Nada Jabado and Foulkes, {William D} and Jacek Majewski",
year = "2016",
month = jun,
doi = "10.1007/s00401-016-1549-x",
language = "English",
volume = "131",
pages = "847--63",
journal = "ACTA NEUROPATHOL",
issn = "0001-6322",
publisher = "Springer",
number = "6",

}

RIS

TY - JOUR

T1 - Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

AU - Rivera, Barbara

AU - Gayden, Tenzin

AU - Carrot-Zhang, Jian

AU - Nadaf, Javad

AU - Boshari, Talia

AU - Faury, Damien

AU - Zeinieh, Michele

AU - Blanc, Romeo

AU - Burk, David L

AU - Fahiminiya, Somayyeh

AU - Bareke, Eric

AU - Schüller, Ulrich

AU - Monoranu, Camelia M

AU - Sträter, Ronald

AU - Kerl, Kornelius

AU - Niederstadt, Thomas

AU - Kurlemann, Gerhard

AU - Ellezam, Benjamin

AU - Michalak, Zuzanna

AU - Thom, Maria

AU - Lockhart, Paul J

AU - Leventer, Richard J

AU - Ohm, Milou

AU - MacGregor, Duncan

AU - Jones, David E

AU - Karamchandani, Jason

AU - Greenwood, Celia M T

AU - Berghuis, Albert M

AU - Bens, Susanne

AU - Siebert, Reiner

AU - Zakrzewska, Magdalena

AU - Liberski, Pawel P

AU - Zakrzewski, Krzysztof

AU - Sisodiya, Sanjay M

AU - Paulus, Werner

AU - Albrecht, Steffen

AU - Hasselblatt, Martin

AU - Jabado, Nada

AU - Foulkes, William D

AU - Majewski, Jacek

PY - 2016/6

Y1 - 2016/6

N2 - Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.

AB - Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.

KW - Journal Article

U2 - 10.1007/s00401-016-1549-x

DO - 10.1007/s00401-016-1549-x

M3 - SCORING: Journal article

C2 - 26920151

VL - 131

SP - 847

EP - 863

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 6

ER -