Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities

Sejin Oh; Jeonghun Yeom; Hee Jin Cho; Ju Hwa Kim; Seon Jin Yoon; Hakhyun Kim; Jason K. Sa; Shinyeong Ju; Hwanho Lee; Myung Joon Oh; Wonyeop Lee; Yumi Kwon; Honglan Li; Seunghyuk Choi; Jang Hee Han; Jong Hee Chang; Eunsuk Choi; Jayeon Kim; Nam Gu Her; Se Hoon Kim; Seok Gu Kang; Eunok Paek; Do Hyun Nam; Cheolju Lee; Hyun Seok Kim

doi:10.1038/s41467-020-17139-y

Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities

Sejin Oh, Jeonghun Yeom, Hee Jin Cho, Ju Hwa Kim, Seon Jin Yoon, Hakhyun Kim, Jason K. Sa, Shinyeong Ju, Hwanho Lee, Myung Joon Oh, Wonyeop Lee, Yumi Kwon, Honglan Li, Seunghyuk Choi, Jang Hee Han, Jong Hee Chang, Eunsuk Choi, Jayeon Kim, Nam Gu Her, Se Hoon KimSeok Gu Kang, Eunok Paek, Do Hyun Nam, Cheolju Lee, Hyun Seok Kim

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Abstract

The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.

Original language	English
Article number	3288
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17139-y
Publication status	Published - 2020 Dec 1

Bibliographical note

Funding Information:
We thank Sang Bum Kim and Daniel H. Kim for critical reading of the manuscript and their helpful discussions. The biospecimens for this study were provided by the Samsung Medical Center BioBank. This study was supported by grants from the National Research Foundation of Korea (2020R1A2C3007792, 2017M3A9F9030559, 2017M3C9A5031595, 2012M3A9B9036676, 2017R1E1A1A01077412, 2019R1A2C3004155, and 2019H1A2A1075632) and the Korea Health Technology R&D project through the Korea Health Industry Development Institute (HI14C1324, HI14C3418).

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

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Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-020-17139-y

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Oh, S., Yeom, J., Cho, H. J., Kim, J. H., Yoon, S. J., Kim, H., Sa, J. K., Ju, S., Lee, H., Oh, M. J., Lee, W., Kwon, Y., Li, H., Choi, S., Han, J. H., Chang, J. H., Choi, E., Kim, J., Her, N. G., ... Kim, H. S. (2020). Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities. Nature communications, 11(1), [3288]. https://doi.org/10.1038/s41467-020-17139-y

@article{792fb51c89b24fd18294e85baa94092a,

title = "Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities",

abstract = "The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.",

author = "Sejin Oh and Jeonghun Yeom and Cho, {Hee Jin} and Kim, {Ju Hwa} and Yoon, {Seon Jin} and Hakhyun Kim and Sa, {Jason K.} and Shinyeong Ju and Hwanho Lee and Oh, {Myung Joon} and Wonyeop Lee and Yumi Kwon and Honglan Li and Seunghyuk Choi and Han, {Jang Hee} and Chang, {Jong Hee} and Eunsuk Choi and Jayeon Kim and Her, {Nam Gu} and Kim, {Se Hoon} and Kang, {Seok Gu} and Eunok Paek and Nam, {Do Hyun} and Cheolju Lee and Kim, {Hyun Seok}",

note = "Funding Information: We thank Sang Bum Kim and Daniel H. Kim for critical reading of the manuscript and their helpful discussions. The biospecimens for this study were provided by the Samsung Medical Center BioBank. This study was supported by grants from the National Research Foundation of Korea (2020R1A2C3007792, 2017M3A9F9030559, 2017M3C9A5031595, 2012M3A9B9036676, 2017R1E1A1A01077412, 2019R1A2C3004155, and 2019H1A2A1075632) and the Korea Health Technology R&D project through the Korea Health Industry Development Institute (HI14C1324, HI14C3418). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-17139-y",

language = "English",

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journal = "Nature Communications",

issn = "2041-1723",

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Oh, S, Yeom, J, Cho, HJ, Kim, JH, Yoon, SJ, Kim, H, Sa, JK, Ju, S, Lee, H, Oh, MJ, Lee, W, Kwon, Y, Li, H, Choi, S, Han, JH, Chang, JH, Choi, E, Kim, J, Her, NG, Kim, SH , Kang, SG, Paek, E, Nam, DH, Lee, C & Kim, HS 2020, 'Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities', Nature communications, vol. 11, no. 1, 3288. https://doi.org/10.1038/s41467-020-17139-y

TY - JOUR

T1 - Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities

AU - Oh, Sejin

AU - Yeom, Jeonghun

AU - Cho, Hee Jin

AU - Kim, Ju Hwa

AU - Yoon, Seon Jin

AU - Kim, Hakhyun

AU - Sa, Jason K.

AU - Ju, Shinyeong

AU - Lee, Hwanho

AU - Oh, Myung Joon

AU - Lee, Wonyeop

AU - Kwon, Yumi

AU - Li, Honglan

AU - Choi, Seunghyuk

AU - Han, Jang Hee

AU - Chang, Jong Hee

AU - Choi, Eunsuk

AU - Kim, Jayeon

AU - Her, Nam Gu

AU - Kim, Se Hoon

AU - Kang, Seok Gu

AU - Paek, Eunok

AU - Nam, Do Hyun

AU - Lee, Cheolju

AU - Kim, Hyun Seok

N1 - Funding Information: We thank Sang Bum Kim and Daniel H. Kim for critical reading of the manuscript and their helpful discussions. The biospecimens for this study were provided by the Samsung Medical Center BioBank. This study was supported by grants from the National Research Foundation of Korea (2020R1A2C3007792, 2017M3A9F9030559, 2017M3C9A5031595, 2012M3A9B9036676, 2017R1E1A1A01077412, 2019R1A2C3004155, and 2019H1A2A1075632) and the Korea Health Technology R&D project through the Korea Health Industry Development Institute (HI14C1324, HI14C3418). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.

AB - The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.

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Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities

Abstract

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