Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

Jinghui Zhang; Gang Wu; Claudia P. Miller; Ruth G. Tatevossian; James D. Dalton; Bo Tang; Wilda Orisme; Chandanamali Punchihewa; Matthew Parker; Ibrahim Qaddoumi; Fredrick A. Boop; Charles Lu; Cyriac Kandoth; Li Ding; Ryan Lee; Robert Huether; Xiang Chen; Erin Hedlund; Panduka Nagahawatte; Michael Rusch; Kristy Boggs; Jinjun Cheng; Jared Becksfort; Jing Ma; Guangchun Song; Yongjin Li; Lei Wei; Jianmin Wang; Sheila Shurtleff; John Easton; David Zhao; Robert S. Fulton; Lucinda L. Fulton; David J. Dooling; Bhavin Vadodaria; Heather L. Mulder; Chunlao Tang; Kerri Ochoa; Charles G. Mullighan; Amar Gajjar; Richard Kriwacki; Denise Sheer; Richard J. Gilbertson; Elaine R. Mardis; Richard K. Wilson; James R. Downing; Suzanne J. Baker; David W. Ellison

doi:10.1038/ng.2611

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

Jinghui Zhang, Gang Wu, Claudia P. Miller, Ruth G. Tatevossian, James D. Dalton, Bo Tang, Wilda Orisme, Chandanamali Punchihewa, Matthew Parker, Ibrahim Qaddoumi, Fredrick A. Boop, Charles Lu, Cyriac Kandoth, Li Ding, Ryan Lee, Robert Huether, Xiang Chen, Erin Hedlund, Panduka Nagahawatte, Michael RuschKristy Boggs, Jinjun Cheng, Jared Becksfort, Jing Ma, Guangchun Song, Yongjin Li, Lei Wei, Jianmin Wang, Sheila Shurtleff, John Easton, David Zhao, Robert S. Fulton, Lucinda L. Fulton, David J. Dooling, Bhavin Vadodaria, Heather L. Mulder, Chunlao Tang, Kerri Ochoa, Charles G. Mullighan, Amar Gajjar, Richard Kriwacki, Denise Sheer, Richard J. Gilbertson, Elaine R. Mardis, Richard K. Wilson, James R. Downing, Suzanne J. Baker, David W. Ellison

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Abstract

The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs.

Original language	English
Pages (from-to)	602-612
Number of pages	11
Journal	Nature Genetics
Volume	45
Issue number	6
DOIs	https://doi.org/10.1038/ng.2611
State	Published - Jun 2013

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Zhang, J., Wu, G., Miller, C. P., Tatevossian, R. G., Dalton, J. D., Tang, B., Orisme, W., Punchihewa, C., Parker, M., Qaddoumi, I., Boop, F. A., Lu, C., Kandoth, C., Ding, L., Lee, R., Huether, R., Chen, X., Hedlund, E., Nagahawatte, P., ... Ellison, D. W. (2013). Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nature Genetics, 45(6), 602-612. https://doi.org/10.1038/ng.2611

@article{6ccc6b0ce49444f28107319b92376c8c,

title = "Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas",

abstract = "The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs.",

author = "Jinghui Zhang and Gang Wu and Miller, {Claudia P.} and Tatevossian, {Ruth G.} and Dalton, {James D.} and Bo Tang and Wilda Orisme and Chandanamali Punchihewa and Matthew Parker and Ibrahim Qaddoumi and Boop, {Fredrick A.} and Charles Lu and Cyriac Kandoth and Li Ding and Ryan Lee and Robert Huether and Xiang Chen and Erin Hedlund and Panduka Nagahawatte and Michael Rusch and Kristy Boggs and Jinjun Cheng and Jared Becksfort and Jing Ma and Guangchun Song and Yongjin Li and Lei Wei and Jianmin Wang and Sheila Shurtleff and John Easton and David Zhao and Fulton, {Robert S.} and Fulton, {Lucinda L.} and Dooling, {David J.} and Bhavin Vadodaria and Mulder, {Heather L.} and Chunlao Tang and Kerri Ochoa and Mullighan, {Charles G.} and Amar Gajjar and Richard Kriwacki and Denise Sheer and Gilbertson, {Richard J.} and Mardis, {Elaine R.} and Wilson, {Richard K.} and Downing, {James R.} and Baker, {Suzanne J.} and Ellison, {David W.}",

note = "Funding Information: We thank W. Evans for advice and support and P. Nagahawatte for submitting the genomic data to EBI. We are grateful for support from Anatomic Pathology and the Hartwell Center of Biotechnology and Bioinformatics at St. Jude Children{\textquoteright}s Research Hospital and from Beckman Coulter Genomics. We acknowledge the St. Jude Children{\textquoteright}s Research Hospital tissue resource facility, from which tissue samples were obtained in accordance with institutional review board approval for the Pediatric Cancer Genome Project. This work was supported by the St. Jude Children{\textquoteright}s Research Hospital–Washington University Pediatric Cancer Genome Project and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children{\textquoteright}s Research Hospital and by a grant from the US National Institutes of Health (NIH; CA096832).",

year = "2013",

month = jun,

doi = "10.1038/ng.2611",

language = "English",

volume = "45",

pages = "602--612",

journal = "Nature Genetics",

issn = "1061-4036",

number = "6",

}

Zhang, J, Wu, G, Miller, CP, Tatevossian, RG, Dalton, JD, Tang, B, Orisme, W, Punchihewa, C, Parker, M, Qaddoumi, I, Boop, FA, Lu, C, Kandoth, C, Ding, L, Lee, R, Huether, R, Chen, X, Hedlund, E, Nagahawatte, P, Rusch, M, Boggs, K, Cheng, J, Becksfort, J, Ma, J, Song, G, Li, Y, Wei, L, Wang, J, Shurtleff, S, Easton, J, Zhao, D, Fulton, RS , Fulton, LL, Dooling, DJ, Vadodaria, B, Mulder, HL, Tang, C, Ochoa, K, Mullighan, CG, Gajjar, A, Kriwacki, R, Sheer, D, Gilbertson, RJ, Mardis, ER, Wilson, RK, Downing, JR, Baker, SJ & Ellison, DW 2013, 'Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas', Nature Genetics, vol. 45, no. 6, pp. 602-612. https://doi.org/10.1038/ng.2611

TY - JOUR

T1 - Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

AU - Zhang, Jinghui

AU - Wu, Gang

AU - Miller, Claudia P.

AU - Tatevossian, Ruth G.

AU - Dalton, James D.

AU - Tang, Bo

AU - Orisme, Wilda

AU - Punchihewa, Chandanamali

AU - Parker, Matthew

AU - Qaddoumi, Ibrahim

AU - Boop, Fredrick A.

AU - Lu, Charles

AU - Kandoth, Cyriac

AU - Ding, Li

AU - Lee, Ryan

AU - Huether, Robert

AU - Chen, Xiang

AU - Hedlund, Erin

AU - Nagahawatte, Panduka

AU - Rusch, Michael

AU - Boggs, Kristy

AU - Cheng, Jinjun

AU - Becksfort, Jared

AU - Ma, Jing

AU - Song, Guangchun

AU - Li, Yongjin

AU - Wei, Lei

AU - Wang, Jianmin

AU - Shurtleff, Sheila

AU - Easton, John

AU - Zhao, David

AU - Fulton, Robert S.

AU - Fulton, Lucinda L.

AU - Dooling, David J.

AU - Vadodaria, Bhavin

AU - Mulder, Heather L.

AU - Tang, Chunlao

AU - Ochoa, Kerri

AU - Mullighan, Charles G.

AU - Gajjar, Amar

AU - Kriwacki, Richard

AU - Sheer, Denise

AU - Gilbertson, Richard J.

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Downing, James R.

AU - Baker, Suzanne J.

AU - Ellison, David W.

N1 - Funding Information: We thank W. Evans for advice and support and P. Nagahawatte for submitting the genomic data to EBI. We are grateful for support from Anatomic Pathology and the Hartwell Center of Biotechnology and Bioinformatics at St. Jude Children’s Research Hospital and from Beckman Coulter Genomics. We acknowledge the St. Jude Children’s Research Hospital tissue resource facility, from which tissue samples were obtained in accordance with institutional review board approval for the Pediatric Cancer Genome Project. This work was supported by the St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital and by a grant from the US National Institutes of Health (NIH; CA096832).

PY - 2013/6

Y1 - 2013/6

N2 - The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs.

AB - The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs.

UR - http://www.scopus.com/inward/record.url?scp=84878723078&partnerID=8YFLogxK

U2 - 10.1038/ng.2611

DO - 10.1038/ng.2611

M3 - Article

C2 - 23583981

AN - SCOPUS:84878723078

SN - 1061-4036

VL - 45

SP - 602

EP - 612

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

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