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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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC3727232 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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

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

Nature genetics 20130414 6

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 ...[more]

PMID: 23583981

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Project description:Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but apart from BRAF mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. These tumors are particularly poorly understood. We performed high-resolution copy-number analysis of 44 diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gains, were observed in 28% of diffuse astrocytomas grade II (DA2s) and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene MYB on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged DA2 demonstrated MYBL1 tandem duplication, and few other events. Two novel, truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth when expressed in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas. IRB approval from all institutions was obtained, and all samples were from patients who provided informed consent or were studied with waiver of the requirement for informed consent by the appropriate IRB. Samples of various histologic subtypes were identified and collected at multiple institutions (Boston Children’s Hospital, Boston, MA, The University of Texas School of Medicine Southwestern, Dallas, TX, Children’s Cancer Hospital, Egypt, Cairo, Johns Hopkins University School of Medicine, Baltimore, MD, Children’s National Medical Center, Washington, DC, The Hospital for Sick Children, Toronto, Canada, Mayo Clinic, Rochester, MN). Central histopathologic review was performed by at least three board-certified neuropathologists using WHO criteria. DNA extraction from archival FFPE samples and Array CGH were performed as previously described (Craig, et al., 2012 PLoS One). GC-normalized copy-number data for the samples were then cleaned of known germline CNVs. Circular Binary Segmentation was used to segment the copy-number data, using parameters [alpha=0.001, undo.splits=sdundo, undo.SD=1.5, min.width=5]. Forty-four samples passed QC metrics (based on aCGH quality metrics for DNA integrity) for inclusion in the GISTIC analysis. Segmented data were analyzed with GISTIC 2.0 to determine statistically significant recurrent broad and focal CNAs. The following parameters were used: minimum segment size = 8, lesion amplitude threshold = 0.2, focal/broad cutoff = 0.9x chromosome arm length, q-value threshold 0.10, and gene confidence level 0.95.

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

Publications

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

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