Genome sequencing identifies somatic <i>BRAF</i> duplication c.1794_1796dupTAC;p.Thr599dup in pediatric patient with low-grade ganglioglioma

Miller, Katherine E.; Kelly, Benjamin J.; Fitch, James; Ross, Nicole; Avenarius, Matthew R.; Varga, Elizabeth; Koboldt, Daniel C.; Boué, Daniel R.; Magrini, Vincent; Coven, Scott; Finlay, Jonathan L.; Cottrell, Catherine E.; White, Peter; Gastier‐Foster, Julie M.; Wilson, Richard K.; Leonard, Jeffrey R.; Mardis, Elaine R.

doi:10.1101/mcs.a002618

Cited by 9 publications

(7 citation statements)

References 26 publications

(28 reference statements)

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“…Pathological examination showed a low-grade brain tumor: ganglioglioma, WHO grade I. Subsequent genome sequencing of the tumor specimen revealed a BRAF p.T599dup mutation ( Miller et al 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we described identification of a BRAF variant resulting in duplication of threonine at codon 599 [NM_004333.4:c.1794_1796dup (p.T599dup)] in a pediatric World Health Organization (WHO) grade I ganglioglioma ( Miller et al 2018 ) using genome sequencing. Prior in vitro studies of p.T599dup demonstrated kinase activity and cellular MEK/ERK activation potential comparable to that of p.V600E ( Eisenhardt et al 2011 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical response to dabrafenib plus trametinib in a pediatric ganglioglioma with BRAF p.T599dup mutation

Miller

Schieffer

Grischow

et al. 2021

Cold Spring Harb Mol Case Stud

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In this follow-up report, we present updated information regarding a previously reported pediatric patient with a World Health Organization grade I ganglioglioma harboring a BRAF p.T599dup mutation (Miller et al. 2018). This patient, based on our initial finding, is receiving combination targeted therapy with a selective BRAF inhibitor (dabrafenib) plus MEK inhibitor (trametinib). The combination therapy was started after the patient experienced progressive tumor growth and worsening neurological symptoms, including visual changes, headaches, and peripheral neuropathy, despite 10 months of treatment with adjuvant chemotherapy (vinblastine). The patient has been receiving dabrafenib plus trametinib for 15 months and continues to have stable disease as well as improved neurological symptoms. Although combinatorial therapy targeting BRAF and MEK using dabrafenib and trametinib, respectively, is indicated for tumors harboring a BRAF p.V600E/K mutation, our report demonstrates efficacy of this combination in a non-V600E BRAF-mutated tumor. The identification of BRAF alterations may assist clinicians in determining alternative targeted treatment strategies, especially considering the paucity of effective treatments for primary brain tumors and the poor prognosis associated with many central nervous system (CNS) diagnoses. Additional case studies or larger cohort reports will continue to clarify the efficacy of BRAF and/or MEK inhibitors in patients whose tumors harbor a BRAF alteration.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical response to dabrafenib plus trametinib in a pediatric ganglioglioma with BRAF p.T599dup mutation

Miller

Schieffer

Grischow

et al. 2021

Cold Spring Harb Mol Case Stud

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“…We next studied a collection of 13 pediatric cancer cases that we sequenced—both tumor and normal—using 10X Genomics Chromium WGS and Whole-Exome Sequencing (WES). One of these cases was studied previously (Miller et al., 2018), and the other twelve are novel to this work. We ran Samovar, MosaicHunter (in both paired and tumor-only modes), and MuTect2 (in both paired and tumor-only modes) on each of the 13 tumor WGS datasets.…”

Section: Resultsmentioning

confidence: 99%

Samovar: Single-Sample Mosaic Single-Nucleotide Variant Calling with Linked Reads

Darby¹,

Fitch²,

Brennan³

et al. 2019

iScience

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Linked-read sequencing enables greatly improves haplotype assembly over standard paired-end analysis. The detection of mosaic single-nucleotide variants benefits from haplotype assembly when the model is informed by the mapping between constituent reads and linked reads. Samovar evaluates haplotype-discordant reads identified through linked-read sequencing, thus enabling phasing and mosaic variant detection across the entire genome. Samovar trains a random forest model to score candidate sites using a dataset that considers read quality, phasing, and linkedread characteristics. Samovar calls mosaic single-nucleotide variants (SNVs) within a single sample with accuracy comparable with what previously required trios or matched tumor/normal pairs and outperforms single-sample mosaic variant callers at minor allele frequency 5%-50% with at least 30X coverage. Samovar finds somatic variants in both tumor and normal whole-genome sequencing from 13 pediatric cancer cases that can be corroborated with high recall with whole exome sequencing. Samovar is available open-source at https://github.com/cdarby/samovar under the MIT license.

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“…We next studied a collection of 13 pediatric cancer cases that we sequenced -both tumor and normal -using 10x Genomics Chromium Whole-Genome Sequencing (WGS) and Whole-Exome Sequencing (WES). One of these cases was studied previously [40], and the other twelve are novel to this work. We ran Samovar, MosaicHunter (in both paired and tumor-only modes), and MuTect2 (in both paired and tumor-only modes) on each of the 13 tumor WGS datasets.…”

Section: Pediatric Cancermentioning

confidence: 99%

Samovar: Single-sample mosaic SNV calling with linked reads

Darby

Fitch

Brennan

et al. 2019

Preprint

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We present Samovar, a mosaic single-nucleotide variant (SNV) caller for linked-read wholegenome shotgun sequencing data. Samovar scores candidate sites using a random forest model trained using the input dataset that considers read quality, phasing, and linked-read characteristics. We show Samovar calls mosaic SNVs within a single sample with accuracy comparable to what previously required trios or matched tumor/normal pairs and outperform single-sample mosaic variant callers at MAF 5%-50% with at least 30x coverage. Furthermore, we use Samovar to find somatic variants in whole genome sequencing of both tumor and normal from 13 pediatric cancer cases that can be corroborated with high recall with whole exome sequencing. Samovar is available open-source at https://github.com/cdarby/samovar under the MIT license.

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Genome sequencing identifies somatic BRAF duplication c.1794_1796dupTAC;p.Thr599dup in pediatric patient with low-grade ganglioglioma

Cited by 9 publications

References 26 publications

Clinical response to dabrafenib plus trametinib in a pediatric ganglioglioma with BRAF p.T599dup mutation

Clinical response to dabrafenib plus trametinib in a pediatric ganglioglioma with BRAF p.T599dup mutation

Samovar: Single-Sample Mosaic Single-Nucleotide Variant Calling with Linked Reads

Samovar: Single-sample mosaic SNV calling with linked reads

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